Top

Intensive Care Medicine

Published in:

01-10-2017 | Review

Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach

Authors: Matteo Bassetti, Garyphallia Poulakou, Etienne Ruppe, Emilio Bouza, Sebastian J. Van Hal, Adrian Brink

Published in: Intensive Care Medicine | Issue 10/2017

Abstract

Purpose

To describe the current standards of care and major recent advances with regard to antimicrobial resistance (AMR) and to give a prospective overview for the next 30 years in this field.

Methods

Review of medical literature and expert opinion were used in the development of this review.

Results

There is undoubtedly a large clinical and public health burden associated with AMR in ICU, but it is challenging to quantify the associated excess morbidity and mortality. In the last decade, antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant Gram-negative bacteria (GNB), in particular carbapenem-resistant Pseudomonas aeruginosa (and other non-fermenting GNB), extended-spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE). The situation appears more optimistic currently for Gram-positive, where Staphylococcus aureus, and particularly methicillin-resistant S. aureus (MRSA), remains a cardinal cause of healthcare-associated infections worldwide. Recent advancements in laboratory techniques allow for a rapid identification of the infecting pathogen and antibiotic susceptibility testing. Their impact can be particularly relevant in settings with prevalence of MDR, since they may guide fine-tuning of empirically selected regimen, facilitate de-escalation of unnecessary antimicrobials, and support infection control decisions.

Currently, antibiotics are the primary anti-infective solution for patients with known or suspected MDR bacteria in intensive care. Numerous incentives have been provided to encourage researchers to work on alternative strategies to reverse this trend and to provide a means to treat these pathogens. Although some promising antibiotics currently in phase 2 and 3 of development will soon be licensed and utilized in ICU, the continuous development of an alternative generation of compounds is extremely important. There are currently several promising avenues available to fight antibiotic resistance, such as faecal microbiota, and phage therapy.

Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533. doi:10.1371/journal.pbio.1002533 CrossRefPubMedPubMedCentral

Bassetti M, Carnelutti A, Peghin M (2017) Patient specific risk stratification for antimicrobial resistance and possible treatment strategies in Gram-negative bacterial infections. Expert Rev Anti Infect Ther 15(1):55–65. doi:10.1080/14787210.2017.1251840 CrossRefPubMed

Ruppé É, Woerther PL, Barbier F (2015) Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care 5:21. doi:10.1186/s13613-015-0061-0 CrossRefPubMedCentral

Karanika S, Karantanos T, Arvanitis M et al (2016) Fecal colonization with extended spectrum beta-lactamase-producing Enterobacteriaceae and risk factors among healthy individuals: a systematic review and meta analysis. Clin Infect Dis 63:310–318CrossRefPubMed

Lee BY, Bartsch SM, Wong KF et al (2016) The potential trajectory of carbapenem-resistant Enterobacteriaceae, an emerging threat to health-care facilities, and the impact of the centers for disease control and prevention toolkit. Am J Epidemiol 183(5):471–479CrossRefPubMedPubMedCentral

Teerawattanapong N, Kengkla K, Dilokthornsakul P et al (2017) Prevention and control of multidrug-resistant Gram-negative bacteria in adult intensive care units: a systematic review and network meta-analysis. Clin Infect Dis 64:51–60CrossRef

Kanamori H, Parobek CM, Juliano JJ et al (2017) A prolonged outbreak of KPC-3-producing Enterobacter cloacae and Klebsiella pneumoniae driven by multiple mechanisms of resistance transmission at a large academic burn center. Antimicrob Agents Chemother 61(2):e01516-16. doi:10.1128/AAC.01516-1

Watkins RR, Smith TC, Bonomo RA (2016) On the path to untreatable infections: colistin use in agriculture and the end of “last resort” antibiotics. Expert Rev Anti Infect Ther 14:785–788. doi:10.1080/14787210.2016.1216314 CrossRefPubMed

Newitt S, Myles PR, Birkin JA et al (2015) Impact of infection control interventions on rates of Staphylococcus aureus bacteraemia in National Health Service acute hospitals, East Midlands, UK, using interrupted time-series analysis. J Hosp Infect 90:28–37. doi:10.1016/j.jhin.2014.12.016 CrossRefPubMed

10.

