Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

Non-linear significant relationship between use of glycopeptides and isolation of vancomycin-resistant Enterococcus species in a university hospital setting

Non-linear significant relationship between use of glycopeptides and isolation of... Background: Emergence of colonization and infection with vancomycin-resistant enterococci (VRE) has become a worldwide challenge. To investigate whether the increasing incidence of VRE isolation can be correlated with use of glycopeptides in the hospital setting, we conducted a hospital-wide two-year study in the university hospital of Vienna. Methods: Within the period from January 2011 through December 2012 all patients with isolation of invasive or non-invasive VRE were retrospectively included. Specialty-specific data concerning the consumption of vancomycin and teicoplanin, fluoroquinolones and third generation cephalosporins in defined daily doses (DDDs) from June 2010 through May 2012 were extracted from the hospital pharmacy computer system. To assess the relationship between the usage of those antibiotics and the incidence of VRE (VRE-rate per 10 000 patients) a Poisson regression was performed. Findings: In the study period 266 patients were colonized or infected with VRE. Specialty-specific VRE isolation was as follows: general surgical units (44 patients), bone marrow transplant unit (35 patients), general medical units (33 patients), cardiothoracic surgery (27 patients), nephrology (26 patients), haematooncology (22 patients), gastroenterology (17 patients), urology (17 patients), and the infectious diseases unit (11 patients). Hospital-wide consumption of glycopeptides was higher for teicoplanin than for vancomycin (26 242 versus 8677 DDDs). Specialty-specific VRE incidence significantly increased with the use of glycopeptides, fluoroquinolones or third generation cephalosporins (p < 0.001). The results of the Poisson regression for vancomycin (p = 0.0018) and teicoplanin (p < 0.0001) separately were both highly significant. Spearman’s correlation coefficient indicated a strong correlation between the two variables (rho = 0.8). Conclusion: Overall usage of glycopeptides, fluoroquinolones or third generation cephalosporins contributed to the emergence of VRE in the hospital setting. Keywords: Glycopeptides, Fluoroquinolones, Third generation cephalosporins, Enterococcus faecium, Enterococcus faecalis * Correspondence: elisabeth.presterl@meduniwien.ac.at Department of Hospital Epidemiology and Infection Control, Medical University of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria Full list of author information is available at the end of the article © 2015 Forstner et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 2 of 7 Introduction was included only in case of material from primary ster- Enterococci are part of the gastrointestinal bacterial flora ile body sites. Enterococcus faecalis was identified by the and urogenital mucosa in healthy humans, but important formation of black colonies on tellurit agar plates, while nosocomial pathogens in a variety of invasive infections other Enterococcus species were identified by VITEK 2 including endocarditis, bloodstream infections, wound GP (bioMérieux) or MALDI-TOF mass spectrometry infections, and meningitis [1, 2]. (Bruker Daltonics GmbH, Bremen, Germany). If the Colonization and infection with vancomycin-resistant vancomycin and teicoplanin disc diffusion test according enterococci (VRE), predominantly but not exclusively with to the current version of the EUCAST methodology [10] Enterococcus faecium, are emerging worldwide [3–5]. The displayed glycopeptide resistance, E tests for both sub- causes are multifactorial, but excessive usage of glycopep- stances following the manufacturer’s instructions (bio- tides in animal husbandry and in human medicine may Mérieux) were performed. Presence of the VanA or further enhance the incidence of VRE [6, 7]. According VanB phenotype was deduced from the observed min- to the European Antimicrobial Resistance Surveillance imal inhibitory concentrations of vancomycin and teico- Report (EARS), the incidence of invasive Austrian iso- planin [11]. lates of vancomycin-resistant E. faecium increased from For avoidance of nosocomial transmissions, a targeted 1.8 % in 2008 to 5.9 % in 2013 [5, 8]. Other neighbouring risk adjusted screening policy with subsequent isolation countries such as