Abstract
Nosocomial outbreaks of bacteria are well documented. Based on these incidents, and the heavy usage of antibiotics in hospitals, it has been assumed that antibiotic resistance evolves in hospital environments. To test this assumption, we studied resistance phenotypes of bacteria collected from patient isolates at a community hospital over a 2.5-year period. A graphical model analysis shows no association between resistance and patient information other than time of arrival. This allows us to focus on time-course data. We introduce a hospital transmission model, based on negative binomial delay. Our main contribution is a statistical hypothesis test called the Nosocomial Evolution of Resistance Detector (NERD). It calculates the significance of resistance trends occurring in a hospital. It can inform hospital staff about the effects of various practices and interventions, can help detect clonal outbreaks, and is available as an R package. We applied the NERD method to each of the 16 antibiotics in the study via 16 hypothesis tests. For 13 of the antibiotics, we found that the hospital environment had no significant effect on the evolution of resistance; the hospital is merely a piece of the larger picture. The p-values obtained for the other three antibiotics (cefepime, ceftazidime, and gentamicin) indicate that particular care should be taken in hospital practices with these antibiotics. One of the three, ceftazidime, was significant after accounting for multiple hypotheses, indicating a trend of decreased resistance for this drug.
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References
Alfredson DA, Korolik V (2007) Antibiotic resistance and resistance mechanisms in Campylobacter jejuni and Campylobacter coli. FEMS Microbiol Lett 277(2):123–132
Altunsoy A, Aypak C, Azap A, Ergonul O, Balik I (2011) The impact of a nationwide antibiotic restriction program on antibiotic usage and resistance against nosocomial pathogens in Turkey. Int J Med Sci 8(4):339–344
Ambrose PG, Bhavnani SM, Jones RN (2003) Pharmacokinetics-pharmacodynamics of cefepime and piperacillin-tazobactam against Escherichia coli and Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases: report from the ARREST program. Antimicrob Agents Chemother 47(5):1643–1646
Appelbaum PC (2006) The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. Clin Microbiol Infect 12(Suppl 1):16–23
Arena F, Giani T, Becucci E, Conte V, Zanelli G, D’Andrea MM, Buonocore G, Bagnoli F, Zanchi A, Montagnani F, Rossolini GM (2013) Large oligoclonal outbreak due to Klebsiella pneumoniae ST14 and ST26 producing the FOX-7 AmpC beta-lactamase in a neonatal intensive care unit. J Clin Microbiol 51(12):4067–4072
Austin DJ, Anderson RM (1999) Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models. Philos Trans R Soc Lond B Biol Sci 354(1384):721–738
Bailar JC 3rd, Travers K (2002) Review of assessments of the human health risk associated with the use of antimicrobial agents in agriculture. Clin Infect Dis 34(Suppl 3):S135–143
Bobenchik AM, Deak E, Hindler JA, Charlton CL, Humphries RM (2015) Performance of Vitek 2 for antimicrobial susceptibility testing of Enterobacteriaceae with Vitek 2 (2009 FDA) and 2014 CLSI breakpoints. J Clin Microbiol 53(3):816–823
Brown EM, Nathwani D (2005) Antibiotic cycling or rotation: a systematic review of the evidence of efficacy. J Antimicrob Chemother 55(1):6–9
Bush K (2010) Alarming beta-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol 13(5):558–564
Bush K (2013) Proliferation and significance of clinically relevant beta-lactamases. Ann N Y Acad Sci 1277:84–90
Carrer A, Lassel L, Fortineau N, Mansouri M, Anguel N, Richard C, Nordmann P (2009) Outbreak of CTX-M-15-producing Klebsiella pneumoniae in the intensive care unit of a French hospital. Microb Drug Resist 15(1):47–54
Casewell M, Friis C, Marco E, McMullin P, Phillips I (2003) The European ban on growth-promoting antibiotics and emerging consequences for human and animal health. J Antimicrob Chemother 52(2):159–161
Doi Y, Paterson DL, Adams-Haduch JM, Sidjabat HE, O’Keefe A, Endimiani A, Bonomo RA (2009) Reduced susceptibility to cefepime among Escherichia coli clinical isolates producing novel variants of CMY-2 beta-lactamase. Antimicrob Agents Chemother 53(7):3159–3161
Doscher E, Kim J, Mira PM, Chan P, Camps M, Lowe T, Barlow M (2016) Molecular surveillance of a small community hospital.’
