Abstract
Klebsiella pneumoniae colonizes mucosal surfaces of healthy humans and is responsible for one third of all Gram-negative infections in hospitalized patients. K. pneumoniae is compatible with acquiring antibiotic resistance elements such as plasmids and transposons encoding various β-lactamases and efflux pumps. Mutations in different proteins such as β-lactamases, efflux proteins, outer membrane proteins, gene replication enzymes, protein synthesis complexes and transcription enzymes also generate resistance to antibiotics. Biofilm formation is another strategy that facilitates antibiotic resistance. Resistant strains can be treated by combination therapy using available antibiotics, though proper management of antibiotic consumption in hospitals is important to reduce the emergence and proliferation of resistance to current antibiotics.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Molecular detection and antimicrobial resistance of Klebsiella pneumoniae from house flies (Musca domestica) in kitchens, farms, hospitals and slaughterhouses. J. Infect. Public Health 9(4), 499–505 (2016).
- 2. Molecular characterization of carbapenem-nonsusceptible enterobacterial isolates collected during a prospective interregional survey in France and susceptibility to the novel ceftazidime–avibactam and aztreonam–avibactam combinations. Antimicrob. Agents Chemother. 60(1), 215–221 (2016).
- 3. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J. Antimicrob. Chemother. 70(7), 2133–2143 (2015).
- 4. Emergence of a plasmid-encoded resistance-nodulation-division efflux pump conferring resistance to multiple drugs, including tigecycline, in Klebsiella pneumoniae. mBio 11(2), e02930–19 (2020). • A good description and example of emergence of plasmid encoded efflux pumps.
- 5. . Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance. FEMS Microbiol. Rev. 41(3), 252–275 (2017).
- 6. . The characteristic of virulence, biofilm and antibiotic resistance of Klebsiella pneumoniae. Int. J. Environ. Res. Public Health. 17(17), 6278 (2020).
- 7. Correlation between biofilm formation and carbapenem resistance among clinical isolates of Klebsiella pneumoniae. Ethiop. J. Health Sci. 29(6), 745–750 (2019). •• The article describes the association between biofilm and antibiotic resistance very well.
- 8. . Epidemiology and virulence of Klebsiella pneumoniae. Microbiol. Spectr. 4(1), 1–17 (2016).
- 9. . Antibiotic resistance related to biofilm formation in Klebsiella pneumoniae. Pathogens 3(3), 743–758 (2014).
- 10. Biofilm formation by clinical isolates and the implications in chronic infections. BMC Infect. Dis. 13, 47 (2013).
- 11. . Effect of subinhibitory concentration of piperacillin/tazobactam on Pseudomonas aeruginosa. J. Med. Microbiol. 53(Pt 9), 903–910 (2004).
- 12. . Biofilm formation and susceptibility to gentamicin and colistin of extremely drug-resistant KPC-producing Klebsiella pneumoniae. J. Antimicrob. Chemother. 69(4), 1027–1034 (2014).
- 13. . Characterization of a DHA-1-producing Klebsiella pneumoniae strain involved in an outbreak and role of the AmpR regulator in virulence. Antimicrob. Agents Chemother. 56(1), 288–294 (2012).
- 14. . The role of exopolysaccharides in dual species biofilm development. J. Appl. Microbiol. 85(Suppl. 1), S13–S18 (1998).
- 15. . Species interactions in mixed-community crystalline biofilms on urinary catheters. J. Med. Microbiol. 56(pt 11), 1549–1557 (2007).
- 16. . Global epidemiology of CTX-M β-lactamases: temporal and geographical shifts in genotype. J. Antimicrob. Chemother. 72(8), 2145–2155 (2017).
- 17. . Trends in human fecal carriage of extended-spectrum β-lactamases in the community: toward the globalization of CTX-M. Clin. Microbiol. Rev. 26(4), 744–758 (2013).
- 18. . Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection 11(6), 315–317 (1983).
- 19. Transferable resistance to third-generation cephalosporins in clinical isolates of Klebsiella pneumoniae: identification of CTX-1, a novel β-lactamase. J. Antimicrob. Chemother. 20(3), 323–334 (1987).
- 20. . Extended-spectrum β-lactamases. Clin. Infec. Dis. 41(Suppl. 4), S273–S275 (2005).
