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Home , Aminocoumarin, Bacitracin, Brilacidin, Coumermycin A1, Isoniazid, Polymyxin B

Index

A Acute bacterial skin and skin structure AAC(6’)-Ib-cr, 344, 351 (ABSSSI), 108 ABC transporter, 468, 469 Adaptation, S. aureus Abscess, 191, 197, 200, 204, 205, 208 attenuated cytotoxicity, evolution of, Accesory gene regulator (agr), 436–443, 488 446–448 adaptive evolution (S. aureus) inconsistent annotation and nomenclature, agrA-bsaA hypothesis, 440 in public databases, 449 agr mutation and host environments, 441 low-virulence MRSA, in hospital, 445–446 description, 436 metabolic changes, to hospital, 450, 451 fitness and protection, 438, 439 MGE diversity, during hospital, 448, 449 global regulators and two-component virulence, in nosocomial , signaling systems, 436 443, 444 host-pathogen interactions, 436, 437 Adjuvant inactivating mutations, , 552 localization of, 439 nonantibiotic, 552 mutability, 442–443 Aeromonas, 473, 474 protection, agr-mediated Agar gradient diffusion, 195 , 443 Agriculture, 391, 392 PSM cytotoxins, 440 Agr quorum-sensing system, 478, 479 quorum sensing, 436 Agr signaling pathway, 480 social cheating, 442 Agr system, 479 stressors, 440 , 176, 343, 345, 351, 368, 369 superoxide, 438 , 600, 602, 603, 607, 608 tolerance, 438, 439 , 117, 118, 122, 169, 170, and clinical S. aureus infections, 432, 433 173, 176, 183, 464, 465, 474, 477, epidemiology, agr dysfunction, 433, 435 481, 490–492, 566 quorum-sensing system, 434 AMEs, 118, 119 Acidipropionibacterium, 200, 201 bacterial resistant strains, spread of, 319, 320 , 274, 285, 286, 364, biofilms, 121, 122 411, 473, 475, 477, 655, 659 natural-product , 540 resistance, signaling P. aeruginosa, 117, 118 mechanisms, 477 permeability and efflux, 120–121 AcrAB-TolC pump, 104 ribosomal protection, 120 Actinomyces, 200, 201 treatment strategies, 122–123

© Springer International Publishing AG, part of Springer Nature 2018 755 I. W. Fong et al. (eds.), in the 21st Century, Emerging Infectious Diseases of the 21st Century, https://doi.org/10.1007/978-3-319-78538-7 756 Index

Aminoglycoside acetyltransferases (AACs), in intensive care units and hospitals, 1 118, 345 international travelers, 5 Aminoglycoside-modifying , 2 (AME), 122 Antibiogram, 194, 209, 210, 304 Aminoglycoside nucleotidyltransferases Antibiotic, 191, 195, 202–204, 207, 209, (ANT), 345, 363 369, 388, 593, 596, 597, 600, 603, Aminoglycoside phosphotransferases (APHs), 609, 610 119, 345 agricultural activities, 391 -clavulanate, 198, 199, 207, 209 discovery and use of, 383 AmpC, 473 in domestic animal manure, 392 AmpC β-lactamase, 99, 347 FDA management, 709 AmpG, 473 foundation, 383 Amphiphilicity, 86 from human therapeutic use, 392 , 207–209, 419, 420 to non-bacterial conditions, 386 Ampicillin-resistant H. influenzae, 384 non-inferiority trial approach, 708 Ampicillin-, 206, 208 One Health approach, 387 AmpR, 473 post-antibiotic era, 383 Amycolamicin, 607, 608 pre-antibiotic era, 712, 713 Anaerobic condition, 625, 629, 636 regulatory agencies, in US and Europe Animal discourage use, 714 antibiotic-resistant , 393 and resistance, in environment antibiotics, in domestic animal manure, 392 (see Environment) feeding facilities, 388 , 712 human-animal interface, 387 uses and abuses, 384 occupational exposure risk, 396 Antibiotic Development to Advance Patient One Health approach, 386 Treatment (ADAPT) Act, 747 One Health concept, 399 Antibiotic discovery, 583, 585 VFD, 391 Antibiotic era, medicine, 534 VRE, 393 Antibiotic mechanism Ansamycins, 543 , 577 Antibacterial, 507, 521 empiric natural-products discovery, 577 pharmacometrics (see Pharmacokinetic-­ OPC-67683, 577, 578 pharmacodynamic (PK-PD)) PA-824, 577, 578 Antibacterial , 596 ridinilazole (SMT 19969), 578 Antibacterial drug, 563, 564, 577, 579, 585, , 577 707–712 Antibiotic-resistant bacteria (ARB), 395 FDA, for clinical trials (see Food and Drug to hospital settings, 383 Administration (FDA)) human activity, 392 regulatory history human wastes, 393 approval, 707 organic livestock, 392 clinical trials, conduct of, 707 organized environmental discovery and development, 708 surveillance, 385 FDA trial requirements, 709 residual ARB/ARGs, 396 indications and endpoints, 708 surveillance efforts, 384 regulatory pathways WWTP (see Wastewater treatment plants approach, by FDA, 709 (WWTP)) authorities, 710, 711 Antibiotic resistance genes (ARGs), 388 intermediate pathways, Tiers B aquaculture, use of, 393, 394 and C, 709 environment (see Environment) Antibacterial drug development, 732 environmental bacteria, 398, 399 Antibacterial drug target, see Antibiotic target environmental dissemination, 385 Antibacterial resistance human activity, 393 acute respiratory infections, 6 in influent wastewater, 397 evolution, of microbial resistance, 1–3 organized environmental surveillance, 385 Index 757

surveillance efforts, 384 mutations in WWTP effluent, 396 in enfuvirtide, 227 Antibiotic resistance infections, see in integrase, 226 -resistant S. aureus in maraviroc, 227 (MRSA) pathways, 227, 228 Antibiotic stewardship, 369 in protease, 225, 226 Antibiotic target, 563–570, 573, 585 in reverse transcriptase, 222–224 new targets () principles advantages, 563 antiretroviral drug, potency of, 219 bacterial infections, 568 degree of killing, 220 benefits and risks, 585 drug-limiting resistance mutations, existing antibiotics, 569 factors, 218, 219 inhibitors, 563 hypersusceptibility, HIV, 220 research programs, 569, 570 key concepts, 218 risks of, 573 mutation development, 218 old targets (enzymes) secondary/compensatory mutations, 221 antibiotics targeting, classes of, 567 reverse transcriptase, 221 benefits and risks, 585 treatment guidelines, 230 , 564–566 zidovudine-selected mutation, 221 DNA synthesis, 567 Antiretroviral therapy (ART), 218 protein synthesis, 566 Antisense, 579 resistance, low frequency of, 568 Antisense-induced strain sensitivity (AISS), 606 , 572 Antitoxins, 417, 421 Anti-infective drug Antiviral agent , 545 HSV and VZV, 235 in vitro target-based drug discovery mechanisms of action, 234 methods, 537 (see also Natural-­ Aquaculture, 384, 387, 393, 394 product antibiotics) Arc, 626, 627, 631–632 quinolone, 535 Ascorbic acid, 623 streptomycin, 540 Aspergillomarasmine, 99 sulfonamide sulfa, 535 Aspiration pneumonia, 197, 204 type B , 545 AstraZeneca, 609 Antimicrobial, 355 ATPase inhibitors, 600, 606–608 pharmacometrics (see Pharmacokinetic-­ ATP-binding cassette (ABC) family, 73, 181 pharmacodynamic (PK-PD)) Aureomycin, 109 Antimicrobial agent susceptibility testing, 43 , 348, 349, 368 Antimicrobial Payment Reform Project, 748 Avycaz®, 724 Antimicrobial (AMPs), 485–488 Azaindole ureas, 609 bacterial signal transduction systems , 355 staphylococci, 487, 488 , 347, 349, 368, 369 streptococci, 485–487 host immune response to infections, 483 mammalian versions, 483 B Antimicrobial resistance (AMR), 411–412 licheniformis, 471 factors, evolution of drug resistance, 431 fitness costs, 432 MazF protein, 625 as a scientific challenge, TB, 412 mother cell lysis, spore formation, 633 selection, drug, 432 , 346, 472, 487