Forslund K, Sunagawa S, Kultima JR, Mende DR, Arumugam M, Typas A, Bork P (2013) Country-specific antibiotic use practices impact the human gut resistome. Genome Res 23(7):1163–1169
Gandon S, Day T, Metcalf CJ, Grenfell BT (2016) Forecasting epidemiological and evolutionary dynamics of infectious diseases. Trends Ecol Evol 31(10):776–788
Garcia-Fernandez A, Villa L, Carta C, Venditti C, Giordano A, Venditti M, Mancini C, Carattoli A (2012) Klebsiella pneumoniae ST258 producing KPC-3 identified in Italy carries novel plasmids and OmpK36/OmpK35 porin variants. Antimicrob Agents Chemother 56(4):2143–2145
Giani T, Arena F, Vaggelli G, Conte V, Chiarelli A, Henrici De Angelis L, Fornaini R, Grazzini M, Niccolini F, Pecile P, Rossolini GM (2015) Large nosocomial outbreak of colistin-resistant, carbapenemase-producing klebsiella pneumoniae traced to clonal expansion of an mgrB deletion mutant. J Clin Microbiol 53(10):3341–3344
Goossens H (2009) Antibiotic consumption and link to resistance. Clin Microbiol Infect 15(Suppl 3):12–15
Hamidian M, Hall RM (2014) Resistance to third-generation cephalosporins in Acinetobacter baumannii due to horizontal transfer of a chromosomal segment containing ISAba1-ampC. J Antimicrob Chemother 69(10):2865–2866
Højsgaard S, Edwards D, Lauritzen SL (2012) Graphical models with R. Springer, New York
Kahlmeter G, Ahman J, Matuschek E (2015) Antimicrobial resistance of escherichia coli causing uncomplicated urinary tract infections: a European update for 2014 and comparison with 2000 and 2008. Infect Dis Ther 4(4):417–423
Kassis-Chikhani N, Decre D, Gautier V, Burghoffer B, Saliba F, Mathieu D, Samuel D, Castaing D, Petit JC, Dussaix E, Arlet G (2006) First outbreak of multidrug-resistant Klebsiella pneumoniae carrying blaVIM-1 and blaSHV-5 in a French university hospital. J Antimicrob Chemother 57(1):142–145
Lauritzen SL (2004) Graphical models. Oxford University, Oxford
Lipsitch M, Bergstrom CT, Levin BR (2000) The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc Natl Acad Sci USA 97(4):1938–1943
Lloyd-Smith JO (2007) Maximum likelihood estimation of the negative binomial dispersion parameter for highly overdispersed data, with applications to infectious diseases. PLoS One 2(2):e180
Lopez-Camacho E, Gomez-Gil R, Tobes R, Manrique M, Lorenzo M, Galvan B, Salvarelli E, Moatassim Y, Salanueva IJ, Pareja E, Codoner FM, Alvarez-Tejado M, Garcillan-Barcia MP, De la Cruz F, Mingorance J (2014) Genomic analysis of the emergence and evolution of multidrug resistance during a Klebsiella pneumoniae outbreak including carbapenem and colistin resistance. J Antimicrob Chemother 69(3):632–636
Machado E, Coque TM, Canton R, Sousa JC, Peixe L (2013) Commensal Enterobacteriaceae as reservoirs of extended-spectrum beta-lactamases, integrons, and sul genes in Portugal. Front Microbiol 4:80
Mansouri M, Ramazanzadeh R, Norabadi P (2011) Cefepime resistance and associated risk factors among Escherichia coli strains isolated from clinical specimens. Chemotherapy 57(2):134–137
Medeiros AA (1997) Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics. Clin Infect Dis 24(Suppl 1):S19–45
Mira PM, Crona K, Greene D, Meza JC, Sturmfels B, Barlow M (2015) Rational design of antibiotic treatment plans: a treatment strategy for managing evolution and reversing resistance. PLoS One 10(5):e0122283