Grundmann H, Schouls LM, Aanensen DM et al (2014) The dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey. EuroSurveill 19:20987CrossRef

11.

Andrey DO, François P, Manzano C et al (2017) Antimicrobial activity of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2013–2014 at the Geneva University Hospitals. Eur J Clin Microbiol Infect Dis 36:343–350. doi:10.1007/s10096-016-2807-5 CrossRefPubMed

12.

Harbarth S, Samore MH (2005) Antimicrobial resistance determinants and future control. Emerg Infect Dis 11:794–800. doi:10.3201/eid1106.050167 CrossRefPubMedPubMedCentral

13.

van Bunnik BAD, Woolhouse MEJ (2017) Modelling the impact of curtailing antibiotic usage in food animals on antibiotic resistance in humans. R Soc Open Sci 4:161067. doi:10.1098/rsos.161067 CrossRefPubMedPubMedCentral

14.

Murray E, Holmes A (2012) Addressing healthcare-associated infections and antimicrobial resistance from an organizational perspective: progress and challenges. J Antimicrob Chemother 67[Suppl 1]:i29–i36. doi:10.1093/jac/dks200 CrossRefPubMed

15.

Brink AJ, Messina AP, Feldman C et al (2017) From guidelines to practice: a pharmacist-driven prospective audit and feedback improvement model for peri-operative antibiotic prophylaxis in 34 South African hospitals. J Antimicrob Chemother 72:1227–1234. doi:10.1093/jac/dkw523 PubMed

16.

Mellmann A, Bletz S, Boking T et al (2016) Real-time genome sequencing of resistant bacteria provides precision infection control in an institutional setting. J Clin Microbiol 54:2874–2881. doi:10.1128/JCM.00790-16 CrossRefPubMedPubMedCentral

17.

Bilinski J, Grzesiowski P, Muszynski J et al (2016) Fecal microbiota transplantation inhibits multidrug-resistant gut pathogens: preliminary report performed in an immunocompromised host. Arch Immunol Ther Exp 64:255–258CrossRef

18.

Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228CrossRefPubMed

19.

Cambray G, Sanchez-Alberola N et al (2014) Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons. Mob DNA 2011(2):6. doi:10.1186/1759-8753-2-6

20.

Girmenia C, Viscoli C, Piciocchi A et al (2015) Management of carbapenem resistant Klebsiella pneumoniae infections in stem cell transplant recipients: an Italian multidisciplinary consensus statement. Haematologica 100:e373–e376CrossRefPubMedPubMedCentral

21.

Patel R (2015) MALDI-TOF MS for the diagnosis of infectious diseases. Clin Chem 61:100–111CrossRefPubMed

22.

Bauer KA, Perez KK, Forrest GN et al (2014) Review of rapid diagnostic tests used by antimicrobial stewardship proGrams. Clin Infect Dis 59[Suppl 3]:S134–S145CrossRefPubMed

23.

Arena F, Viaggi B, Galli L et al (2015) Antibiotic susceptibility testing: present and future. Pediatr Infect Dis J 34:1128–1130CrossRefPubMed

24.

Banerjee R, Özenci V, Patel R (2016) Individualized approaches are needed for optimized blood cultures. Clin Infect Dis 63:1332–1339CrossRefPubMed

25.

Kostrzewa M, Sparbier K, Maier T et al (2013) MALDI-TOF MS: an upcoming tool for rapid detection of antibiotic resistance in microorganisms. Proteomics Clin Appl 7:767–778CrossRefPubMed

26.

Gaibani P, Galea A, Fagioni M et al (2016) Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of KPC-producing Klebsiella pneumoniae. J Clin Microbiol 54:2609–2613CrossRefPubMedPubMedCentral

27.

Salimnia H, Fairfax MR, Lephart PR et al (2016) Evaluation of the filmarray blood culture identification panel: results of a multicenter controlled trial. J Clin Microbiol 54:687–698CrossRefPubMedPubMedCentral

28.

Leone M, Malavieille F, Papazian L et al (2013) Routine use of Staphylococcus aureus rapid diagnostic test in patients with suspected ventilator-associated pneumonia. Crit Care 17(4):R170CrossRefPubMedPubMedCentral

29.