Anti-mutant AUC24/MIC ratios, 656–658 Bacitracin resistance, 346 Antiretroviral resistance, 218–228 Bacteremia, 13, 21, 28, 29, 200, 204, 443, algorithm-based determinations, 446, 447 229, 230 in vivo, 437 DRAMs, 217 MRSA, 433 HIV resistance tests, 228 persistent, S. aureus, 434, 435 758 Index

Bacterial persistence, 416 resistance Bacterial resistance, 303, 304, 311–314, description, 464 316–326 drug targets, 464 DNA transfer, 302, 303 sp., 464, 466 epidemiology, in special populations S. aureus, 466, 468 among travelers, 325, 326 S. pneumoniae, 469 daycare centers, 321, 322 Bactericidal activity long-term care facilities, 322, 323 factors, in ROS accumulation, 625–627 sports teams, 323, 324 ROS-lethality hypothesis, 624, 625 intra-species variability, 303 ROS-mediated toxicity, 627, 628 molecular typing methods (see Molecular Bacteriostatic, 624, 625, 629–631, 638 typing methods) Bacteroides caccae, 205 mutational resistance, 301 Bacteroides fragilis group, 194–196 pathways, to antibiotics, 300 clinical disease and taxonomic changes, 205 patterns, 309, 310 mechanisms of resistance, 207 phenotypic typing methods resistance patterns, 206, 207 antibiogram, 303, 304 Bacteroides ovatus, 206 serotyping, 304 Bacteroides thetaiotaomicron, 205–207 selection, pathogens, 300 Bacteroides vulgatus, 205, 206 spread, of resistant strains Bangladesh regimen, 183 aminoglycoside resistance, 319, 320 Bayesian logistic regression, 697–699 resistance, 320, 321 Bedaquiline, 422, 577 fluoroquinolone resistance, 318, 319 drug resistance, in M. , 179, KPC, 316, 317 180 MRSA, 311, 312 Benzothiazole, 609 NDM, 317, 318 , 87, 88 -resistant S. pneumoniae, Beta-lactam resistance, 470–474 312–314 signaling mechanisms VRE, 314, 316 Enterococcus sp., 472 typing systems, 303 gram-negative bacteria, 473, 474 Bacterial signal transduction systems, 464, S. aureus, 470–472 466, 468–477, 484–494 S. pneumoniae, 470 beta-lactam resistance B20 health initiative report, 744 described, 469 Bifidobacterium, 200, 201 Enterococcus sp., 472 Bilophila wadsworthia, 208, 209 gram-negative bacteria, 473, 474 Biofilms, 121, 122 S. aureus, 470–472 and antimicrobial resistance, 489 S. pneumoniae, 470 description, 488 biofilms and antimicrobial resistance, 488 eDNA, 489 P. aeruginosa, 489–492 mature and resistant, 489 staphylococci, 492, 493 P. aeruginosa biofilm formation, 489–491 CpxR TCS system and persister, 494 resistance, 481–483 S. aureus biofilm formation, 492, 493 host AMPs, resistance to susceptibility of, 488 Salmonellae, 484, 485 Bioisosterism, 608 staphylococci, 487, 488 Biomedical Advanced Research and streptococci, 485–487 Development Authority (BARDA), persisters (see Persister cells) 72, 728 polymyxin resistance Biomedical innovation, 731 A. baumannii, 477 Bioshield Act of 2004, 728 Enterobacteriaceae, 475–477 Biosludge, 395 P. aeruginosa, 477 Biosynthetic gene clusters, 555 S. aureus, signaling mechanisms, Bipyridyl, 624, 634, 636 478, 479 Bloodstream infection, 197, 204 Index 759

BlrAB, 473, 474 CisRS, 472, 473 Bone marrow transplant (BMT), 240 , 355 Bordetella species, 485 Class C β-lactamase (AmpC), 91–93 Breakpoint-setting organization, 193–195 Class I phenotypic tolerance, 417–420 Brivudine/bromovinyldeoxyuridine mechanisms of, 419, 420 (BVDU), 235 Class II phenotypic tolerance, 417, 418, Broth microdilution, 194, 195, 210 420–423 to existing TB drugs, 422 mechanisms of, 420–422 C , 96, 97, 99, 100, 347–349, 368 CAMP-resistance mechanisms Cleavage complexes, 596–598, 600, 608, 609 Salmonellae, 484, 485 , 196, 198, 199, 201–210, 342, staphylococci, 487, 488 355, 356 streptococci, 485–487 Clindamycin resistance Campylobacter gracilis, 209 MRSA, 44 Candida glabrata, 285, 289 Clinical and Laboratory Standards Institute , 176, 177, 182 (CLSI), 193–196, 201–203 , 93, 198, 199, 201, 204–210, 285–287, 347 drug resistance, in M. tuberculosis, Carbapenemases, 93–94, 345, 347, 349, 363 180, 181 Carbapenem-resistant Enterobacteriaceae Clonal evolution (CRE), 118 heteroresistance, 277, 278 Catalytic inhibitors, 596, 600–609 Clonal heteroresistance, 272, 277 Cationic AMPs (CAMPs), 483, 484 , 600, 602 CcdB, 600 Closthioamide, 607 , 285, 286, 347, 368, 369 Clostridioides difficile , 347, 368, 369 clinical disease and taxonomic , 347, 368, 369 changes, 202 Ceftaroline, 282, 285 resistance mechanisms, 203 , 347 resistance patterns, 202, 203 , 347, 368, 369 butyricum, 205 Cell division, 463, 468, 478 Clostridium cellulolyticum, 607 Centers for Disease Control and Prevention Clostridium clostridioforme, 204 (CDC), 722–723 Clostridium difficile, 191, 202, 285, Central nervous system (CNS), 200 288, 606 CepA gene, 207 Clostridium innocuum, 204 , 92, 198, 201, 203, 205–207, , 204, 205 209, 282, 285, 286 Clostridium ramosum, 204 , 91, 93, 347 Clostridium septicum, 204 Cervicofacial lesions, 200 Clostridium tertium, 204 CfiA gene, 207 CMY ß-lactamase, 347 Cfr gene, 356, 358 Coda, 342, 370 CfxA gene, 207 Colistin, 285–288, 349–350, 474, Chatham House Report, 742 476, 490 Chemical diversity, 549, 553, 554, 556 bacterial resistant strains, spread of, , 341, 352, 358, 362, 547 320, 321 Chloramphenicol acetyl transferase (CAT), heteroresistance, 126 358, 363 resistance, 349 , 543 Colonization Chromosome, 197 S. aureus, agr role, 435 Cidofovir (CDV), 234, 235, 238, 241, 243, Colonizer, 200 245, 248, 251, 252 Combating Antibiotic-Resistant Bacteria , 203, 351, 508, 513, 596, 606, Biopharmaceutical Accelerator 644–647, 649–651, 653, 655, 657 (CARB-X), 72, 117 760 Index