Germany reported an even more dra- (single room or, if not possible, strict contact isolation) matic increase to 14.5 % of the proportion of invasive of patients colonized or infected with VRE is imple- vancomycin-resistant E. faecium [8]. mented at our institution. The aim of the present study was to investigate whether this increasing incidence of VRE isolation in Antibiotic usage our patients can be correlated with use of glycopeptides Glycopeptides, fluoroquinolones and third generation in the hospital setting. cephalosporins were classified according to the anatomical therapeutic chemical (ATC) system. In our institution the Methods following agents were used: vancomycin, teicoplanin, Study location and study population ciprofloxacin, levofloxacin, moxifloxacin, ceftriaxone, cef- The General Hospital of Vienna, Austria, is a 2133–bed otaxime, ceftazidime and cefixime. Hospital-wide and central hospital and the seat of the clinics of the Medical specialty-specific data on consumption of those antibiotics University of Vienna. Each year more than 100 000 were derived from the hospital pharmacy for the period patients receive inpatient treatment and a total of 1.25 from June 1, 2010 through and including May 31, 2012. million patients attend the outpatient clinics [9]. The Antibiotic usage was measured in defined daily doses university hospital is a renowned centre for solid (DDDs). In accordance with the ATC classification/DDD organ transplantation - Europe-wide leading in lung index 2013, the glycopeptide DDDs used were vanco- transplantation-and haematooncology. After the study mycin 2 g and teicoplanin 0.4 g, the fluoroquinolone was approved by the local ethics committee of the Medical DDDs used were levofloxacin 0.5 g, moxifloxacin 0.4 g University of Vienna (EC No. 2004/2013), we retrospect- and ciprofloxacin 1 g for oral administration or 0.5 g for ively included all patients in the hospital with any isolation parenteral administration, the third generation cephalo- of VRE during the period of January 1, 2011 through sporin DDDs used were ceftriaxone 2 g, cefotaxime 4 g, December 31, 2012. The study was retrospective and ceftazidime 4 g and cefixime 0.4 g [12]. observational with no interventions, therefore the need for informed consent was waived. The numbers of pa- Statistical analysis tients colonized or infected with VRE isolated from sur- In order to assess the relationship between the antibiotic veillance cultures and invasive cultures (from blood or usage and the incidence of VRE (VRE-rate per 10 000 other normally sterile body sites) were obtained from the patients), a Poisson regression model was fitted with the hospital’s database (RDA/Archimed ALERT, Department number of VRE-positive patients as the dependent vari- of Infection Control and Hospital Epidemiology) for able, logarithm of the mean usage of glycopeptides, patients with multi-drug resistant pathogens. fluoroquinolones or third generation cephalosporins as In case of VRE screening selective enrichment media independent variable and the total number of patients in (brain-heart infusion containing vancomycin and ceftazi- each unit as an offset. dime as well as chromID VRE, bioMérieux, Marcy As in a previous surveillance study by Kritsotakis et al. l’Etoile, France) were inoculated, while clinical samples a dynamic relationship between antimicrobial use of gly- for non-targeted culture were processed following stand- copeptides and an increase in the VRE incidence was ard procedures dependent on the type of specimen, i.e. identified with average delays between 2 and 6 months non-selective enrichment broth (brain-heart infusion) [13], we selected to compare time-delayed 2-year periods Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 3 of 7 of 6 months between antibiotic consumption and VRE were general surgical (44 patients), followed by the bone isolation. marrow transplantation (BMT) unit (35 patients), general Model diagnostics revealed that the non-transformed medicine (33 patients), cardiothoracic surgery (27 patients), mean usage did not fit the data well due to a high lever- nephrology (26 patients), haematooncology (22 patients), age point (influential point). Further to control for pos- gastroenterology (17 patients), urology (17 patients), and sible violations of the distribution assumptions, White’s the infectious diseases unit (11 patients) (Fig. 1). robust covariance estimator was calculated [14]. Z-tests