Dureau AF, Duclos G, Antonini F et al (2017) Rapid diagnostic test and use of antibiotic against methicillin-resistant Staphylococcus aureus in adult intensive care unit. Eur J Clin Microbiol Infect Dis 36(2):267–272CrossRefPubMed

30.

Cambau E, Durand-Zaleski I, Bretagne S et al (2017) Performance and economic evaluation of the molecular detection of pathogens for patients with severe infections: the EVAMICA open-label, cluster-randomised, interventional crossover trial. Intensive Care Med. doi:10.1007/s00134-017-4766-4 PubMed

31.

Schnabel RM, Boumans ML, Smolinska A et al (2015) Electronic nose analysis of exhaled breath to diagnose ventilator-associated pneumonia. Respir Med 109(11):1454–1459CrossRefPubMed

32.

Montuschi P, Mores N, Trove A et al (2013) The electronic nose in respiratory medicine. Respir Int Rev Thorac Dis 85(1):72e84

33.

Hanson CW 3rd, Thaler ER (2005) Electronic nose prediction of a clinical pneumonia score: biosensors and microbes. Anesthesiology 102(1):63–68CrossRefPubMed

34.

Hockstein NG, Thaler ER, Torigian D et al (2004) Diagnosis of pneumonia with an electronic nose: correlation of vapor signature with chest computed tomography scan findings. Laryngoscope 114(10):1701–1705CrossRefPubMed

35.

Bassetti M, De Waele JJ, Eggimann P et al (2015) Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria. Intensive Care Med 41(5):776–795. doi:10.1007/s00134-015-3719-z CrossRefPubMed

36.

Grall N, Massias L, Nguyen TT et al (2013) Oral DAV131, a charcoal-based adsorbent, inhibits intestinal colonization by β-lactam-resistant Klebsiella pneumoniae in cefotaxime-treated mice. Antimicrob Agents Chemother 57:5423–5425. doi:10.1128/AAC.00039-13 CrossRefPubMedPubMedCentral

37.

van Nood E, Vrieze A, Nieuwdorp M et al (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368:407–415. doi:10.1056/NEJMoa1205037 CrossRefPubMed

38.

Vollaard EJ, Clasener HA (1994) Colonization resistance. Antimicrob Agents Chemother 38:409–414CrossRefPubMedPubMedCentral

39.

Gosalbes MJ, Vázquez-Castellanos JF, Angebault C et al (2016) Carriage of Enterobacteria producing extended-spectrum β-lactamases and composition of the gut microbiota in an Amerindian Community. Antimicrob Agents Chemother 60:507–514. doi:10.1128/AAC.01528-15 CrossRef

40.

Donskey CJ, Chowdhry TK, Hecker MT et al (2000) Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 343:1925–1932. doi:10.1056/NEJM200012283432604 CrossRefPubMedPubMedCentral

41.

Bhalla A, Pultz NJ, Ray AJ et al (2003) Antianaerobic antibiotic therapy promotes overgrowth of antibiotic-resistant, Gram-negative bacilli and vancomycin-resistant enterococci in the stool of colonized patients. Infect Control Hosp Epidemiol 24:644–649. doi:10.1086/502267 CrossRefPubMed

42.

Bernard J, Armand-Lefèvre L, Luce E et al (2016) Impact of a short exposure to levofloxacin on faecal densities and relative abundance of total and quinolone-resistant Enterobacteriaceae. Clin Microbiol Infect 22(7):646.e1–4. doi:10.1016/j.cmi.2016.04.015

43.

Ruppé E, Lixandru B, Cojocaru R et al (2013) Relative fecal abundance of extended-spectrum-β-lactamase-producing Escherichia coli strains and their occurrence in urinary tract infections in women. Antimicrob Agents Chemother 57:4512–4517. doi:10.1128/AAC.00238-13 CrossRefPubMedPubMedCentral

44.

Woerther P-L, Micol J-B, Angebault C et al (2015) Monitoring antibiotic-resistant enterobacteria faecal levels is helpful in predicting antibiotic susceptibility of bacteraemia isolates in patients with haematological malignancies. J Med Microbiol 64:676–681. doi:10.1099/jmm.0.000078 CrossRefPubMed

45.