- 21. . Extended-spectrum β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev. 14(4), 933–951; table of contents (2001).
- 22. . A structure-based classification of class A β-lactamases, a broadly diverse family of enzymes. Clin. Microb. Rev. 29(1), 29–57 (2016).
- 23. . Global dissemination of carbapenemase-producing Klebsiella pneumoniae: epidemiology, genetic context, treatment options, and detection methods. Front. Microbiol. 7, 895 (2016). •• The article describes the complexity of antibiotic resistance to Klebsiella properly.
- 24. . Carbapenemases: the versatile β-lactamases. Clin. Microb. Rev. 20(3), 440–458 (2007).
- 25. Functional analysis of the active site of a metallo-β-lactamase proliferating in Japan. Antimicrob. Agents Chemother. 44(9), 2304–2309 (2000).
- 26. . Clonal dissemination of carbapenemase-producing Klebsiella pneumoniae: two distinct sub-lineages of Sequence Type 11 carrying bla(KPC-2) and bla(OXA-48). Int. J. Antimicrob. Agents. 52(5), 658–662 (2018).
- 27. . Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 48(1), 15–22 (2004).
- 28. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob. Agents Chemother. 53(12), 5046–5054 (2009).
- 29. . NDM metallo-β-lactamases and their bacterial producers in health care settings. Clin. Microb. Rev. 32(2), e00115–e00118 (2019).
- 30. Novel carbapenem-hydrolyzing β-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 45(4), 1151–1161 (2001).
- 31. . The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae. Clin. Microb. Rev. 28(3), 565–591 (2015).
- 32. Interspecies spread of Klebsiella pneumoniae carbapenemase gene in a single patient. Clin. Infec. Dis. 49(11), 1736–1738 (2009).
- 33. . Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrob. Agents Chemother. 54(1), 177–183 (2010).
- 34. . Ertapenem resistance among extended-spectrum-β-lactamase-producing Klebsiella pneumoniae isolates. J. Clin. Microb. 47(4), 969–974 (2009).
- 35. . Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC β-lactamase, and the foss of an outer membrane protein. Antimicrob. Agents Chemother. 41(3), 563–569 (1997).
- 36. . Persistence of antibiotic resistance in bacterial populations. FEMS Microbiol. Rev. 35(5), 901–911 (2011).
- 37. . Comparison between carbapenems and β-lactam/β-lactamase inhibitors in the treatment for bloodstream infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae: a systematic review and meta-analysis. Open Forum Infect Dis. 4(2), 1–8 (2017).
- 38. . Multidrug-resistant Klebsiella pneumoniae: mechanisms of resistance including updated data for novel β-lactam-β-lactamase inhibitor combinations. Expert Rev. Anti Infect. Ther. 19(11), 1457–1468 (2021).
- 39. . Piperacillin–tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. J. Infect. 64(5), 533–534 (2012).
- 40. Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo. J. Antimicrob. Chemother. 74(11), 3211–3216 (2019). • The article describes a novel resistance mechanism antibiotic resistance against new antibiotic ceftazidime/avibactam.
- 41. Ceftazidime–avibactam, meropenen–vaborbactam, and imipenem–relebactam in combination with aztreonam against multidrug-resistant, metallo-β-lactamase-producing Klebsiella pneumoniae. Eur. J. Clin. Microbiol. 1–5 (2021).
- 42. . Piperacillin–tazobactam-resistant/third-generation cephalosporin-susceptible Escherichia coli and Klebsiella pneumoniae isolates: resistance mechanisms and in vitro–in vivo discordance. Int. J. Antimicrob. Agents 55(3), 105885 (2020). • The article describes the mechanisms underlying resistance against TZP and difficulties in MIC testing properly.
- 43. Re-evaluation of cefepime or piperacillin–tazobactam to decrease use of carbapenems in extended-spectrum β-lactamase-producing Enterobacterales bloodstream infections (REDUCE-BSI). Antimicrob. Steward. Healthc. Epidemiol. 2(1), e39 (2022).
- 44. Differential contribution of AcrAB and OqxAB efflux pumps to multidrug resistance and virulence in Klebsiella pneumoniae. J. Antimicrob. Chemother. 70(1), 81–88 (2015).
