Abstract
Antibiotic resistance is one of the greatest worldwide challenges to modern medicine, and society at large, and one of the least appreciated by practitioners and the lay community. Many strains of multi-drug resistant bacteria such as methicillin and vancomycin-resistant Staphylococcus aureus and multi-drug resistant Mycobacterium tuberculosis continue to plague both developed and underdeveloped countries alike. Collectively over 700,000 deaths occur annually as a consequence of infections from antibiotic-resistant bacteria. Presently, many scientists and clinicians seek to find solutions to this ever-growing crisis. Today, the most common causes of hospital-acquired and multi-drug resistant infections are the ESKAPE group of bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), six genera and species with a host of mechanisms to survive against even extremely potent antibiotics. Limited research currently focuses on discovering or developing novel compounds that will hopefully turn the tide and tackle the problem of resistance, but significant changes in healthcare and consumer practices will be necessary as well, to successfully address this dilemma. This review provides a status report on a rather silent global crisis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Not applicable.
References
Abadi ATB, Rizvanov AA, Haertlé T, Blatt NL (2019) World Health Organization report: current crisis of antibiotic resistance. BioNanoScience 9:778–788. https://doi.org/10.1007/s12668-019-00658-4
About Antibiotic Resistance. (2020) Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/about.html Accessed 8/15/20
Acinetobacter CDC (2021) Acinetobacter in healthcare settings. Centers for Disease Control and Prevention. https://www.cdc.gov/hai/organisms/acinetobacter.html
Acinetobacter Pathogen Page. (2020) Carbapenem-Resistant Acinetobacter Pathogen Page. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/acinetobacter-508.pdf
Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y (2006) Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother 50:43–48. https://doi.org/10.1128/AAC.50.1.43-48.2006
Anderl JN, Franklin MJ, Stewart PS (2000) Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob Agents Chemother 44:1818–1824. https://doi.org/10.1128/AAC.44.7.1818-1824.2000
Ashurst J V & Dawson A Klebsiella pneumoniae (2020) In: StatPearls [internet]. Treasure Island (FL): StatPearls Publishing; 2020
Banin E, Vasil ML, Greenberg EP (2005) Iron and Pseudomonas aeruginosa biofilm formation. PNAS 102:11076–11081. https://doi.org/10.1073/pnas.0504266102
Bantar C, Sartori B, Vesco E et al (2003) A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, antibiotic consumption, cost savings, and bacterial resistance. Clin Infect Dis 37:180–186. https://doi.org/10.1086/375818
Basséres E, Endres BT, Dotson KM, Alam MJ, Garey KW (2016) Novel antibiotics in development to treat Clostridium difficile infection. Curr Opin Gastroenterol 33:1–7. https://doi.org/10.1097/MOG.0000000000000332
Biggest Threats and Data. (2020) Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/biggest-threats.html#extend
Bjorkman A, Phillips-Howard PA (1991) Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bull World Health Organ 69:297–304
Bond CA, Raehl CL (2005) Clinical and economic outcomes of pharmacist-managed aminoglycoside or vancomycin therapy. Am J Health Syst Pharm 62:1596–1605. https://doi.org/10.2146/ajhp040555
Bowater L (2017) The microbes fight Back: antibiotic resistance. Royal Society of Chemistry, Cambridge
Castanheira, M, Huband, M D, Mendes, R E, & Flamm, R K (2017) Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. Antimicrob. Agents. Chemother. 61: 1–12. https://doi.org/10.1128/AAC.00567-17https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf accessed 8.26.2020 “CDC”
Chambers HF (2001) The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 7:178–182. https://doi.org/10.3201/eid0702.010204
Chellat MF, Raguž L, Riedl R (2016) Targeting antibiotic resistance. Angew Chem Int Ed 55:6600–6626. https://doi.org/10.1002/anie.201506818
CRE CDC. (2020) Carbapenem-resistant Enterobacteriaceae (CRE). Centers for Disease Control and Prevention. https://www.cdc.gov/hai/organisms/cre/
Davies J, Davies D (2010) Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 74:417–433. https://doi.org/10.1128/MMBR.00016-10