Combination therapy CovRS, 486 anti-mutant antibiotic, 660 CovRS TCS system, 486 bacterial resistance, 659 CprRS, 477 colistin with , 659 Cpx, 626, 627, 631 in vitro dynamic models, 659 Cpx TCS system, 481–483 and , 659, 660 CreBC, 474 and , 659 CroRS, 472 Commensal, 200 CTX-M family β-lactamases, 91, 349, 368 Community-associated MRSA (CA-MRSA), Cubicin®, 723 46, 47 Cure antimicrobial agents, use of, 49 antimicrobial agents, ability of, 410 antimicrobial susceptibility testing, 43, 44 claim hinges, 410 clinical presentation, 48 definition, 410 epidemiologic risk factors, 59 of gonorrhea, 411 age and sex, 46 S. aureus pneumonia, 415 geographic characteristics, 46 TB, 415 HIV infection, 47 Current incentive landscape illicit drug use, 47 BARDA, 728 race, ethnicity and socioeconomic international approaches, 729–730 status, 47 US approaches, 728–729 temporary housing, 47 Cutibacterium, 200, 201 management Cyclothialidines, 600, 602, 604, 608 /antimicrobial classes, 51 Cystic fibrosis, 473, 485, 488, 490, 491 clinical presentation, 48 decolonization, 51, 52 developments, in antimicrobial D treatment, 50 Dalvance®, 724 severe/invasive MRSA infections, 50 Daptomycin (DAP), 282, 285, 288, 646, skin/soft tissue infections, 49 649, 658 mechanisms of resistance, 41–42 description, 477 mecA gene, 42 mechanism of action, 478 mechanisms of virulence, 43 S. aureus, resistance, 478, 479 molecular origins, 45 Daycare centers, 321, 322 molecular typing, 44, 45 Debate, for drug discovery, 563 phenotypic and molecular , 108 characterization, 45 , 167, 181, 182 prevention De-linkage programs, 738–740 medical providers and infection control Dental caries, 200 practitioners, 55 Diagnosis-related group (DRG), 736 patients and members, 56 Diazabicyclooctane (DBO), 565 Public Health Officials, 54, 55 Dificid®, 737 strategies, 54 Digital PCR, 279–281 emergence, in US, 40–41 Dihydrofolate reductase (DHFR) swine crop fields, 58 inhibitor, 572 transmission of, 52 Dimethyl sulfoxide, 623 livestock-association, 58 DNA cleavage, 510, 512–514, 597 outbreaks of MRSA, in community, , 600, 602 53, 54 binding, 596, 597, 599 pets and horizontal transmission, 57 catalytic inhibitors, 600–609 Complex mutant TEMs (CMT), 100 cyclothialidines, 602, 604 Conventional culture methods, 6 non-small molecule inhibitors, Coordinated efforts, 4–7 599, 600 Corynebacterium striatum, 285, 288 DNA gyrase, 178 , 600, 601 DNA synthesis, 567 Index 761

DNA topoisomerase Enterobacter, 411 antibacterial chemotherapy, 596 Enterobacteriaceae, 364 DNA cleavage site, 596, 597 polymyxin resistance, signaling double-strand break, 595 mechanisms, 475–477 structural and mechanistic aspects, 595 , 464, 472 topological forms, 595 , 411, 464, 467, 478 Doripenem, 347, 368, 653, 659 Enterococcus faecium, aureus, Dose selection, Monte Carlo simulation , concentration-time profiles, 688 Acinetobacter baumannii, description, 687 P. aeruginosa, and Enterobacter murine-lung infection model, 691 spp. (ESKAPE), 71 optimal application, 688 Enterococcus sp. PK-PD target attainment analyses, 687 signaling mechanisms and susceptibility breakpoint, 689 beta-lactam resistance, 472 Doxycycline, 113, 360 vancomycin resistance, 464, 466 DRIVE-AB Consortium, 743 Environment, 388, 390 Drug development, 671 ARGs See also Pharmacokinetic-­ AmpC β-lactamases, 390 pharmacodynamic (PK-PD) in field useE. coli, 388 Drug discovery Gram-negative and Gram-positive, 388 ampicillin, 565 molecular assays, 388 benzylpenicillin, 564, 565 as , 390 Drug for Neglected Diseases Initiative Burkholderia spp. and Pseudomonas (DNDi), 730 spp., 389 Drug resistance-associated mutations Clostridium difficile spores, 391 (DRAMs), 217 databases, 389 Drug-resistant infections, 715 functional genomic studies, 389 Drug susceptibility testing (DST), 167 human influences, 392, 393 D-serine (D-Ser), 353 nucleotide sequence-dependent Duke-Margolis Center for Health Policy, 748 methods, 389 resistome, 389 , 116 E Erm gene, 207 Economic incentives , 195, 196, 206, 209, 347, 368 AstraZeneca’s antibiotic portfolio, 723 , 342, 355, 356, 361, 362, 540 gram-negative outer membrane, 724 , 270, 273, 274, 285, 286, 646, OTAs, 729 649–651, 653–656, 658 pull incentives, 727 Aeromonas CreBC TCS, 474 reinvigorate innovation, 724 ArcAB two-component system, 631 strong incentive, 724–726 PhoPQ/PmrAB signaling, 476 structures and considerations, 731–733 polymyxin resistance, 475, 476 types, 726 with quinolones, 622 EF-4, 632 respiration, 630 Effluent TCA cycle, 630 WWTP, 396 Etest, 195, 208 Efflux, 207 Efflux pump inhibitors (EPIs), 82, 83 drug resistance, in M. tuberculosis, 164, Eggerthella lenta, 200, 201 182, 183 ENABLE project, 730 Ethylenediaminetetraacetic acid Endocarditis, 433 (EDTA), 94 S. aureus, 437, 449 Etoposide, 598 vegetations, 436 Eubacterium, 200, 201 Energy-dependent efflux proteins, 359 Eukaryotic-like serine/threonine kinases Enfuvirtide, 227 (eSTKs), 462, 463, 468, 472 762 Index

European Committee for Antimicrobial topoisomerase IV, 510 Susceptibility Testing (EUCAST), use and over-use, 514 193, 195, 196, 203 Food and Drug Administration (FDA), European Medicines Agency Committee for 712–714 Medicinal Products for Human antibacterial drugs, clinical trials of Use, 714 community-acquired pneumonia, 713 Evolution of microbial resistance mortality-plus endpoint, 714 antibiotic discovery, history, 3, 4 non-inferiority design, 712 antimicrobial chemotherapy, 1 pre-antibiotic era, 712 integrons, discovery, 3 primary and secondary endpoint, 713 origin of antibiotics, 1 clinical trials, conduct of, 707 penicillinase-producing bacteria, 2 development, new antibiotics, 709, 710 public education, on antibiotic use, 8 evolution, FDA policy, 709, 711 resistant bacteria, logarithmic growth, 3 GAIN Act, 709 vancomycin, 2, 3 management, 709 Existing antibiotics, 563, 564, 568, 569, 576, pathogen-specific antibacterial drugs, 715 583, 585 reboot process, 709 Expected net present value (ENPV), 726 recalcitrance, 708 Extended-spectrum β-lactamases (ESBLs), 71, statistical margin, 707 89–93, 96, 100, 101, 122, 393 trial design requirements, 709 Extensive drug resistance (XDR-TB), 167, typical clinical development plan, 710 170, 183, 184 workshops and advisory committee meetings, 715 Fosfomycin, 352, 548 F cell via GlpT and UhpT transporters, 482 FabI, 571 discovery, 481 , 548 mechanisms, 481 magna, 198 susceptibility, 483 Fluconazole, 285, 289 Fosfomycin resistance, 352 Fluoroquinolones (FQs), 101, 103, 105–108, and Cpx regulatory system, 482 177, 178, 272–275, 284, 285, FQs resistance, 19, 23, 26, 29, 30 350–352, 419, 422, 477, 488, 495, bacterial resistant strains, spread of, 567, 593, 594, 596, 609, 625, 318, 319 628, 635 S. pneumoniae lethal action, 620 and clinical implications, 29, 30 in clinical use, 507 mechanism of resistance, 19 C7 substituent, 518–520 non-susceptibility, 26 C8 substituent, 520, 521 risk factors, 23 ciprofloxacin, 508 surveillance rate, 26 disease-causing organisms, 508 susceptibility data, 26 to gonorrhea, 514 Francisella species, 485 and gyrase/topoisomerase IV interactions, FurA, 172 516, 517 resistance, 352 history of, 508 Fusobacterium necrophorum, 191, 208, 209 mechanism, 513, 514 Fusobacterium nucleatum, 208, 209 MGIs, 522 NBTIs, 521, 522 Neisseria gonorrhoeae, 514 G plasmid-mediated resistance, 515 Ganciclovir (GCV) resistance mutation, 515 HCMV infections, 233 spiropyrimidinetriones, 523 , 177, 183, 645, 651, 657 structures, 509 Generating Antibiotic Incentives Now (GAIN) target-mediated resistance, 508, 515 Act, 729 topoisomerase II, 510 Genome era of antibiotic research, 569 Index 763