- 45. Klebsiella pneumoniae isolate from a New York City hospital belonging to sequence type 258 and carrying blaKPC-2 and blaVIM-4. Antimicrob. Agents Chemother. 60(3), 1924–1927 (2016).
- 46. SHV hyperproduction as a mechanism for piperacillin–tazobactam resistance in extended-spectrum cephalosporin-susceptible Klebsiella pneumoniae. Microb. Drug Resist. 26(4), 334–340 (2020).
- 47. Piperacillin/tazobactam resistance in a clinical isolate of Escherichia coli due to IS26-mediated amplification of bla(TEM-1B). Nat. Commun. 11(1), 4915 (2020).
- 48. Characterization of piperacillin/tazobactam-resistant Klebsiella oxytoca recovered from a nosocomial outbreak. PLOS ONE 10(11), e0142366 (2015).
- 49. . In vitro–in vivo discordance with humanized piperacillin–tazobactam exposures against piperacillin–tazobactam-resistant/pan-β-lactam-susceptible Klebsiella pneumoniae strains. Antimicrob. Agents Chemother. 61(7), e00491–17 (2017).
- 50. . Building a better test for piperacillin–tazobactam susceptibility testing: would that it were so simple (it's complicated). J. Clin. Microbiol. 58(2), e01649–19 (2020). • The article describes the mechanisms underlying resistance against piperacillin–tazobactam and difficulties in MIC testing properly.
- 51. Multicenter evaluation of the new Etest gradient diffusion method for piperacillin–tazobactam susceptibility testing of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex. J. Clin. Microbiol. 58(2), e01042–19 (2020).
- 52. . MIC-based dose adjustment: facts and fables. J. Antimicrob. Chemother. 73(3), 564–568 (2018).
- 53. . In-vitro selection of ceftazidime/avibactam resistance in OXA-48-like-expressing Klebsiella pneumoniae: in-vitro and in-vivo fitness, genetic basis and activities of β-lactam plus novel β-lactamase inhibitor or β-lactam enhancer combinations. Antibiotics 10(11), 1318 (2021).
- 54. . OXA-48-mediated ceftazidime–avibactam resistance is associated with evolutionary trade-offs. Msphere 4(2), e00024–e00019 (2019).
- 55. . Selection of mutants with resistance or diminished susceptibility to ceftazidime/avibactam from ESBL- and AmpC-producing Enterobacteriaceae. J. Antimicrob. Chemother. 73(12), 3336–3345 (2018).
- 56. In vitro selection of ceftazidime–avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob. Agents Chemother. 59(9), 5324–5330 (2015).
- 57. Emergence of ceftazidime/avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China. Clin. Microbiol. Infect. 26(1), 124.e121–124.e124 (2020).
- 58. . AmpC β-lactamases in Klebsiella pneumoniae: an emerging threat to the paediatric patients. JPMA 68(6), 893–897 (2018).
- 59. . Detection of Amp C genes encoding for β-lactamases in Escherichia coli and Klebsiella pneumoniae. Indian J. Med. Microbiol. 30(3), 290–295 (2012).
- 60. . Distribution of ESBLs, AmpC β-lactamases and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal and urinary tract infections in the Asia-Pacific region during 2008-14: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J. Antimicrob. Chemother. 72(1), 166–171 (2016).
- 61. . Evaluation of phenotypic tests for detection of Amp C β-lactamases in clinical isolates from a tertiary care hospital of Rawalpindi, Pakistan. J. Pak. Med. Assoc. 66(6), 658–661 (2016).
- 62. Mobile genetic elements related to the diffusion of plasmid-mediated AmpC β-lactamases or carbapenemases from Enterobacteriaceae: findings from a multicenter study in Spain. Antimicrob. Agents Chemother. 59(9), 5260–5266 (2015).
- 63. . AmpC β-lactamases. Clin. Microb. Rev. 22(1), 161–182 (2009).
- 64. . Can we really use ß-lactam/ß-lactam inhibitor combinations for the treatment of infections caused by extended-spectrum ß-lactamase-producing bacteria? Clin. Infect. Dis. 54(2), 175–177 (2021).
- 65. The role of RND-type efflux pumps in multidrug-resistant mutants of Klebsiella pneumoniae. Sci. Rep. 10(1), 10876 (2020).