Ruppé E, Armand-Lefèvre L, Estellat C et al (2015) High rate of acquisition but short duration of carriage of multidrug-resistant Enterobacteriaceae after travel to the tropics. Clin Infect Dis 61:593–600. doi:10.1093/cid/civ333 CrossRefPubMed

46.

Weiss E, Zahar J-R, Lesprit P et al (2015) Elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams. Clin Microbiol Infect 21:649. doi:10.1016/j.cmi.2015.03.013 PubMed

47.

Kaleko M, Bristol JA, Hubert S et al (2016) Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe 41:58–67. doi:10.1016/j.anaerobe.2016.05.015 CrossRefPubMed

48.

de Gunzburg J, Ducher A, Modess C et al (2015) Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: a proof of concept study in healthy subjects. J Clin Pharmacol 55:10–16. doi:10.1002/jcph.359 CrossRefPubMed

49.

50.

Manges AR, Steiner TS, Wright AJ (2016) Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review. Infect Dis Lond Engl 48:587–592. doi:10.1080/23744235.2016.1177199 CrossRef

51.

Stool transplantation to reduce antibiotic resistance transmission. https://clinicaltrials.gov/ct2/show/NCT02461199. Accessed 10 July 2017

52.

Fecal transplant for MDR pathogen decolonization. https://clinicaltrials.gov/ct2/show/NCT02906774. Accessed 10 July 2017

53.

FMT for multidrug resistant organism reversal. https://clinicaltrials.gov/ct2/show/NCT02312986. Accessed 10 July 2017

54.

Biotherapy for MRSA enterocolitis. https://clinicaltrials.gov/ct2/show/NCT02390622. Accessed 10 July 2017

55.

FMT for MDRO colonization after infection in renal transplant recipients. https://clinicaltrials.gov/ct2/show/NCT02922816. Accessed 10 July 2017

56.

Khanna S, Pardi DS, Kelly CR et al (2016) A novel microbiome therapeutic increases gut microbial diversity and prevents recurrent Clostridium difficile infection. J Infect Dis 214:173–181. doi:10.1093/infdis/jiv766 CrossRefPubMed

57.

Bar-Yoseph H, Hussein K, Braun E (2016) Natural history and decolonization strategies for ESBL/carbapenem-resistant Enterobacteriaceae carriage: systematic review and meta-analysis. J Antimicrob Chemother 71:2729–2739CrossRefPubMed

58.

Buffie CG, Bucci V, Stein RR et al (2015) Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517:205–208. doi:10.1038/nature13828

59.

d’Herelle F (1931) Bacteriophage as a treatment in acute medical and surgical infections. Bull N Y Acad Med 7:329–348PubMedPubMedCentral

60.

Reardon S (2014) Phage therapy gets revitalized. Nat News 510:15. doi:10.1038/510015a CrossRef

61.

Wright A, Hawkins CH, Anggård EE et al (2009) A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34:349–357. doi:10.1111/j.1749-4486.2009.01973.x CrossRefPubMed

62.

Sarker SA, Sultana S, Reuteler G et al (2016) Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4:124–137. doi:10.1016/j.ebiom.2015.12.023 CrossRefPubMedPubMedCentral

63.

Standard treatment associated with phage therapy versus placebo for diabetic foot ulcers infected by S. aureus. https://clinicaltrials.gov/ct2/show/NCT02664740. Accessed 10 July 2017

64.

Evaluation of phage therapy for the treatment of Escherichia coli and Pseudomonas aeruginosa wound infections in burned patients. https://clinicaltrials.gov/ct2/show/NCT02116010. Accessed 10 July 2017

65.

Verbeken G, De Vos D, Vaneechoutte M et al (2007) European regulatory conundrum of phage therapy. Future Microbiol 2:485–491. doi:10.2217/17460913.2.5.485 CrossRefPubMed

66.

Bikard D, Euler CW, Jiang W et al (2014) Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. Nat Biotechnol 32:1146–1150. doi:10.1038/nbt.3043 CrossRefPubMedPubMedCentral

67.

Jun SY, Jung GM, Yoon SJ et al (2014) Preclinical safety evaluation of intravenously administered SAL200 containing the recombinant phage endolysin SAL-1 as a pharmaceutical ingredient. Antimicrob Agents Chemother 58:2084–2088. doi:10.1128/AAC.02232-13 CrossRefPubMedPubMedCentral

68.