Genome sequencing quinolones, 101–109 adaptation, S. aureus infection, 447–449 resistance, β-lactamase inhibitors, 99–101 Genomic island, 352, 367 resistance mechanisms, 106–108 Genotypic tests, 228 ribosomal protection, 113–114 , 342, 343, 345, 361 RND family, 76 , 567, 599 efflux pumps, 131 Gingivitis, 197 pumps, 74–77 Glf, 172 target mutations, 113–114 A Global AMR Innovation Fund, 741 , 109–111 Global Launch Reward, 743 tetracycline-modifying enzymes, 113–114 Global surveillance, 5, 7, 8 third-generation , 115 Global Union for Antibiotics Research type II topoisomerases, 108–109 and Development (GUARD) Gram-negative bacteria initiative, 743 beta-lactam resistance, signaling GlpT, 481–483 mechanisms, 473, 474 Glycopeptide, 353, 354, 544 Gram-negative organisms, 360 Glycopeptide resistance, 353, 354 Gram-negative outer membrane, 724 Golden Age of antibiotics, 569 Gram-positive anaerobic bacilli, 200, 201 Gram-negative anaerobic cocci, 197 Gram-positive cocci, 196–199, 210 B. fragilis group, 205–207 Gram-positive non-spore-forming anaerobic other than B. fragilis group, 208–209 bacilli, 200 Gram-negative bacilli, 110–113, 117–124, 130 GraRS, 487, 488 active efflux, 73–75 GraSR, 468 (see Aminoglycosides) GraX, 468 AmpC, 91–93 Group 2be, 347 antibacterial/antimicrobial resistance, 131 GUARD initiative, 743 antibiotic susceptibility, 79–82 Gynecological , 197 asymmetric outer membrane, 131 GyrA mutations, 207 carbapenemases, 93–94 Gyramide, 605, 606 cellular activity, antibiotics, 82–85 Gyrase, 593, 595, 597, 600, 604, 605, chemical structure 607–609 aminoglycosides, 117, 122 cellular roles of, 512 , 130 E. coli, 515 chemical structure, quinolones, 102 M. tuberculosis, 521 in clinic, 115–116 NBTIs, 522 compound accumulation, 82–87 as poisons, 513 compound penetration, 85–87 and topoisomerase IV interactions, 516–518 efflux pump water-metal ion bridge and gyrase, 516–518 MFS family, 110–113 GyrB inhibitors, 608 RND family, 113 families and placement, 73 ESBLs, 90, 91 H glycylcyclines, 110, 116–117 , 285, 286 healthcare-related science, 131 Healthcare-associated MRSA (HA-MRSA), influx and efflux via mutation, 104, 105 40, 45 β-lactam, 87 Health, National Institute of Allergy and β-lactamase inhibitors, 87–101 and Infectious Diseases β-lactamases, 88–94 (NIH/NIAID), 728 , 78 Helicobacter pylori, 285, 286 MDR, 71–72 Heritable AMR, 413–414 non-β-lactamase-mediated resistance, 95 mechanisms, 414 OM bilayer, 77, 79 misuse, 413 PMQR, 105–106 overuse, 413 (see Polymyxins) underuse, 414 764 Index

Herpes simplex virus (HSV), 244–252 VraS, 468 antiviral agents, 235 WalK, 468 resistance History of drug development clinical significance, incidence and risk antibiotic discovery, 3 factors, 246, 247 antimicrobial chemotherapy, 1 management, by drug-resistant HSV HIV infection strains, 250–252 and tuberculosis, 165, 166, 173, 183 phenotypic and genotypic assays, Hospital-associated and ventilator-associated 244, 245 bacterial pneumonia (HABP/ thymidine kinase (TK), mutations, VABP), 122 248, 249 Human Herpesvirus activity, environment, 388, 389, 392 antiviral agents, 233–235 and agricultural activities, 391 Heteroresistance, 126, 274, 281, 285–288 and agricultural contamination, 390 agar proportion method, 278 and animal medicine, 386 Candida glabrata, invasive fungus, 289 human-animal interface, 387 description, 269 human-to-human transmission, 387 detection, 270–272 One Health concept, 399 emergence of resistance, 269 pathogens, 395 gram-negative bacteria therapeutic use, 392 A. baumannii, 285, 286 Human cytomegalovirus (HCMV), 236–244 E. coli, 286 ganciclovir, 233 H. influenzae, 286 resistance H. pylori, 286 clinical significance, incidence and risk K. pneumoniae, 287 factors, 238–240 P. aeruginosa, 287 genotypic assays, 237 S. enterica, 287 HCMV UL97 and UL54 mutations, gram-positive bacteria 241, 242 C. difficile, 288 management, infections, 242–244 C. striatum, 288 phenotypic assays, 236 E. cloacae, 288 systemic treatment, 233 S. pneumoniae, 288 Human immunodeficiency virus (HIV), 269, MIC, 269 274–277 mixed infections, 276 Hydrophilic fluoroquinolones, 351 MRSA, 270 Hydrophilicity, 85, 104 with M. tuberculosis (see Hypersusceptibility, HIV, 220 tuberculosis (Mtb)) with other pathogens, 284, 285 PAP, 271 I as pathogens, 274 Imidazopyrazinones (IPYs), 597 with S. aureus (see Staphylococcus , 201, 203, 208, 285, 286, 342, 347, aureus) 368, 369 tolerance, antimicrobial, 273 Immune system, 414 types, clonal heteroresistance, 272, 273 Immunity, 409, 410, 414, 415, 417, 420, 422 Heteroresistant VISA (hVISA) strains, Induced resistance, 272 282–284 Infectious Diseases Society of America Histidine kinase, 462 (IDSA), 733 BlrAB, 473 InhA, 171, 172 CiaH, 469 Inhibitors GraS, 468 bacteriostatic, 552 PhoQ, 476, 486 β-lactamase, 539 PmrB, 477 resistance, 552 VanS, 466 , 544 VraR, 468 InnovFin Infectious Diseases, 730 Index 765

Insertion sequence (IS), 356, 365 Klebsiella pneumoniae carbapenemases Integrase strand transfer inhibitor (INSTI), (KPC), 93 226, 227 bacterial resistant strains, spread of, Integrated aquaculture, 393 316, 317 Integrative and conjugative elements ß-lactamase, 347 (ICE), 367 Integrative mobilizable element (IME), 367 L Integrons, 3, 351, 355, 359, 360, 367 ß-Lactam resistance, 16, 21, 22, 28, 29 Interferon gamma (IFNγ), 415 antibiotics, described, 16 International coordination, 746–747 and clinical implications, 28–29 Intra-abdominal abscess, 191, 197, 199 efficacy of, 16 Invasive pneumococcal disease (IPD) low concentrations, use of, 17 resistance, 29 and , 14 non-vaccine serotypes, 27 MDR pneumococcus, 20 PCV13 role, 28 penicillin-resistant bacteremic infection, 21 prevention of, 27 penicillin susceptibility, 17 iPLEX Gold, 280 S. pneumoniae ISCR, 360, 365, 367 antibiotics, 16 (INH), 415, 418, 419 and clinical implications, 28, 29 BMRC streptomycin trial, 164 mechanism, 16 drug resistance, in M. tuberculosis, MIC, 16 171, 172 penicillin resistance, 16 monoresistant tuberculosis, 182 risk factors, 21, 22 and rifampin, 172 β-Lactamase inhibitors (BLIs), 565 (INH), 171 β-Lactamases, 199, 203–205, 208, 209, In vitro dynamic models, 643, 644 346–349, 564–568, 581 AUC24/MIC ratio, 657 β-Lactam-β-lactamase inhibitor combination, bacteria to antibiotic combinations, 659 196, 198, 199, 201, 205–207, in S. aureus, 644 209, 210 β-Lactams lethal action, 620 J natural-product antibiotics, 538, 539 Januvia®, 724 Legionella pneumophilia, 485 Joint Programming Initiative on Antimicrobial Lego-regulatory pull incentives, 727, 729 resistance (JPIAMR), 730 Lemierre disease, 191, 208 Joints, 198 Letermovir, 253 foreign-body infections, 200 Lethal action, antimicrobial, 620–622 Leukocidin, 433 Levofloxacin, 596, 645, 648, 652, 657 K drug resistance, in M. tuberculosis, Kanamycin, 624, 628, 630, 635 177, 179 ahpCF deletion, 627 LiaRS, 486 lethal activity, 622, 623 Limited population approval pathway, 748 Kanamycin B, 345 , 355 Kanamycins, 343, 345, 351, 368, 369 Lincosamide, 355–357 KatG, 171, 172 Lincosamide nucleotidyltransferases (LnuA), , 355 363 Kibdelomycin, 567, 606 Linezolid, 167, 181, 183, 342, 358, 368, 566, Kibdelosporangium, 606 649, 654, 658, 659 Klebsiella pneumonia, 411 “anti-mutant” effects, 659 Klebsiella pneumoniae, 270, 274, 285, and rifampicin combinations, 659, 660 287, 475, 476, 646, 649, 650, Lipid synthesis, 571–572 657, 659 Lipopeptides, 545 766 Index