Davin-Regli A, Pagès J (2015) Enterobacter aerogenes and Enterobacter cloacae; versatile bacterial pathogens confronting antibiotic treatment. Front Microbiol 6:1–10. https://doi.org/10.3389/fmicb.2015.00392
D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (2011) Antibiotic resistance is ancient. Nature 000:1–5. https://doi.org/10.1038/nature10388
Dellit TH, Owens RC, McGowan JE Jr et al (2007) Infectious diseases society of America and the society for healthcare epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44:159–177
Diancourt L, Passet V, Verhoef J, Grimont PAD, Brisse S (2005) Multilocus sequence typing of Klebsiella pneumoniae nosocomial isolates. J Clin Microbiol 43:4178–4182. https://doi.org/10.1128/JCM.43.8.4178-4182.2005
Dijkshoorn L, Nemec A, Seifert H (2007) An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nature 5:939–951. https://doi.org/10.1038/nrmicro1789
Dinges MM, Orwin PM, Schlievert PM (2000) Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 13:16–34. https://doi.org/10.1128/CMR.13.1.16
Enterobacteriaceae Pathogen Page. (2020) Carbapenem-Resistant Enterobacteriaceae Pathogen Page. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/CRE-508.pdf
ESBL Pathogen page. (2020) Extended-Spectrum Beta-lactamase (ESBL) producing Enterobacteriaceae pathogen page. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/esbl-508.pdf
Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavromanolakis E, Samonis G (2010) Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob Agents 35:1–17. https://doi.org/10.1016/j.ijantimicag.2009.10.019
Fishman NO (2006) Impact of an antimicrobial stewardship program: clinical outcomes. Am J Med 119:S53–S61. https://doi.org/10.1016/j.ajic.2006.05.237
Fleming-Dutra KE, Hersh AL, Shapiro DJ et al (2016) Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 315:1864–1873. https://doi.org/10.1001/jama.2016.4151
Floris L, Cluck D, Singleton A (2020) Understanding antimicrobial resistance. U.S. Pharmacist 45:HS10–HS16
Frieri M, Kumar K, Boutin A (2017) Antibiotic Resistance. J Inf Secur 10:369–378. https://doi.org/10.1016/j.jiph.2016.08.007
Gasink LB, Edelstein PH, Lautenbach E, Synnestvedt M, Fishman NO (2009) Risk factors and clinical impact of Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae. Infect Control Hosp Epidemiol 30:1180–1185. https://doi.org/10.1086/648451
He Y, Tian J, Chen X, Sun W, Zhu H, Li Q, Lei L, Yao G, Xue Y, Wang J, Li H, Zhang Y (2016) Fungal naphtho-γ-pyrones: potent antibiotics for drug-resistant microbial pathogens. Nature 6:1–9. https://doi.org/10.1038/srep24291
Heikens E, Bonten MJM, Willems RJL (2007) Enterococcal surface protein Esp is important for biofilm formation of Enterococcus faecium E1162. J Bacteriol 189:8233–8240. https://doi.org/10.1128/JB.01205-07
Holmes AH, Moore LS, Sundsfjord A et al (2016) Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 387:176–187. https://doi.org/10.1016/S0140-6736(15)00473-0
Howard A, O’Donoghue M, Feeney A, Sleator RD (2012) Acinetobacter baumannii: an emerging opportunistic pathogen. Virulence 3:243–250. https://doi.org/10.4161/viru.19700
Hug JJ, Bader CD, Remškar M, Cirnski K, Müller R (2018) Concepts and methods to access novel antibiotics from Actinomycetes. Antibiotics 7:1–47. https://doi.org/10.3390/antibiotics7020044
Hutchings MI, Truman AW, Wilkinson B (2019) Antibiotics: past, present, and future. Curr Opin Microbiol 51:72–80. https://doi.org/10.1016/j.mib.2019.10.008
Kanj SS, Kanafani ZA (2011) Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-Spectrum β-lactamase–producing Enterobacteriaceae, Carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc 86:250–259. https://doi.org/10.4065/mcp.2010.0674
Khardori N, Stevaux C, Ripley K (2020) Antibiotics: from the beginning to the future: part I. Ind J Ped 87:39–42. https://doi.org/10.1007/s12098-019-03087-z
Kmietowicz Z (2017) Few novel antibiotics in the pipeline, WHO warns. BMJ 358:1. https://doi.org/10.1136/bmj.j4339
Koulenti, D, Xu, E, Mok, I Y S, Song, A, Karageorgopoulos, D E, Armaganidis, A, Lipman, J, & Tsiodras, S (2019) Novel antibiotics for multidrug-resistant gram-positive microorganisms. Microorganisms 7: 1–24. https://doi.org/10.3390/microorganisms7080270
Landwehr W, Wolf C, Wink J (2016) Actinobacteria and Myxobacteria-two of the Most important bacterial resources for novel antibiotics. Curr Top Microbiol Immunol 10:1–30. https://doi.org/10.1007/82_2016_503
Larone, D H (2011) Medically Important Fungi: A Guide to Identification. Washington, DC 5th ed.