- 66. CusS-CusR two-component system mediates tigecycline resistance in carbapenem-resistant Klebsiella pneumoniae. Front. Microbiol. 10, 3159 (2019).
- 67. . A tripartite efflux pump involved in gastrointestinal colonization by Klebsiella pneumoniae confers a tolerance response to inorganic acid. Infect. Immun. 76(10), 4633–4641 (2008).
- 68. Properties and expression of a multidrug efflux pump AcrAB-KocC from Klebsiella pneumoniae. Biol. Pharm. Bull. 31(4), 577–582 (2008).
- 69. . Functional study of the novel multidrug efflux pump KexD from Klebsiella pneumoniae. Gene 498(2), 177–182 (2012).
- 70. . Gene cloning and characterization of KdeA, a multidrug efflux pump from Klebsiella pneumoniae. Biol. Pharm. Bull. 30(10), 1962–1964 (2007).
- 71. Proteomic changes of Klebsiella pneumoniae in response to colistin treatment and crrB mutation-mediated colistin resistance. Antimicrob. Agents Chemother. 64(6), e02200-19 (2020).
- 72. Co-existence of a novel plasmid-mediated efflux pump with colistin resistance gene mcr in one plasmid confers transferable multidrug resistance in Klebsiella pneumoniae. Emerg. Microbes Infect. 9(1), 1102–1113 (2020).
- 73. . Characterization of RarA, a novel AraC family multidrug resistance regulator in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 56(8), 4450–4458 (2012).
- 74. . KmrA multidrug efflux pump from Klebsiella pneumoniae. Biol. Pharm. Bull. 29(3), 550–553 (2006).
- 75. . Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem. Biophys. Res. Commun. 453(2), 254–267 (2014).
- 76. IS5 element integration, a novel mechanism for rapid in vivo emergence of tigecycline nonsusceptibility in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 58(10), 6151–6156 (2014).
- 77. A virulence associated siderophore importer reduces antimicrobial susceptibility of Klebsiella pneumoniae. Front. Microbiol. 12, 52 (2021).
- 78. . SmvA is an important efflux pump for cationic biocides in Klebsiella pneumoniae and other Enterobacteriaceae. Sci. Rep. 9(1), 1–11 (2019).
- 79. . Role of novel multidrug efflux pump involved in drug resistance in Klebsiella pneumoniae. PLOS ONE 9(5), e96288 (2014).
- 80. . Investigation of efflux-mediated tetracycline resistance in Shigella isolates using the inhibitor and real time polymerase chain reaction method. Iran. J. Pathol. 12(1), 53 (2017).
- 81. The rapid emergence of tigecycline resistance in blaKPC-2 harboring Klebsiella pneumoniae, as mediated in vivo by mutation in tetA during tigecycline treatment. Front. Microbiol. 9, 648 (2018).
- 82. KPC-2-producing Klebsiella pneumoniae ST147 in a neonatal unit: clonal isolates with differences in colistin susceptibility attributed to AcrAB-TolC pump. Int. J. Antimicrob. Agents 55(3), 105903 (2020). •• They properly describe a novel mechanism underlying resistance against colistin as one of the last effective antibiotics against extremely drug-resistant Klebsiella.
- 83. . KpnEF, a new member of the Klebsiella pneumoniae cell envelope stress response regulon, is an SMR-type efflux pump involved in broad-spectrum antimicrobial resistance. Antimicrob. Agents Chemother. 57(9), 4449–4462 (2013).
- 84. . Efflux mediated colistin resistance in diverse clones of Klebsiella pneumoniae from aquatic environment. Microb. Pathog. 102, 109–112 (2017).
- 85. . Molecular typing and virulence analysis of multidrug resistant Klebsiella pneumoniae clinical isolates recovered from Egyptian hospitals. Sci. Rep. 6(1), 38929 (2016).
- 86. . Alliance of efflux pumps with β-lactamases in multidrug-resistant Klebsiella pneumoniae isolates. Microb. Drug Resist. 25(8), 1155–1163 (2019). • The article describes the important role of efflux pumps in resistance against β-lactam antibiotics.