The total hospital-wide numbers of antimicrobial were performed using the coefficients of the Poisson DDDs were as follows: model and the robust standard errors. P-values of ≤0.05 8677 for vancomycin, 26 242 for teicoplanin, 64 788 were considered to be statistically significant. All calcula- for ciprofloxacin, 32 264 for levofloxacin, 22 155 for tions were performed using R 3.0.2. moxifloxacin, 13 080 for ceftriaxone, 10 910 for cefotaxime, 6958 for ceftazidime, and 1651 for cefixime. Total con- Results sumption of glycopeptides, fluoroquinolones and third In the pre-study period from 2004 through 2010, a con- generation cephalosporins per specialty is shown in Fig. 2. tinuous increase in the number of VRE-positive patients Specialty-specific VRE incidence significantly increased was detected in the hospital, from a single documented with the use of glycopeptides, fluoroquinolones or third case of VRE in 2004 (corresponding to 0.001 patients generation cephalosporins (p < 0.001). Figure 3 shows a per 10 000 admissions), 67 cases of VRE in 2007 (corre- non-linear relationship with a dramatic increase in the sponding to 0.066 patients per 10 000 admissions) to a incidence of VRE with high glycopeptide, fluoroquinolone peak of 129 VRE-positive patients in 2010 (correspond- or third generation cephalosporin usage. The results of ing to 0.125 patients per 10 000 admissions). the Poisson regression for vancomycin (p = 0.0018) and During the subsequent two-year study period, a total teicoplanin separately (p < 0.0001) were both highly sig- of 99 635 patients were admitted to the hospital in 2011 nificant. Spearman’s correlation coefficient indicated a and 102 083 in 2012. The overall VRE incidence was strong correlation between the two variables (rho = 0.8). 0.131 per 10 000 admissions in the first year and 0.156 per 10 000 admissions in the second year. Among these Discussion patients, 261 patients were colonized or infected with a In the present study we identified a positive non-linear single VRE species (E. faecium, n = 258; E. faecalis,n=3), relationship between the specialty-specific isolation of and five patients were colonized with 2 VRE species VRE and total glycopeptide, fluoroquinolone or third (E. faecium, n=5; E. faecalis,n=4; E. raffinosus,n=1). generation cephalosporin consumption. Most patients The VanA phenotype was detected in the VRE isolates of with VRE-positive cultures were simply colonized, but 234 (88 %) patients and VanB phenotype in 33 (12 %) 6.8 % experienced bloodstream infection caused by patients. vancomycin-resistant E. faecium. Despite less clinical As shown in the Table 1, most patients were only colo- relevance of VRE compared to infections caused by nized by non-invasive VRE-isolates, which were isolated methicillin-resistant Staphylococcus aureus (MRSA), from screening cultures (faeces or rectal swab, followed management of invasive VRE infections is challenging by skin swab, oropharyngeal swab). Among 87 patients because of limited treatment options. Furthermore, en- with proven VRE-infection, 18 patients developed VRE terococcal bacteraemia was associated with increased bacteraemia with E. faecium. risk of death in allogeneic haematopoietic stem cell A total of 201 patients were admitted to inpatient transplant recipients [15]. During a 7-year surveillance wards, 52 patients to intensive care units and 13 were study, a dynamic relationship was identified between outpatients. The specialties most frequently involved antimicrobial use of glycopeptides, fluoroquinolones, Table 1 Hospital-wide trends in colonizing and invasive vancomycin-resistant Enterococcus (VRE) species during the study period 2011 through 2012 Species Annual total no. (%) patients with VRE Annual no. (%) patients only colonized with VRE Annual no. (%) patients infected with VRE 2011 2012 2011 2012 2011 2012 Any Enterococcus sp. 123 (100) 143 (100) 87 (71) 92 (64) 36 (29) 51 (36) E. faecium 123 (100) 140 (98) 87 (71) 90 (63) 36 (29) 50 (35) E. faecalis 3 (2.4) 4 (2.8) 3 (2.4) 2 (1.4) 0 2 (1.4) E. raffinosus 1 (0.8) 0 1 (0.8) 0 0 0 In case of isolation of more than one Enterococcus spp. in one patient, the patient was only counted once for the category any Enterococcus sp. Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 4 of 7 a higher incidence of VRE-bloodstream infection and previ- ous hospital use of other, non-glycopeptide, antimicrobials Surgical units such as the third-generation cephalosporin ceftriaxone BMT unit [17]. In a recent systematic review it was not possible to General medical units Cardiothoracic surgery conclusively determine a potential role for reduction of Nephrology vancomycin use in controlling VRE [18]. But, in a retro- Haematooncology spective case–control study in a university hospital of Gastroenterology Korea, vancomycin use significantly prolonged the duration Urology Infectious Diseases of VRE carriage among intensive care patients already colo- Dermatology nized with vancomycin-resistant E. faecium [19]. However, Transplant unit because of the high tenacity of VRE in the environment, Trauma unit measures other than reduction of glycopeptide use, such as Neurology Psychiatry isolation of patients and enforced environmental cleaning, Paediatrics are necessary to control its spread [20]. Patients who are at Emergency risk are consequently screened at admittance and isolated Otorhinolaryngology in single rooms. We also hypothesize that in our hospital Gynaecology Ophthalmology the departments most frequently involved treat patients with chronic diseases for a long period of time, and VRE Total no. patients with VRE emerge due to glycopeptide use. Fig. 1 Specialty-specific isolation of VRE in the General Hospital of Vancomycin and teicoplanin are used therapeutically in Vienna during the two-year study period our hospital to treat invasive infections with gram-positive multi-drug resistant microorganisms or as empirical and extended-spectrum cephalosporins and an increase therapy in severe sepsis or septic shock in intensive care in the incidence of VRE, with average delays between 2 and immunosuppressed patients. During the period 2000 and 6 months [13]. In contrast, other studies do not report through 2011, vancomycin was used most frequently in such a direct relationship between glycopeptide use and our institution as first-line treatment in patients with VRE isolation [16] but have shown an association between MRSA bacteraemia, followed by teicoplanin [21]. Defined daily doses of antibiotics 0 10000 20000 30000 40000 Surgical units BMT unit General medical units Cardiothoracic Surgery Nephrology Haematooncology Gastroenterology Urology Infectious Diseases Dermatology Transplant unit Trauma unit Neurology Psychiatry Paediatrics Emergency Otorhinolaryngology Gynaecology Opththalmology Glycopeptides Fluoroquinolones 3rd gen cephalosporins Fig. 2 Specialty-specific usage of glycopeptides, fluoroquinolones and third generation cephalosporins in the General Hospital of Vienna during the period June 2010 to June 2012 Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 5 of 7 Fig. 3 Non-linear relationship between the usage of glycopeptides (a), fluoroquinolones (b) or third generation cephalosporins (c) and VRE-rate per 10 000 patients. The points indicate observations and the solid line the fit of the Poisson regression model Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 6 of 7 Furthermore, in patients with moderate to severe colitis References 1. Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin caused by Clostridium difficile, oral glycopeptides can resistance. Nat Rev Microbiol. 2012;10:266–78. promote acquisition of gastrointestinal VRE [22], whereas 2. Rivera AM, Boucher HW. Current concepts in antimicrobial therapy against the use of other oral antimicrobial agents against C. select gram-positive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. difficile, such as fidaxomicin, decrease the risk of VRE Mayo Clin Proc. 2011;86:1230–43. acquisition [23]. 3. Centers for Disease Control and Prevention. National Nosocomial Infections A limitation of our study was that we could not assess Surveillance (NNIS) System report, data summary from January 1990-May 1999. Am J Infect Control. 1999;27:520–32. the impact of oral versus intravenous use of glycopep- 4. McCracken M, Wong A, Mitchell R, et al. Molecular epidemiology of tides on the incidence of VRE separately. During the ob- vancomycin-resistant enterococcal bacteraemia: results from the Canadian servation period, only the intravenous formulations of Nosocomial Infection Surveillance Program, 1999–2009. J Antimicrob Chemother. 2013;68:1505–9. vancomycin and teicoplanin were provided for oral use, 5. European Centre for Disease Prevention and Control. Antimicrobial resistance because no oral formulations were available. surveillance in Europe 2011. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2012. 6. Patel R. Clinical impact of vancomycin-resistant enterococci. J Antimicrob Conclusions Chemother. 2003;51 Suppl S3:iii13–21. We demonstrated a positive non-linear relationship be- 7. Novais C, Freitas AR, Silveira E, Antunes P, Silva R, Coque TM, et al. Spread of multidrug-resistant Enterococcus to animals and humans: an underestimated tween the specialty-specific isolation of VRE and glycopep- role for the pig farm environment. J Antimicrob Chemother. 2013;68:2746–54. tide, fluoroquinolone or third generation cephalosporin 8. European Centre for Disease Prevention and Control. Antimicrobial resistance usage in the University Hospital of Vienna. Although VRE surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2014. incidence is increasing in our institution, the increase re- 9. Fehringer K. Annual Report 2011 Vienna General Hospital – Medical mains moderate, and is probably controlled by infection University Campus. http://www.akhwien.at/default.aspx?did=61147. control measures. Nevertheless, to minimize the spread of Accessed October 31, 2013. 10. European Committee on Antimicrobial Susceptibility Testing. glycopeptide-resistant Enterococcus species in the hospital Antimicrobial susceptibility testing EUCAST disk diffusion method. Vers. setting, the implementation of a program for prudent use 5.0, 2015 January 26. http://www.eucast.org/ast_of_bacteria/ of glycopeptides, fluoroquinolones and third generation disk_diffusion_methodology/. 11. Swenson JM, Patel JP, Jorgensen JH. Special phenotypic methods for cephalosporins is warranted. detecting antibacterial resistance. In: Murray PR et al. (eds.), Manual of th Clinical Microbiology, 9 edition, 2007; 1:21173–92. Competing interests 12. World Health Organization. Collaborating centre for drug statistics The authors declare that they have no competing interests. methodology. ATC/DDD Index 2013. http://www.whocc.no/atc_ddd_index/. Accessed December 20, 2012. 13. Kritsotakis EI, Christidou A, Roumbelaki M, Tselentis Y, Gikas A. The dynamic Authors’ contribution relationship between antibiotic use and the incidence of vancomycin-resistant CF, EP and WG designed the protocol of the study. DM, TW and MM provided Enterococcus: time-series modeling of 7-year surveillance data in a tertiary-care the microbiological data, the RDA/Archimed/Alert data and data on antimicrobial hospital. Clin Microbiol Infect. 2008;14:747–54. usage. DK performed the statistical analyses. CF prepared the present manuscript. 14. White H. A heteroskedasticity-consistent covariance matrix estimator and a MD, DM, WG and EP were major contributors in writing the manuscript. direct test for heteroskedasticity. Econometrica. 1980;48:817–38. All authors read and approved the final manuscript. 15. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, et al. Enterococcal bacteremia is associated with increased risk of mortality in Acknowledgments recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect The authors thank all colleagues in the Department of Hospital Epidemiology Dis. 2012;55:764–70. and Infection Control who routinely entered the surveillance data of patients 16. Peel T, Cheng AC, Spelman T, Huysmans M, Spelman D. Differing risk factors with positive VRE cultures into the RDA/Archimed Alert System of the General for vancomycin-resistant and vancomycin-sensitive enterococcal bacteraemia. Hospital of Vienna, Austria. Clin Microbiol Infect. 2012;18:388–94. 17. McKinnell JA, Kunz DF, Chamot E, Patel M, Shirley RM, Moser SA, et al. Association between vancomycin-resistant Enterococci bacteremia and Funding ceftriaxone usage. Infect Control Hosp Epidemiol. 2012;33:718–24. This work was supported by internal funding. 18. de Bruin MA, Riley LW. Does vancomycin prescribing intervention affect vancomycin-resistant enterococcus infection and colonization in hospitals? Author details A systematic review. BMC Infect Dis. 2007;7:24. Department of Medicine I, Division of Infectious Diseases and Tropical 19. Yoon YK, Lee SE, Lee J, Kim HJ, Kim JY, Park DW, et al. Risk factors for Medicine, Medical University of Vienna, Währinger Gürtel 18–20 1090, Vienna, prolonged carriage of vancomycin-resistant Enterococcus faecium among Austria. Center for Infectious Diseases and Infection Control, Jena University patients in intensive care units: a case–control study. J Antimicrob Chemother. Hospital, Jena, Germany. Department of Hospital Epidemiology and 2011;66:1831–8. Infection Control, Medical University of Vienna, Währinger Gürtel 18–20 1090, 20. Marcel JP, Alfa M, Baquero F, Etienne J, Goossens H, Harbarth S, et al. Vienna, Austria. Section for Medical Statistics, Medical University of Vienna, Healthcare-associated infections: think globally, act locally. Clin Microbiol Währinger Gürtel 18–20 1090, Vienna, Austria. Division of Clinical Infect. 