Jun SY, Jung GM, Yoon SJ et al (2013) Antibacterial properties of a pre-formulated recombinant phage endolysin, SAL-1. Int J Antimicrob Agents 41:156–161. doi:10.1016/j.ijantimicag.2012.10.01 CrossRefPubMed

69.

Czaplewski L, Bax R, Clokie M et al (2016) Alternatives to antibiotics—a pipeline portfolio review. Lancet Infect Dis 16:239–251. doi:10.1016/S1473-3099(15)00466-1 CrossRefPubMed

70.

Mellata M, Mitchell NM, Schödel F et al (2016) Novel vaccine antigen combinations elicit protective immune responses against Escherichia coli sepsis. Vaccine 34:656–662. doi:10.1016/j.vaccine.2015.12.014 CrossRefPubMed

71.

Cywes-Bentley C, Skurnik D, Zaidi T et al (2013) Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens. Proc Natl Acad Sci USA 110:E2209–E2218. doi:10.1073/pnas.1303573110 CrossRefPubMedPubMedCentral

72.

Warrener P, Varkey R, Bonnell JC et al (2014) A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models. Antimicrob Agents Chemother 58:4384–4391. doi:10.1128/AAC.02643-14 CrossRefPubMedPubMedCentral

73.

Hua L, Hilliard JJ, Shi Y et al (2014) Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia. Antimicrob Agents Chemother 58:1108–1117. doi:10.1128/AAC.02190-13 CrossRefPubMedPubMedCentral

74.

Skurnik D, Roux D, Pons S et al (2016) Extended-spectrum antibodies protective against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 71:927–935. doi:10.1093/jac/dkv448 CrossRefPubMedPubMedCentral

75.

Lowy I, Molrine DC, Leav BA et al (2010) Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362:197–205. doi:10.1056/NEJMoa0907635 CrossRefPubMed

76.

Cdiffense: Clostridium difficile vaccine trial. http://www.cdiffense.org/. Accessed 10 July 2017

77.

Skurnik D, Cywes-Bentley C, Pier GB (2016) The exceptionally broad-based potential of active and passive vaccination targeting the conserved microbial surface polysaccharide PNAG. Expert Rev Vaccines 15:1041–1053. doi:10.1586/14760584.2016.1159135 CrossRefPubMedPubMedCentral

78.

Shu M-H, MatRahim N, NorAmdan N et al (2016) An Inactivated Antibiotic-Exposed Whole-Cell Vaccine Enhances bactericidal activities against multidrug-resistant Acinetobacter baumannii. Sci Rep 6:22332. doi:10.1038/srep22332 CrossRefPubMedPubMedCentral

79.

AMR Review. https://amr-review.org/Publications. Accessed 23 Jan 2017

80.

Köhler T, Perron GG, Buckling A et al (2010) Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa. PLoS Pathog 6:e1000883. doi:10.1371/journal.ppat.1000883 CrossRefPubMedPubMedCentral

81.

van Delden C, Köhler T, Brunner-Ferber F et al (2012) Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial. Intensive Care Med 38:1118–1125. doi:10.1007/s00134-012-2559-3 CrossRefPubMed

82.

Crowther GS, Baines SD, Todhunter SL et al (2013) Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection. J Antimicrob Chemother 68:168–176. doi:10.1093/jac/dks359 CrossRefPubMed

Title: Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach
Authors: Matteo Bassetti
Garyphallia Poulakou
Etienne Ruppe
Emilio Bouza
Sebastian J. Van Hal
Adrian Brink
Publication date: 01-10-2017
Publisher: Springer Berlin Heidelberg
Published in: Intensive Care Medicine / Issue 10/2017
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-017-4878-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach

Abstract

Purpose

Methods

Results

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Please log in to get access to this content

Other articles of this Issue 10/2017

The ten pressures of the respiratory system during assisted breathing

Optimal timing of renal replacement therapy in patients with acute kidney injury in the context of sepsis

What does it mean for a critically ill patient to fare well?

Is the literature inconclusive about the harm of HES? We are not sure

Intensive care medicine in 2050: precision medicine

Is the literature inconclusive about the harm from HES? No