Lipopolysaccharides (LPS), 77, 81, 84, 85, molecular characteristics, 41, 42 120, 124–129, 474–477, 485, 572 molecular origins, 45 Long-term care facilities (nursing homes), molecular typing, 44, 45 322, 323 staphylococcal carriage studies, 41 LpxC inhibitors, 572 novel potential sources Lyrica®, 724 livestock and MRSA, 58 pets and MRSA, 57 and phagocyte interactions, 437 M surgical site infections, 433 resistance, 17–19, 22, 23, 26, 29 transmission of, 52 S. pneumoniae vaccine and novel prevention/treatment antibiotic consumption, 22 approaches, 57 bacterial protein synthesis, 17 vancomycin resistance, 56, 57 and clinical implications, 29 virulence, in hospital environment, 445 mechanisms, 17, 19 Methylation, 199, 205 risk factors, 22, 23 Methyl transferase, 356 surveillance rate, 26 , 196, 198, 199, 201–205, worldwide genotype distribution, 18 207–210, 285, 286, 288 Macrolides, 355–357, 566, 568 MexAB-OprM efflux pump, 80, 83 natural-product antibiotics, 540, 543 MexXY efflux pump, 80 Macrophages, 437 MexXY-OprM efflux pump, 121 Macrorestriction, 307 MfpA, 600 Magic bullet theory, 535 MgrA, 468 Maraviroc, 227 Microbial diversity, 553, 554 Maribavir, 253 Microbiota, 410 Market entry rewards (MER), 744 Microcin B17 (MccB17), 599, 600 Matrix-assisted laser desorption/ionization-­ Minimal bactericidal concentration (MBC), time of flight mass spectrometry 620, 638 (MALDI-TOF MS), 194, 210 Minimal inhibitory concentrations (MICs), 72, MazEF, 625, 627 104, 107, 112, 192–195, 201–204, MazF protein, 625–627 206, 207, 209, 620 Medicare reimbursement, 736 Minimum preventive concentration (MPC), 352 Megafund model, 731 , 113, 360, 368 Megasphaera, 197 Misuse, antimicrobial, 412, 413 , 13, 17, 19, 29 Mixed infections, 275–277 , 192, 198, 347, 368, 369 Mobile genetic elements (MGE), 203 , 478, 489 discovery and identification, 448 Metallo-β-lactamases (MBLs), 89, 94, 97, 99, genomic rearrangement, 449 207, 346, 363 identification and discovery, 449 Methicillin heteroresistance, 281, 282 phages, 448 Methicillin-resistant S. aureus (MRSA), to S. aureus adaptation, 448 40–45, 48–58, 270, 274, staphylococcal, 448 282–284, 289 Molecular epidemiology, see Molecular typing bacteremia, 433 methods community-associated infections/ Molecular mechanisms of resistance, 341, 343 CA-MRSA (see Community-­ Molecular typing methods, 306, 307 associated MRSA (CA-MRSA)) MLST, 308, 309 HA-MRSA, 444 PCR fingerprinting microbiology advantages, 306 antimicrobial susceptibility testing, RAPD/AP-PCR, 306 43, 44 Rep-PCR, 306 colonization with S. aureus, 41 VNTR/MLVA analysis, 307 mechanisms of resistance, 41, 42 PFGE, 307, 308 mechanisms of virulence, 42, 43 plasmid analysis, 305 Index 767

ribotyping, 305 DST, 167 WGS, 309 GeneXpert system, 168 Monoresistant strains line probe assay, 168 of M. tuberculosis, 164, 172, 182 molecular biology techniques, 169 Monotherapy, 657, 658 genotypic detection, drug resistance, 169 Moxifloxacin, 201, 203, 205–207, 209, 596, heteroresistance 598, 645, 650, 652, 657, 659 clonal evolution, 277, 278 drug resistance, in M. tuberculosis, 169, consequences of, 278–279 170, 177–179 DNA-based detection methods, MTS strip, 195 279–281 Multidrug and toxic-compound extrusion heterogeneity, types of, 275, 276 (MATE), 73, 181 in individual tuberculosis patients, Multidrug-resistant (MDR) 274, 275 pathogens, 383 line probe assay, 170 S. pneumoniae, 20 multidrug resistance mechanisms, 181 Multidrug-resistant tuberculosis (MDR-TB) phenotypic testing, 169, 170 advanced fluoroquinolones, 167 pre-XDR-TB, 167 bedaquiline, 179 sputum cultures, 163 definition, 164 Mycobacterium tuberculosis gyrase inhibitors heteroresistance, 277, 278 (MGIs), 522 InhA mutations, 172 Myxococci, 553 mechanisms, 181 PZA resistance, 175 rifampin monoresistance, 173 N treatment of, 182 Naphthoquinones, 606 WHO-recommended approach, 182 Narrow-spectrum antibiotics, 575 Multilocus sequence typing (MLST), 308, 309 Nasopharyngeal carriage, pneumococcus, 14, Multiple-/extensively-drug resistant (MDR 21, 25 and XDR), 669–672, 676, 687, 692, Natural-product antibiotics, 538–540, 696, 700 543–545, 547, 548, 551–555 Multiple locus variable analysis (MLVA), 307 antibacterials, 548 Municipal wastewater, 395 chemical libraries, 549 , 357 classes, discovery and introduction, Mupirocin-resistant isoleucyl-tRNA 535, 536 synthetases, 357 discovery of penicillin, 537 Mutant prevention concentration (MPC), 644, drugs and modes of action 645, 647–650, 653–656, 658–660 aminoglycosides, 540 Mutant selection window (MSW), 644, 645, ansamycins, 543 647, 651–656 chloramphenicol, 547 Mutasynthesis, 601 fidaxomicin, 548 Mutation, 600 fosfomycin, 548 Mycobacterium smegmatis, 421 glycopeptides, 544 Mycobacterium tuberculosis (Mtb), 167–169, β-lactams, 538, 539 171–181, 274–281, 412, 606 lipopeptides, 545 antituberculosis drugs resistance macrolides, 540, 543 bedaquiline, 179, 180 , 547 clofazimine, 180, 181 streptogramins, 545 fluoroquinolones (FQ), 177–179 , 543 INH, 171, 172 future of PZA, 173–175 adjuvants, 552 rifampin and rifamycins, 172, 173 bacteriostatic, combination of, 552 streptomycin, 175–177 discarded scaffolds, revisiting, 551 detection and diagnosis, drug resistance genomes, 554 diagnosis, 168 metagenome mining, 555 768 Index