2008;14:895–907. Microbiology, Department of Laboratory Medicine, Medical University of 21. Forstner C, Dungl C, Tobudic S, Mitteregger D, Lagler H, Burgmann H. Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. Hospital Pharmacy, Predictors of clinical and microbiological treatment failure in patients with General Hospital of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective Center of Medical Statistics, Informatics and Systems Intelligence, Medical cohort study in a region with low MRSA prevalence. Clin Microbiol Infect. University of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. 2013;19:E291–7. Received: 15 February 2015 Accepted: 24 May 2015 22. Shin JW, Yong D, Kim MS, Chang KH, Lee K, Kim JM, et al. Sudden increase of vancomycin-resistant enterococcal infections in a Korean tertiary care Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 7 of 7 hospital: possible consequences of increased use of oral vancomycin. J Infect Chemother. 2003;9:62–7. 23. Nerandzic MM, Mullane K, Miller MA, Babakhani F, Donskey CJ. Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection. Clin Infect Dis. 2012;55 Suppl 2:S121–6. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance & Infection Control Springer Journals

Non-linear significant relationship between use of glycopeptides and isolation of vancomycin-resistant Enterococcus species in a university hospital setting

Loading next page...
 
/lp/springer-journals/non-linear-significant-relationship-between-use-of-glycopeptides-and-tjI8Blu1eb

References (22)

Publisher
Springer Journals
Copyright
Copyright © 2015 by Forstner et al.
Subject
Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
eISSN
2047-2994
DOI
10.1186/s13756-015-0064-5
pmid
26078865
Publisher site
See Article on Publisher Site

Abstract

Background: Emergence of colonization and infection with vancomycin-resistant enterococci (VRE) has become a worldwide challenge. To investigate whether the increasing incidence of VRE isolation can be correlated with use of glycopeptides in the hospital setting, we conducted a hospital-wide two-year study in the university hospital of Vienna. Methods: Within the period from January 2011 through December 2012 all patients with isolation of invasive or non-invasive VRE were retrospectively included. Specialty-specific data concerning the consumption of vancomycin and teicoplanin, fluoroquinolones and third generation cephalosporins in defined daily doses (DDDs) from June 2010 through May 2012 were extracted from the hospital pharmacy computer system. To assess the relationship between the usage of those antibiotics and the incidence of VRE (VRE-rate per 10 000 patients) a Poisson regression was performed. Findings: In the study period 266 patients were colonized or infected with VRE. Specialty-specific VRE isolation was as follows: general surgical units (44 patients), bone marrow transplant unit (35 patients), general medical units (33 patients), cardiothoracic surgery (27 patients), nephrology (26 patients), haematooncology (22 patients), gastroenterology (17 patients), urology (17 patients), and the infectious diseases unit (11 patients). Hospital-wide consumption of glycopeptides was higher for teicoplanin than for vancomycin (26 242 versus 8677 DDDs). Specialty-specific VRE incidence significantly increased with the use of glycopeptides, fluoroquinolones or third generation cephalosporins (p < 0.001). The results of the Poisson regression for vancomycin (p = 0.0018) and teicoplanin (p < 0.0001) separately were both highly significant. Spearman’s correlation coefficient indicated a strong correlation between the two variables (rho = 0.8). Conclusion: Overall usage of glycopeptides, fluoroquinolones or third generation cephalosporins contributed to the emergence of VRE in the hospital setting. Keywords: Glycopeptides, Fluoroquinolones, Third generation cephalosporins, Enterococcus faecium, Enterococcus faecalis * Correspondence: elisabeth.presterl@meduniwien.ac.at Department of Hospital Epidemiology and Infection