- 87. . Landscape of resistance-nodulation-cell division (RND)-type efflux pumps in Enterobacter cloacae complex. Antimicrob. Agents Chemother. 60(4), 2373–2382 (2016).
- 88. . The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin. Microbiol. Rev. 28(2), 337–418 (2015).
- 89. . Identification and molecular characterisation of CmeB, a Campylobacter jejuni multidrug efflux pump. FEMS Microbiol. Lett. 206(2), 185–189 (2002).
- 90. Contribution of OqxAB efflux pumps to quinolone resistance in extended-spectrum-β-lactamase-producing Klebsiella pneumoniae. J. Antimicrob. Chemother. 68(1), 68–73 (2013).
- 91. . First emergence of acrAB and oqxAB mediated tigecycline resistance in clinical isolates of Klebsiella pneumoniae pre-dating the use of tigecycline in a Chinese hospital. PLoS ONE 9(12), e115185 (2014).
- 92. . Contribution of OqxAB efflux pump in selection of fluoroquinolone-resistant Klebsiella pneumoniae. Can. J. Infect. Dis. Med. Microbiol. 2018, 4271638 (2018).
- 93. . Relationship between antibiotic resistance, efflux pumps, and biofilm formation in extended-spectrum β-lactamase producing Klebsiella pneumoniae. J. Chemother. 30(6–8), 354–363 (2018).
- 94. Efflux pumps AcrAB and OqxAB contribute to nitrofurantoin resistance in an uropathogenic Klebsiella pneumoniae isolate. Int. J. Antimicrob. Agents 54(2), 223–227 (2019).
- 95. Tigecycline susceptibility and the role of efflux pumps in tigecycline resistance in KPC-producing Klebsiella pneumoniae. PLOS ONE 10(3), e0119064 (2015).
- 96. . Tigecycline resistance among Klebsiella pneumoniae isolated from febrile neutropenic patients. J. Med. Microbiol. 67(7), 972 (2018).
- 97. Resistance to ceftazidime–avibactam is due to transposition of KPC in a porin-deficient strain ofKlebsiella pneumoniae with increased efflux activity. Antimicrob. Agents Chemother. 61(10), e00989–17 (2017).
- 98. . Development of tigecycline resistance in carbapenemase-producing Klebsiella pneumoniae sequence type 147 via AcrAB overproduction mediated by replacement of the ramA promoter. Ann. Lab. Med. 40(1), 15–20 (2020).
- 99. . In vivo evolution of tigecycline-non-susceptible Klebsiella pneumoniae strains in patients: relationship between virulence and resistance. Int. J. Antimicrob. Agents 48(5), 485–491 (2016).
- 100. . Molecular analysis of the ramRA locus in clinical Klebsiella pneumoniae isolates with reduced susceptibility to tigecycline. New Microbiol. 40(2), 135–138 (2017).
- 101. Comparative effects of overproducing the AraC-type transcriptional regulators MarA, SoxS, RarA and RamA on antimicrobial drug susceptibility in Klebsiella pneumoniae. J. Antimicrob. Chemother. 71(7), 1820–1825 (2016).
- 102. Envelope proteome changes driven by RamA overproduction in Klebsiella pneumoniae that enhance acquired β-lactam resistance. J. Antimicrob. Chemother. 73(1), 88–94 (2018).
- 103. Overexpression of OqxAB and MacAB efflux pumps contributes to eravacycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae. Emerg. Microbes Infect. 7(1), 139 (2018).
- 104. Distribution and spread of the mobilised RND efflux pump gene cluster tmexCD-toprJ in clinical Gram-negative bacteria: a molecular epidemiological study. Lancet Microbe 3(11), e846–e856 (2022).
- 105. . A putative RND-type efflux pump, H239_3064, contributes to colistin resistance through CrrB in Klebsiella pneumoniae. J. Antimicrob. Chemother. 73(6), 1509–1516 (2018).
- 106. . Antibiotic resistance by enzymatic modification of antibiotic targets. Trends Mol. Med. 26(8), 768–782 (2020).
- 107. . Aminoglycoside resistance determinants in multiresistant Escherichia coli and Klebsiella pneumoniae clinical isolates from Turkish and Syrian patients. Acta Microbiol. Immunol. Hung. 66(3), 327–335 (2019).