Natural-product antibiotics (cont.) Novel target, 565, 570, 573 microbial natural-product diversity, 553 , 567, 600, 602, 605–608 resistance inhibitors, 552 Nucleoside reverse transcriptase inhibitors synthetic biology, diversity through, 555 (NRTIs), 222–224, 226 “magic bullet” theory, 535 Nucleotidyltransferases, 355 medicinal therapies, 533, 534 synthetic antibiotics, 535 Waksman platform, 550 O Natural products, 604, 606 Obstetrical sepsis, 197 NDM ß-lactamase, 347, 363 Office of Health Economics Report, 744 Neck abscess, 197 One-component systems, 462 Neisseria gonorrhoeae, 514 One Health approach, 386–388, 399, 401 Net present value (NPV), 725 O’Neill Report, 741–742 Neutrophils, 437, 440, 444 OptrA, 344, 357, 358 New antibiotics/new antibacterial drug, OqxAB, 351, 357, 361, 369 577–582 Orbactiv®, 724 antibacterial activity in vitro Osteomyelitis, 200 antibiotic potentiators, 581 Other Transactional Authority (OTA), 728 immunomodulatory agents, 582 Otitis media, 13, 17, 29 surface-binding mAbs, 580, 581 Outer membrane factor (OMF), 74–76 virulence mechanism, 581, 582 Overuse, 413 antifolates, 572 OXA ß-lactamase, 349 lipid synthesis, 571, 572 Oxadiazole, 609 mechanism of action (see Antibiotic Oxazole, 599 mechanism) Oxazolidinones, 358, 566 membrane-active compounds Oxyimino- ß-lactam, 347, 349 (formerly PMX-30063), 578 , 543 minor groove, DNA, 579 phage lysins, 579 pheromonicins, 579 P POL-7080, 578 Panton-Valentine leukocidin (PVL), 43, 46, 48 protein synthesis, 570, 571 Parabacteroides distasonis, 205, 206 RNA polymerase, 572, 573 ParRS, 477 transcription/translation Parvimonas micra, 198 antisense, 579 Pathogen riboswitches, 580 gram-negative, 540 New Delhi metallo-β-lactamase (NDM), 94 gram-positive, 545 bacterial resistant strains, spread of, Pelvic actinomycosis, 200 317, 318 Penicillin-binding proteins (PBPs), 85, 87–89, description, 317 95, 97, 199, 203, 205, 207, 564, New technology add-on payment (NTAP), 737 565, 568 NimB gene, 199 Penicillin-resistant Neisseria gonorrhoeae, 384 Nim gene, 207 Penicillin-resistant pneumoniae synthase (iNOS), 415 (PRSP) resistance, 357 spread of resistance strain, 312–314 , 357 , 196, 198, 199, 205, 207–209, 281, Non-nucleoside reverse transcriptase inhibitors 285, 286, 288 (NNRTIs), 222, 224–226, 229 Penicillium notatum, 534, 535 Non-small molecule inhibitors, 599, 600 , 351, 644, 645 glycopeptides, 536, 544 Normal flora, 197, 200 lipopeptides, 536, 545 Novclobiocins, 601, 602 non-ribosomal, 553 Novel bacterial topoisomerase inhibitors pentapeptide, 538 (NBTIs), 521, 522 streptogramins, 545 Index 769

Peptide deformylase (PDF), 571 Pharmacometrics, see Pharmacokinetic-­ biosynthesis, 478 pharmacodynamic (PK-PD) Peptidyltransferase, 355 Phase 3 clinical trials, 732 Peptoniphilus asaccharolyticus, 198, 199 Phenicol, 358 Peptoniphilus harei, 198, 199 Phenicol resistance, 358 anaerobius, 197–199 Phenotypic screen, 569, 570, 572, 573, Peptostreptococcus canis, 197 576, 577 Peptostreptococcus russellii, 197 Phenotypic tests, 228 Peptostreptococcus stomatis, 197, 199 Phenotypic tolerance Periodontitis, 197 bacterial persistence, 416 Permeabilization, 478 classes, 417–419 Persister cells definition, 416 in vivo, 496 heritable AMR, 417 quorum-sensing mechanisms, 495, 496 history of, 409 SOS response system, 495 penicillin, purification of, 416 TA signaling systems, 494, 495 persisters, 409, 416 Persisters, 409, 416, 417, 419, 420 Phenotypic typing methods Pew’s roadmap, 724 antibiogram, 303, 304 Pharmacodynamics, 643, 650, 661 serotyping, 304 Pharmacokinetic-pharmacodynamic (PK-PD), Pheromonicins, 579 672, 674–676, 678, 679, 681, 682, PhoPQ system, 125, 475–477, 484–486, 490 684, 687–689, 691–700 Phosphorylation, 468, 473, 476, 479, 481, benefits, 669 486, 487 clinical data package , 470 Bayesian approaches, 697–700 Piperacillin-, 196, 198, 204, clinical studies, 692 206, 209 clinical trial design, 699 PK-PD dosing optimization, 733 continuous/time-to-event efficacy PK-PD target attainment analyses, 687 endpoints, 693, 694 PK-PD target for efficacy, 674 drug exposure, estimation of, 693 Plaque reduction assay, 245, 246 MDR/XDR pathogens, 692 Plasmid-mediated efflux genes, 356 objectives, PK-PD analyses, 694–696 Plasmid-mediated resistance optimized / fluoroquinolones, 515 regimens, 695, 696 Plasmids, 197, 207, 341, 343, 346, 347, 349 prerequisites, 693 accessory functions, 365 for safety endpoints, 694 classification, 364 critical preclinical questions, 670 genomic islands, 367 Monte Carlo simulation (see Dose gram-negative organisms, 364 selection, Monte Carlo simulation) host, 364 plasma concentration-time curve, integron, 365 672, 673 MOB classification, 364 population PK modeling, 685–687 mobilization, 365 pre-clinical PK-PD data package multiresistance regions, 365 evaluation, 678, 679, 681, 682 oligopeptides, 364 index with efficacy, 672, 674 phage particles, 367 NDA, 672 Tn3-family complex, 366, 367 resistance prevention, 682, 684 transposable element, 367 targets for efficacy, 674, 675 , 123 variability, 676, 678 resistance, 355, 356 pre-clinical toolbox, antimicrobial drug Pleuromutilins, 547, 566 development, 671 PmrAB, 475–477, 484, 490 principles, 669 Pneumococcal conjugate vaccine 7-valent , 643, 645, 651–653, 655, (PCV7), 27 659, 660 Policy initiatives and reports, 740–744 770 Index

Polydrug resistance, 167 Programmed cell death (PCD), 620, 632, 633 Polyketide, 540, 543, 545, 548, 553 , 535 Polymerase chain reaction (PCR) Propionibacterium acnes, 200 fingerprinting Propionibacterium avidum, 200 advantages, 306 Propionibacterium freudenreichii, 200 RAPD/AP-PCR, 306 Propionibacterium granulosum, 200 Rep-PCR, 306 Propionibacterium humerusii, 200, 201 VNTR/MLVA analysis, 307 Proportion method, agar, 278 Polymicrobial, 194, 196–198, 200, 208, 209 Protease, 221 Polymyxin B, 130, 474 inhibitor class, antiretrovirals, 225 Polymyxin B nonapeptide (PMBN), 124, Protein-DNA-drug complexes, 597 130, 607 Proton-motive force (PMF), 74 Polymyxin resistance, 475–477 Protein synthesis signaling mechanisms EF-Tu, 571 A. baumannii, 477 inhibitors, 566 Enterobacteriaceae, 475–477 PDF, 571 P. aeruginosa, 477 tRNA-synthetases, 571 Polymyxins , 287, 411, 645, 646, agents, 129–131 649, 650, 653, 657, 734 vs. beta-lactams and aminoglycosides, 474 biofilm formation, 489–492 clinical use, 474 polymyxin resistance, signaling colistin-resistant strains, 124 mechanisms, 477 cyclic peptides, 474 Pseudopropionibacterium, 200 emergence of resistance, 474 Pseudopropionibacterium propionicum, ESKAPE pathogens, 124 200, 201 intrinsic resistance, 124 Pull incentives, 727–728, 733 LPS molecules, 124 Pulmonary actinomycosis, 200 mechanism, 124 Pulsed-field gel electrophoresis (PFGE), 44, mutations, 127–128 45, 307–309, 313, 322, 324 negative charge status of LPS, 125–127 Push incentives, 726 plasmid-mediated modification, 128–129 (PZA), 415 toxic hydroxyl radicals, 124 drug resistance in M. tuberculosis, 173 Polyresistant strains, M. tuberculosis, 167, 181 mechanism of action, 174 Polysaccharide-protein conjugate vaccine monoresistance, 167 (PCV13), 27 multidrug-resistant strains, Population analysis profile (PAP), 271, 283 M. tuberculosis, 175 Population PK modeling, 685–687 phenotypic and genotypic resistance, 175 Porphyromonas, 208, 209 pncA mutations, 174 Portfolio approach, 731–732 POA, 174 PPV23 vaccine, 27 prodrug, 174 Pre-clinical PK-PD evaluation, see short-course regimen, 164 Pharmacokinetic-pharmacodynamic traditional phenotypic drug-susceptibility (PK-PD) testing, 174 Preemptive therapy, 235 Pyrazolopyridones, 609 Pre-extensively drug resistant, 181 Preiss-Handler pathway, 174 President Advisory Committee on Combating Q Antibiotic-Resistant Bacteria QepA, 351, 362, 363 (PACCARB), 748 Qnr, 350, 351, 600 Prevotella, 208, 209 Qualified infectious disease Prioritization, 744–746 products, 729 Priority review voucher (PRV), 735, 744 Quellung method, 25 Pritelivir, 253 Quinazolinediones (QZDs), 597, 610 Probiotics, 200 , 609 Index 771