Control, Medical University of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria Full list of author information is available at the end of the article © 2015 Forstner et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 2 of 7 Introduction was included only in case of material from primary ster- Enterococci are part of the gastrointestinal bacterial flora ile body sites. Enterococcus faecalis was identified by the and urogenital mucosa in healthy humans, but important formation of black colonies on tellurit agar plates, while nosocomial pathogens in a variety of invasive infections other Enterococcus species were identified by VITEK 2 including endocarditis, bloodstream infections, wound GP (bioMérieux) or MALDI-TOF mass spectrometry infections, and meningitis [1, 2]. (Bruker Daltonics GmbH, Bremen, Germany). If the Colonization and infection with vancomycin-resistant vancomycin and teicoplanin disc diffusion test according enterococci (VRE), predominantly but not exclusively with to the current version of the EUCAST methodology [10] Enterococcus faecium, are emerging worldwide [3–5]. The displayed glycopeptide resistance, E tests for both sub- causes are multifactorial, but excessive usage of glycopep- stances following the manufacturer’s instructions (bio- tides in animal husbandry and in human medicine may Mérieux) were performed. Presence of the VanA or further enhance the incidence of VRE [6, 7]. According VanB phenotype was deduced from the observed min- to the European Antimicrobial Resistance Surveillance imal inhibitory concentrations of vancomycin and teico- Report (EARS), the incidence of invasive Austrian iso- planin [11]. lates of vancomycin-resistant E. faecium increased from For avoidance of nosocomial transmissions, a targeted 1.8 % in 2008 to 5.9 % in 2013 [5, 8]. Other neighbouring risk adjusted screening policy with subsequent isolation countries such as Germany reported an even more dra- (single room or, if not possible, strict contact isolation) matic increase to 14.5 % of the proportion of invasive of patients colonized or infected with VRE is imple- vancomycin-resistant E. faecium [8]. mented at our institution. The aim of the present study was to investigate whether this increasing incidence of VRE isolation in Antibiotic usage our patients can be correlated with use of glycopeptides Glycopeptides, fluoroquinolones and third generation in the hospital setting. cephalosporins were classified according to the anatomical therapeutic chemical (ATC) system. In our institution the Methods following agents were used: vancomycin, teicoplanin, Study location and study population ciprofloxacin, levofloxacin, moxifloxacin, ceftriaxone, cef- The General Hospital of Vienna, Austria, is a 2133–bed otaxime, ceftazidime and cefixime. Hospital-wide and central hospital and the seat of the clinics of the Medical specialty-specific data on consumption of those antibiotics University of Vienna. Each year more than 100 000 were derived from the hospital pharmacy for the period patients receive inpatient treatment and a total of 1.25 from June 1, 2010 through and including May 31, 2012. million patients attend the outpatient clinics [9]. The Antibiotic usage was measured in defined daily doses university hospital is a renowned centre for solid (DDDs). In accordance with the ATC classification/DDD organ transplantation - Europe-wide leading in lung index 2013, the glycopeptide DDDs used were vanco- transplantation-and haematooncology. After the study mycin 2 g and teicoplanin 0.4 g, the fluoroquinolone was approved by the local ethics committee of the Medical DDDs used were levofloxacin 0.5 g, moxifloxacin 0.4 g University of Vienna (EC No. 2004/2013), we retrospect- and ciprofloxacin 1 g for oral administration or 0.5 g for ively included all patients in the hospital with any isolation parenteral administration, the third generation cephalo- of VRE during the period of January 1, 2011 through sporin DDDs used were ceftriaxone 2 g, cefotaxime 4 g, December 31, 2012. The study was retrospective and ceftazidime 4 g and cefixime 0.4 g [12]. observational with no interventions, therefore the need for informed consent was waived. The numbers of pa- Statistical analysis tients colonized or infected with VRE isolated from sur- In order to assess the relationship between the antibiotic veillance cultures and invasive cultures (from blood or usage and the incidence of VRE (VRE-rate per 10 000 