Lesch JE (2007) The first miracle drugs: how the sulfa drugs transformed medicine. New York, New York
Maragakis LL, Perl TM (2008) Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Antimicrobial Resistance 46:1254–1263. https://doi.org/10.1086/529198
Martens E, Demain AI (2017) The antibiotic resistance crisis, with a focus on the United States. J Antibiotics 70:520–526. https://doi.org/10.1038/ja.2017.30
MDR Pseudomonas. (2020) Multidrug-resistant Pseudomonas aeruginosa pathogen page. Centers for Disease Control and Prevention https://www.cdc.gov/drugresistance/pdf/threats-report/pseudomonas-aeruginosa-508.pdf
Mezzatesta ML, Gona F, Stefani S (2012) Enterobacter cloacae complex: clinical impact and emerging antibiotic resistance. Future Microbiol 7:887–902. https://doi.org/10.2217/fmb.12.61
Michael CA, Dominey-Howes D, Labbate M (2014) The antimicrobial resistance crisis: causes, consequences, and management. Front Public Health 2:1–8. https://doi.org/10.3389/fpubh.2014.00145
Mohammad H, Mayhoub AS, Cushman M, Seleem MN (2015) Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant staphylococci. J Antibiot (Tokyo) 68:1–23. https://doi.org/10.1038/ja.2014.142
More SJ (2020) European perspectives on efforts to reduce antimicrobial usage in food animal production. Irish Vet J 73:2. https://doi.org/10.1186/s13620-019-0154-4
Moloney MG (2016) Natural products as a source for novel antibiotics. Trends Pharmacol Sci 37:689–701. https://doi.org/10.1016/j.tips.2016.05.001
MRSA. (2020) Methicillin-Resistant Staphylococcus aureus. Centers for Disease Control and Prevention. https://www.cdc.gov/mrsa/community/index.html
MRSA Pathogen page (2020). Methicillin-resistant Staphylococcus aureus pathogen page. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/mrsa-508.pdf
Munita JM, Arias CA (2016) Mechanisms of antibiotic resistance. Microbiol Spectr 4:1–37. https://doi.org/10.1128/microbiolspec.VMBF-0016-2015
Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, Cornaglia G, Garau J, Gniadkowski M, Hayden MK, Kumarasamy K, Livermore DM, Maya JJ, Nordmann P, Patel JB, Paterson DL, Pitout J, Villegas MV, Wang H, Woodford N, Quinn JP (2009) Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 13:785–796. https://doi.org/10.1016/S1473-3099(13)70190-7
Nordmann P, Cuzon G, Naas T (2009) The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 9:228–236. https://doi.org/10.1016/S1473-3099(09)70054-4
Obama White House Archives. (2015) https://obamawhitehouse.archives.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf accessed 8.26.2020
O’Driscoll T, Crank CW (2015) Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infection and Drug Resist 8:217–230. https://doi.org/10.2147/IDR.S54125
Peleg AY, Seifert H, Paterson DL (2008) Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 21:538–582. https://doi.org/10.1128/CMR.00058-07
Poole K (2011) Pseudomonas aeruginosa: resistance to the max. Front Microbiol 2:1–13. https://doi.org/10.3389/fmicb.2011.00065
Pseudomonas aeruginosa in Healthcare Settings. (2020) Centers for Disease Control and Prevention. https://www.cdc.gov/hai/organisms/pseudomonas.html“Pseudomonas CDC”
Quirós RE, Valerio M (2015) Are cultural determinants related with the use of antibiotics and emergence of multidrug resistant microorganisms? Open Forum Infect Dis 2:203. https://doi.org/10.1093/ofid/ofv133.80
Ramalingam AJ (2015) History of antibiotics and evolution of resistance. Research J Pharm and Tech 8:1719–1724. https://doi.org/10.5958/0974-360X.2015.00309.1
Romo AL, Quiroz R (2019) Appropriate use of antibiotics: an unmet need. Ther Adv Urol 11:9–17. https://doi.org/10.1177/1756287219832174