Quinolone resistance determining regions Resistance-nodulation-cell division (RND) (QRDRs), 103 family, 73, 74, 77, 79, 82, 86, 95, Quinolones, 101–109, 273, 350 104, 106, 109, 112, 113, 116, 120, 131 Resistance prevention, 682, 684 R Resistant (R), 191, 198, 201, 202, 204, Random amplification of polymorphic DNA 205, 207 with arbitrarily primed PCR CLSI breakpoint, 195 (RAPD/AP-PCR), 306 EUCAST resistant breakpoint, 195 Rational drug design, 567, 570 metronidazole-resistant strains, 207 Reactive nitrogen species (RNS), 415, 418 Resistant bacteria enrichment

Reactive oxygen species (ROS), 415, 418, 624 AUC24/MPC ratio, 647–650 antimicrobial-mediated killing, 620, 621 T>MPC, use of, 655, 656 antioxidant consumption, 635, 636 TMSW (time in MSW), 651, 653–655 Arc, role of, 631–632 Resistome, 389, 394 bactericidal (see Bactericidal activity) Respiration, 630 causality, 632 Respiratory infection, 197 challenges, ROS-mediated stress-response Restriction fragment length polymorphism hypothesis, 628, 629 (RFLP) analysis, 305 chemical perturbations, 623, 624 , 623, 635 drug uptake and killing, Rethinking clinical trials, 732–733 complexities of, 631 Return on investment (ROI), 726 during infection, 636, 637 Reverse transcriptase, 221 E. coli ArcAB two-component system, 631 Ribosomal protection proteins (RRPs), genetic perturbations, 622, 623 19, 113 in vitro systems, 636 , 199, 205 and PCD, 619–620, 632, 633 Ribotyping, 305 quinolone concentration, paradoxical Rifampin, 413, 418, 420–423 tolerance, 633, 634 drug resistance, in M. tuberculosis, respiration, role of, 630 172, 173 respiratory chain, 630 monoresistance, 166 TCA cycle, 630 and PZA, 173 thymineless death, 632, 634, 635 short-course regimen, 164 Reimbursement strategies, 736–737 , 359, 417 Reinvigorating Antibiotic and Diagnostic Risk factors, for S. pneumoniae, 21, 22 Innovation (READI) Act, 747 to fluoroquinolone resistance, 23 Repetitive-element PCR (Rrep-PCR), 306, 307 to macrolide resistance, 22, 23 Research programs, 569, 570 to multidrug-resistance, 23 Resistance, 536 to penicillin resistance to aminoglycosides, 540 age extremes, 21 chloramphenicol, 547 antibiotic consumption and resistance clinical macrolide resistance, 543 selection, 21 to colistin, 547 bacteremia, 21 fosfomycin, 548 β-lactam antibiotic, use of, 21 to glycopeptide antibiotics, 544 macrolides, 22 inhibitors, 552 non-susceptibility, to β-lactamases, 539 erythromycin, 21 pharmacological and toxicological penicillin dust exposure, properties, 537 case-­controlled study, 22 in rifamycin-binding site, 544 RNA polymerase, 572, 573 streptogramins, type A and B, 545 ROS-lethality hypothesis, 624 tetracycline, in gram-negative rRNA, 199 bacteria, 543 rRNA methyltransferases (RMTs), 120 Resistance genes, 361, 363 Rv0678 (gene), 180 772 Index

S Sputum culture positive Salmonella, 411, 476, 481, 492, 496 TB, 163, 176–177, 179 bacterial CAMP-resistance mechanisms, 16S rRNA methyltransferase, 343, 345, 361 484, 485 23S rRNA methyltransferase, 342, 358 Salmonella enterica, 273, 285, 287 Staphylococcal chromosomal cassette SarA, 468, 488 (SCCmec), 42, 46 Serine ß-lactamase, 346 , 39, 281–284, 433, Serotypes, 304 644–651, 653, 654, 656–660 IPD, 27 ability of antibiotics, 415 macrolide-resistant infection, 23 agr role and S. aureus infections (see MDR pneumococcus, 20 Accesory gene regulator (agr)) multidrug-resistant pneumococcal description, 39 infection, 23 heteroresistance non-vaccine, 30 methicillin, 281–282 NVT, 28 vancomycin, 282–284 PCV13, 27 MecA (PBP2a)-mediated regulation, 471 pneumococcal and antibiotic resistance, 25 MRSA (see Methicillin-resistant S. aureus Shigella, 411 (MRSA)) Shunt, CNS, 200 penicillin-resistant, 39 SigI (a sigma factor that regulates katG signaling mechanisms expression), 172 beta-lactam resistance, 470, 471 Signal transduction daptomycin resistance, 478, 479 description, 461 vancomycin resistance, 466, 468 eSTKs, 462 vancomycin tolerance, 437 resistance sensory and response Stewardship, 725 mechanisms, 462 (see also Bacterial (pneumococcus), signal transduction systems) 14, 16, 17, 19, 20, 25–30, 285, 288, Simocyclinone D8 (SD8), 603 645, 652, 653, 657 Simocyclinones, 600, 603, 604 antimicrobial resistance SIRTURO®, 723 fluoroquinolone resistance, 19 Sivextro®, 723, 724 macrolide resistance, 17, 19 Small multidrug resistance (SMR), 73, 181 MDR S. pneumoniae, 20 Small regulatory , 475, 476 penicillin and ß-lactam-resistant, 16, 17 Soft tissue infection, 191, 204 RRP, 19 Solid organ transplants (SOT), 235 tetracyclines, use of, 19 Spirivia®, 724 timeline of, 14, 16 Spiropyrimidinetrione, 108, 522, 523, to other antibiotics, 19 598, 610 bacteremia, 13 Sports teams, 323, 324 cause of death, 13 Spread of resistance clinical outcome aminoglycoside, 319, 320 fluoroquinolone resistance, 29, 30 carbapenem, among β-lactam resistance, 28, 29 Enterobacteriaceae, 308 macrolide resistance, 29 colistin, 320, 321 global acceleration, 25 fluoroquinolone, 318, 319 vs. ß-lactams and macrolides, 14 KPC, 316, 317 mortality rates, 13 MLST, 308 nasopharyngeal carriage rate, 14 MRSA, 311, 312 pneumococcal serotypes, 25 NDM, 317, 318 principal mechanisms, resistance, 14, 15 PRSP, 312–314 risk factors VRE, 314 environmental, 20 Sputum, 277, 278, 280, 417 host, 20 (see also Risk factors, for S. Sputum culture negative pneumoniae) TB, 163, 179 to use of antibiotics, 20 Index 773

signaling mechanisms Thiazole, 600 beta-lactam resistance, 470 Thiophene compounds, 598, 599 vancomycin resistance, 469 Thiophenes, 599, 610 surveillance report , 623, 624, 632, 634–636 fluoroquinolone resistance, rate of, 26 Thymidine kinase (TK) on invasive pneumococcal disease, 25 in HSV resistance, 244, 245 macrolide resistance, rates of, 26 in VZV resistance, 245, 246 transmission, 14 Thymineless death, 629, 630, 632, 634, 635 vaccines on resistance Thymine starvation, 622, 635 PCV7, 27 , 113, 360, 368 PCV13, 27, 28 Tigecycline Evaluation and Surveillance Trial PPV23 vaccine, 27 (TEST), 115 B, 355 , 343, 345, 351, 361 Streptogramins, 355–357, 545 Tobramycin powder, 123 Streptomyces, 600, 602, 604 Tolerance Streptomycin, 2, 163, 540 agr evolution, S. aureus, 438 Stress response, 620, 623, 625–627, 629, Topoisomerase IV