Navas E (2002) Problems associated with potential massive use of antimicrobial agents as prophylaxis or therapy of a bioterrorist attack. Clin Microbiol Infect 8(8):534–539
Pitout JD, Gregson DB, Church DL, Elsayed S, Laupland KB (2005) Community-wide outbreaks of clonally related CTX-M-14 beta-lactamase-producing Escherichia coli strains in the Calgary health region. J Clin Microbiol 43(6):2844–2849
Poirier C, Dinh A, Salomon J, Grall N, Andremont A, Bernard L (2015) Antibiotic cycling prevents urinary tract infections in spinal cord injury patients and limits the emergence of multidrug resistant organism. J Infect 71(4):491–493
R Core Team (2013) R: A language and environment for statistical computing. Austria, R Foundation for Statistical Computing, Vienna
Redgrave LS, Sutton SB, Webber MA, Piddock LJ (2014) Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol 22(8):438–445
Rodriguez-Rojas A, Rodriguez-Beltran J, Couce A, Blazquez J (2013) Antibiotics and antibiotic resistance: a bitter fight against evolution. Int J Med Microbiol 303(6–7):293–297
Snitkin ES, Zelazny AM, Thomas PJ, Stock F, Group NCSP, Henderson DK, Palmore TN, Segre JA (2012) Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci Transl Med 4(148):147ra116
Tzouvelekis LS, Tzelepi E, Tassios PT, Legakis NJ (2000) CTX-M-type beta-lactamases: an emerging group of extended-spectrum enzymes. Int J Antimicrob Agents 14(2):137–142
Venables WN, Ripley BD (2002) Modern applied statistics with S. Springer, New York
Wang P, Hu F, Xiong Z, Ye X, Zhu D, Wang YF, Wang M (2011) Susceptibility of extended-spectrum-beta-lactamase-producing Enterobacteriaceae according to the new CLSI breakpoints. J Clin Microbiol 49(9):3127–3131
Woodford N, Ward ME, Kaufmann ME, Turton J, Fagan EJ, James D, Johnson AP, Pike R, Warner M, Cheasty T, Pearson A, Harry S, Leach JB, Loughrey A, Lowes JA, Warren RE, Livermore DM (2004) Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum beta-lactamases in the UK. J Antimicrob Chemother 54(4):735–743
World Health Organization. (2002) Impacts of Antimicrobial Growth Promoter Termination in Denmark, from apps.who.int/iris/bitstream/10665/68357/1/WHO_CDS_CPE_ZFK_2003.1.pdf
Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, Cavalcoli JD, VanDevanter DR, Murray S, Li JZ, Young VB, LiPuma JJ (2012) Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci USA 109(15):5809–5814
Acknowledgements
We thank Dignity Health Mercy Medical Center and especially Robert Salcido, Glenn Bruss, and Robert Streeter for providing clinical data and strains. We thank Joe Kileel for help organizing the data and defining the final data set. We are grateful to Lior Pachter for very helpful comments on an earlier version of this paper. This study was funded by CITRIS Seed Grant #: 2015-324. Anna Seigal and Bernd Sturmfels were supported by the National Science Foundation (DMS-1419018).
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Seigal, A., Mira, P., Sturmfels, B. et al. Does Antibiotic Resistance Evolve in Hospitals?. Bull Math Biol 79, 191–208 (2017). https://doi.org/10.1007/s11538-016-0232-7
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DOI: https://doi.org/10.1007/s11538-016-0232-7