Sadikot RT, Blackwell TS, Christman JW, Prince AS (2005) Pathogen–host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 171:1210–1223. https://doi.org/10.1164/rccm.200408-1044SO
Santesmases MJ, Gradmann C (2011) Circulation of antibiotics: an introduction. Dynamis. 31:293–303. https://doi.org/10.4321/S0211-95362011000200002
Schultsz C, Geerlings S (2012) Plasmid-Mediated Resistance in Enterobacteriaceae. Drugs 72:1–16 0012-6667/12/0001-0001
Serpi M, Ferrari V, Pertusati F (2016) Nucleoside derived antibiotics to fight microbial drug resistance: new utilities for an established class of drugs? J Med Chem 59:10343–10382. https://doi.org/10.1021/acs.jmedchem.6b00325
Shang Z, Salim AA, Khalil Z, Bernhardt PV, Capon RJ (2016) Fungal biotransformation of tetracycline antibiotics. J Org Chem 81:6186–6194. https://doi.org/10.1021/acs.joc.6b01272
Silber J, Kramer A, Labes A, Tasdemir D (2016) From discovery to production: biotechnology of marine Fungi for the production of new antibiotics. Mar Drugs 14:1–20. https://doi.org/10.3390/md14070137
Small World Initiative (2020) https://www.smallworldinitiative.org Accessed 1/1/21
Strateva T, Yordanov D (2009) Pseudomonas aeruginosa – a phenomenon of bacterial resistance. J Med Microbiol 58:1133–1148. https://doi.org/10.1099/jmm.0.009142-0
Stierle AA, Stierle DB, Decato D, Priestley ND, Alverson JB, Hoody J, McGrath K, Klepacki D (2017) The Berkeleylactones, antibiotic macrolides from fungal Coculture. J Nat Prod 80:1150–1160. https://doi.org/10.1021/acs.jnatprod.7b00133
Tan SY, Tatsumura Y (2015) Alexander Fleming (1881–1955): Discoverer of Penicillin. Singapore Med. J 56:366–367. https://doi.org/10.11622/smedj.2015105
Vancomycin-resistant Enterococci (VRE) in Healthcare Settings. (2020) Centers for Disease Control and Prevention. https://www.cdc.gov/hai/organisms/vre/vre.html
VRE Pathogen Page. (2020) Vancomycin-Resistant Enterococci Pathogen Page. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/vre-508.pdf
Vuotto C, Longo F, Balice MP, Donelli G, Varaldo PE (2014) Antibiotic resistance related to biofilm formation in Klebsiella pneumoniae. Pathogens 3:743–758. https://doi.org/10.3390/pathogens3030743
Willems RJL, Top J, Santen M, Robinson DA, Coque TM, Baquero F, Grundmann H, Bonten MJM (2005) Global spread of Vancomycin-resistant Enterococcus faecium from distinct nosocomial genetic complex. Emerg Infect Dis 11:821–828. https://doi.org/10.3201/eid1106.041204
World Health Organization Antibiotic Resistance. (2020) World Health Organization. https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
Zaman SB, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain N (2017) A review on antibiotic resistance: alarm bells are ringing. Cureus. 1403:1–9. https://doi.org/10.7759/cureus.1403
Code availability
Not applicable.
Funding
support for this work was provided by the Ball State University (BSU) Department of Biology, and the BSU ASPiRE internal grants program.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics approval
Not applicable.
Consent for publication
Each author consents to publish, and affirms that this work has not been, nor is being, considered for publication elsewhere.
Consent to participate
Not applicable.
Conflicts of interest/competing interests
Not applicable.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Church, N.A., McKillip, J.L. Antibiotic resistance crisis: challenges and imperatives. Biologia 76, 1535–1550 (2021). https://doi.org/10.1007/s11756-021-00697-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11756-021-00697-x