632, 638 A2B2 heterotetramer, 510 Strong incentive canonical mechanism, 512 NPV metric, 725 catalytic strand-passage activities, 513 stability, 724–725 cellular functions of, 511 stewardship, 725 and gyrase, 510, 516 sustainability, 725 mutations, in E. coli, 515 Substrate profile, 346 poisons, 513 Sulbactam, 347–349, 368 subunits of, 510 Sulfonamide resistance, 359 target-mediated resistance, 508, 515 Superoxide, 438 Toxin, 421 Susceptible (S), 191, 192, 198, 199, 201, 204 Toxin-antitoxin (TA), 494, 495, 625, 634, 635 Synercid®, 355 Traditional antibiotics, 575 Synthetic biology, 537, 551, 555, 556 Trans-Atlantic Task Force on Antimicrobial Resistance (TATFAR), 740, 746 Transcription factor, 462, 463, 468, 469 T CrgR, 487 Target-directed antibiotic discovery, 569, LysR-type, 473 575–576, 582, 584 MecI, 471 Target-directed discovery programs, 583, 584 TCS, 479 Target-mediated resistance Transglycosylase, 88 fluoroquinolones, 508, 515 Transmissible antibiotic resistance Tazobactam, 347–349, 368 amikacin, 368 Tcr bacteria, 394, 398 aminoglycoside, 343, 345 T cell epitopes, 413 ampicillin, 341 Teflaro®, 724 antibiotics, 369 , 465, 466, 468 application, 368 Teicoplanin resistance, 353 bacitracin, 346 Teixobactin, 577 ceftazidime-avibactam, 369 , 201 chloramphenicol, 358 TEM-1 ß-lactamase, 363, 366 colistin, 349–350 TEM-1 plasmid-mediated β-lactamase, 302 diazabicyclooctane, 368 TetA efflux pump, 111 fluoroquinolone, 350–352 Tetracycline resistance, 359, 368 fosfomycin, 352 Tetracyclines, 109–112, 115, 198, 203, fusidic acid, 352 359–360, 566, 568, 584, 585 genes, 361, 363 in aquaculture, 394 glycopeptide, 353, 354 natural-product antibiotics, 543 glycopeptide avoparcin, 369 774 Index

Transmissible antibiotic resistance (cont.) S. aureus VISA phenotypes, 468 human medicine, 369 S. pneumoniae, 469 β-lactamases, 346–349, 368 Type II topoisomerases, 567 lincosamide, 355–357 macrolides, 355–357 mobilization, 366 U molecular mechanisms, 343–354 UhpT, 481, 482 mupirocin, 357 UK Ministry of Treasury, 741 nitrofurantoin, 357 Underuse, 413, 414 nitroimidazole, 357 Urogenital infection, 200 oxazolidinone, 358 Usual drug resistance (UDR), 670, 671, 676, oxyimino group, 368 692, 694, 696, 699–701 phenicol, 358 plasmid-mediated colistin, 341 representatives, 344–345 V rifamycin, 359 , 98 semisynthetic , 368 Vaccines, pneumococcal Shigella, 341 PCV7, 27 sources, 362–363 PCV13, 27 streptogramin, 355–357 PPV23, 27 sulfonamide, 359 Valganciclovir (VGCV), 233, 238, 239 tetracycline, 359–360 VanA, 464–466 , 360–361 VanA-type glycopeptide resistance, 354 Transpeptidase, 88, 564, 565 VanB, 465 Transported segment (T), 595 Vancomycin, 2, 3, 19, 29, 196, 201–204, 210, Transposon, 349, 353, 355, 358, 360 646, 650, 651, 658 Traveler’s diarrhea, 326 heteroresistance, with S. aureus, 282–284 Triazaacenaphthylenes, 598, 599 intermediate heteroresistance, 282–284 Tricarboxylic acid (TCA) cycle, 630 nosocomial pneumonia, treatment of, 443 Tricyclic GyrB/ParE (TriBE) inhibitors, 567 VRE, 274 Trimethoprim, 360–361 VISA, 270 Trimethoprim resistance, 360 Vancomycin intermediate-resistant S. aureus Tuberculosis (TB), 166, 167, 182, 183 (VISA), 3, 270, 282–284, 437 annual Global TB Report, WHO’s, 166 Vancomycin resistance, 353, 354, 464, 466, clinical consequences, drug resistance, 166 468, 469 drug-resistant, 164 signaling mechanisms MDR-TB, 164, 165 Enterococcus sp., 464, 466 resistance pattern S. aureus, 466, 468 isoniazid monoresistance, 166 S. pneumoniae, 469 polydrug resistance, 167 and tolerance signaling mechanisms, 465 PZA monoresistance, 167 Vancomycin-resistant E. faecium (VRE) streptomycin monoresistance, 166 environment, human influences on, 393 XDR-TB, 167 One Health approach, 387, 388 treatment, drug-resistant TB spread, of bacterial resistant strains, Bangladesh regimen, 183 314, 316 isoniazid-monoresistant, 182 VanD, 464 multidrug-resistant, 182 VanE, 464 WHO-recommended approach, 182 VanG, 464, 472 treatment and resistance generation, VanH, 465 163, 164 VanX, 465 Two-component signaling (TCS) VanY, 465 bacterial signaling, 463 VanZ, 465 Cpx system, 481–483 Variable-number tandem repeats described, 462 (VNTR), 307 Index 775

Varicella-zoster virus (VZV), 245–247, 249, human pathogens, 395 250, 252 municipal wastewater, 395 antiviral agents, 235 occupational exposure risk, 396 resistance plasmids, metagenome analysis of, 397 clinical significance, incidence and risk residual ARB/ARGs, 396 factors, 247 tet genes, 397 management, by drug-resistant VZV whole genome sequencing, 397 strains, 252 Water-metal ion bridge, 517–519 phenotypic and genotypic assays, Whole-genome sequencing (WGS), 309 245, 246 TB, 169 thymidine kinase (TK), mutations, WHO Global TB Report, 165, 166 249, 250 WHO treatment guidelines, drug-resistant Veillonella, 197, 199 tuberculsis, 182, 183 Veterinary feed directive (VFD), 384, 391 World Health Organization (WHO) Virco™ Vircotype (or virtual phenotype) inexpensive antibiotics, availability of, 5 report, 229 multinational global collaboration, 7 Virulence, S. aureus infection new antibiotics, R&D of, 7 agr-mediated, 435, 442 World Health Day in 2011, 7 global regulator, 433 in nosocomial pneumonia, 443, 444 RNAIII-dependent regulation, 434 X Voucher programs, 734–735 XDR-TB (extensively drug-resistant TB), 167, VraFG, 468, 488 170, 183, 184 VraSR, 468, 478

Y W Yersinia pestis, 485 WalKR, 468, 478 YihE, 627 Wastewater treatment plants (WWTP) biosludge and effluents, 395, 396 biosolids and final effluents, 400 Z and by-products, 395 Zerbaxa®, 724 conventional wastewater treatment, 396 Zidovudine pathways, 228 environmental contamination, 396 Zoliflodacin, 567 and human health, 395 Zones of inhibition, 550