- 108. . Aminoglycoside modifying enzymes. Drug Resist. Updat. 13(6), 151–171 (2010).
- 109. Optimizing aminoglycoside selection for KPC-producing Klebsiella pneumoniae with the aminoglycoside-modifying enzyme (AME) gene aac(6′)-Ib. J. Antimicrob. Chemother. 76(3), 671–679 (2021).
- 110. Emergence of the novel aminoglycoside acetyltransferase variant aac (6′)-Ib-D179Y and acquisition of colistin heteroresistance in carbapenem-resistant Klebsiella pneumoniae due to a disrupting mutation in the DNA repair enzyme MutS. mBio 11(6), e01954–e01920 (2020).
- 111. Generating genotype-specific aminoglycoside combinations with ceftazidime/avibactam for KPC-Producing Klebsiella pneumoniae. Antimicrob. Agents Chemother. 65(9), e0069221 (2021).
- 112. Aminoglycoside concentrations required for synergy with carbapenems against Pseudomonas aeruginosa determined via mechanistic studies and modeling. Antimicrob. Agents Chemother. 61(12), (2017).
- 113. . Virulence evolution, molecular mechanisms and prevalence of ST11 Carbapenem-resistant Klebsiella pneumoniae in China: a review over ten last years. J. Glob. Antimicrob. Resist. 23, 174–180 (2020).
- 114. Widespread dissemination of aminoglycoside resistance genes armA and rmtB in Klebsiella pneumoniae isolates in Taiwan producing CTX-M-type extended-spectrum β-lactamases. Antimicrob. Agents Chemother. 53(1), 104–111 (2009).
- 115. Vertical and horizontal dissemination of an IncC plasmid harbouring rmtB 16S rRNA methylase gene, conferring resistance to plazomicin, among invasive ST258 and ST16 KPC-producing Klebsiella pneumoniae. J. Glob. Antimicrob. Resist. 24, 183–189 (2021).
- 116. . Increased prevalence of aminoglycoside resistance in clinical isolates of Escherichia coli and Klebsiella spp. in Norway is associated with the acquisition of AAC (3)-II and AAC (6′)-Ib. Diag. Microb. Infecti. Dis. 78(1), 66–69 (2014).
- 117. In vitro activity of apramycin against carbapenem-resistant and hypervirulent Klebsiella pneumoniae isolates. Front. Microbiol. 11, 425 (2020).
- 118. . Emergence of Klebsiella pneumoniae harboring the aac (6′)-Ian amikacin resistance gene. Antimicrob. Agents Chemother. 62(12), e01952–e01918 (2018).
- 119. . Macrolide resistance based on the Erm-mediated rRNA methylation. Curr. Drug. Targets Infect. Disord. 4(3), 193–202 (2004).
- 120. Characterization of quinolone resistance mechanisms in Enterobacteriaceae recovered from diseased companion animals in Europe. Vet. Microbiol. 194, 23–29 (2016).
- 121. Frequency of DNA gyrase and topoisomerase IV mutations and plasmid-mediated quinolone resistance genes among Escherichia coli and Klebsiella pneumoniae isolated from urinary tract infections in Azerbaijan, Iran. J. Glob. Antimicrob. Resist. 17, 39–43 (2019).
- 122. . Analysis of mutational patterns in quinolone resistance-determining regions of GyrA and ParC of clinical isolates. Int. J. Antimicrob. Agents 53(3), 318–324 (2019).
- 123. . Topoisomerase inhibitors: fluoroquinolone mechanisms of action and resistance. Cold Spring Harb. Perspect. Med. 6(9), a025320 (2016).
- 124. . Double-serine fluoroquinolone resistance mutations advance major international clones and lineages of various multi-drug resistant bacteria. Front. Microbiol. 8, 2261 (2017).
- 125. Fitness cost associated with resistance to fluoroquinolones is diverse across clones of Klebsiella pneumoniae and may select for CTX-M-15 type extended-spectrum β-lactamase. Eur. J. Clin. Microbiol. Infect. Dis. 33(5), 837–843 (2014).
- 126. . Mutations in DNA gyrase and topoisomerase IV in ciprofloxacin-nonsusceptible extended-spectrum b-Lactamase-producing Escherichia coli and Klebsiella pneumoniae. Clin. Lab. 63(3), 535–541 (2020).
- 127. Determination of gyrA and parC mutations and prevalence of plasmid-mediated quinolone resistance genes in Escherichia coli and Klebsiella pneumoniae isolated from patients with urinary tract infection in Iran. J. Glob. Antimicrob. Resist. 13, 197–200 (2018).
- 128. Whole genome sequencing snapshot of multi-drug resistant Klebsiella pneumoniae strains from hospitals and receiving wastewater treatment plants in Southern Romania. PLOS ONE 15(1), e0228079 (2020).
- 129. qnr, aac(6′)-Ib-cr and qepA genes in Escherichia coli and Klebsiella spp.: genetic environments and plasmid and chromosomal location. J. Antimicrob. Chemother. 67(4), 886–897 (2012).
- 130. . The structure of bacterial outer membrane proteins. Biochim. Biophys. Acta 1565(2), 308–317 (2002).
- 131. . Alterations in outer membrane permeability favor drug-resistant phenotype of Klebsiella pneumoniae. Microb. Drug Resist. 23(4), 413–420 (2017).
- 132. Resistance to carbapenems in sequence type 11 Klebsiella pneumoniae is related to DHA-1 and loss of OmpK35 and/or OmpK36. J. Med. Microbiol. 61(2), 239–245 (2012).
- 133. . A protein important for antimicrobial peptide resistance, YdeI/OmdA, is in the periplasm and interacts with OmpD/NmpC. J. Bacteriol. 191(23), 7243–7252 (2009).
- 134. . Different culture medium formulations induce variant protein expression patterns of outer membrane porins in Klebsiella pneumoniae. J. Chemother. 23(1), 9–12 (2011).
- 135. An outbreak of NDM-1-producing Klebsiella pneumoniae, associated with OmpK35 and OmpK36 porin loss in Tunisia. Microb. Drug Resist. 24(8), 1137–1147 (2018).
- 136. . Mechanisms of ertapenem resistance in Enterobacteriaceae isolates in a tertiary university hospital. J. Investig. Med. 64(5), 1042–1049 (2016).
- 137. First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling. BMC Microbiol. 20(1), 218 (2020).
- 138. . Outer membrane profiles of clonally related Klebsiella pneumoniae isolates from clinical samples and activities of cephalosporins and carbapenems. Antimicrob. Agents Chemother. 42(7), 1636–1640 (1998).
- 139. . OmpK26, a novel porin associated with carbapenem resistance in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 55(10), 4742–4747 (2011).
- 140. . Role of Klebsiella pneumoniae LamB porin in antimicrobial resistance. Antimicrob. Agents Chemother. 55(4), 1803–1805 (2011).
- 141. . High-level carbapenem resistance in a Klebsiella pneumoniae clinical isolate is due to the combination of bla(ACT-1) β-lactamase production, porin OmpK35/36 insertional inactivation, and down-regulation of the phosphate transport porin phoe. Antimicrob. Agents Chemother. 50(10), 3396–3406 (2006).
- 142. . Functional characterization of a novel outer membrane porin KpnO, regulated by PhoBR two-component system in Klebsiella pneumoniae NTUH-K2044. PLOS ONE 7(7), e41505 (2012).
- 143. Colistin resistance associated with outer membrane protein change in Klebsiella pneumoniae and Enterobacter asburiae. Acta Microbiol. Immunol. Hung. 64(2), 217–227 (2017).
- 144. Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin. Sci. Rep. 8(1), 1–11 (2018).
- 145. In vivo emergence of colistin resistance in Klebsiella pneumoniae producing KPC-type carbapenemases mediated by insertional inactivation of the PhoQ/PhoP mgrB regulator. Antimicrob. Agents Chemother. 57(11), 5521–5526 (2013).
- 146. . Molecular and epidemiological surveillance of polymyxin-resistant Klebsiella pneumoniae strains isolated from Brazil with multiple mgrB gene mutations. Int. J. Med. Microbiol. 310(7), 151448 (2020).
- 147. . Epidemiology and molecular characterisation of colistin-resistant Klebsiella pneumoniae isolates from immunocompromised patients in Tunisia. Int. J. Antimicrob. Agents 52(6), 861–865 (2018).