other normally sterile body sites) were obtained from the patients), a Poisson regression model was fitted with the hospital’s database (RDA/Archimed ALERT, Department number of VRE-positive patients as the dependent vari- of Infection Control and Hospital Epidemiology) for able, logarithm of the mean usage of glycopeptides, patients with multi-drug resistant pathogens. fluoroquinolones or third generation cephalosporins as In case of VRE screening selective enrichment media independent variable and the total number of patients in (brain-heart infusion containing vancomycin and ceftazi- each unit as an offset. dime as well as chromID VRE, bioMérieux, Marcy As in a previous surveillance study by Kritsotakis et al. l’Etoile, France) were inoculated, while clinical samples a dynamic relationship between antimicrobial use of gly- for non-targeted culture were processed following stand- copeptides and an increase in the VRE incidence was ard procedures dependent on the type of specimen, i.e. identified with average delays between 2 and 6 months non-selective enrichment broth (brain-heart infusion) [13], we selected to compare time-delayed 2-year periods Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 3 of 7 of 6 months between antibiotic consumption and VRE were general surgical (44 patients), followed by the bone isolation. marrow transplantation (BMT) unit (35 patients), general Model diagnostics revealed that the non-transformed medicine (33 patients), cardiothoracic surgery (27 patients), mean usage did not fit the data well due to a high lever- nephrology (26 patients), haematooncology (22 patients), age point (influential point). Further to control for pos- gastroenterology (17 patients), urology (17 patients), and sible violations of the distribution assumptions, White’s the infectious diseases unit (11 patients) (Fig. 1). robust covariance estimator was calculated [14]. Z-tests The total hospital-wide numbers of antimicrobial were performed using the coefficients of the Poisson DDDs were as follows: model and the robust standard errors. P-values of ≤0.05 8677 for vancomycin, 26 242 for teicoplanin, 64 788 were considered to be statistically significant. All calcula- for ciprofloxacin, 32 264 for levofloxacin, 22 155 for tions were performed using R 3.0.2. moxifloxacin, 13 080 for ceftriaxone, 10 910 for cefotaxime, 6958 for ceftazidime, and 1651 for cefixime. Total con- Results sumption of glycopeptides, fluoroquinolones and third In the pre-study period from 2004 through 2010, a con- generation cephalosporins per specialty is shown in Fig. 2. tinuous increase in the number of VRE-positive patients Specialty-specific VRE incidence significantly increased was detected in the hospital, from a single documented with the use of glycopeptides, fluoroquinolones or third case of VRE in 2004 (corresponding to 0.001 patients generation cephalosporins (p < 0.001). Figure 3 shows a per 10 000 admissions), 67 cases of VRE in 2007 (corre- non-linear relationship with a dramatic increase in the sponding to 0.066 patients per 10 000 admissions) to a incidence of VRE with high glycopeptide, fluoroquinolone peak of 129 VRE-positive patients in 2010 (correspond- or third generation cephalosporin usage. The results of ing to 0.125 patients per 10 000 admissions). the Poisson regression for vancomycin (p = 0.0018) and During the subsequent two-year study period, a total teicoplanin separately (p < 0.0001) were both highly sig- of 99 635 patients were admitted to the hospital in 2011 nificant. Spearman’s correlation coefficient indicated a and 102 083 in 2012. The overall VRE incidence was strong correlation between the two variables (rho = 0.8). 0.131 per 10 000 admissions in the first year and 0.156 per 10 000 admissions in the second year. Among these Discussion patients, 261 patients were colonized or infected with a In the present study we identified a positive non-linear single VRE species (E. faecium, n = 258; E. faecalis,n=3), relationship between the specialty-specific isolation of and five patients were colonized with 2 VRE species VRE and total glycopeptide, fluoroquinolone or third (E. faecium, n=5; E. faecalis,n=4; E. raffinosus,n=1). generation cephalosporin consumption. Most patients The VanA phenotype was detected in the VRE isolates of with VRE-positive cultures were simply colonized, but 234 (88 %) patients and VanB phenotype in 33 (12 %) 6.8 % experienced bloodstream infection caused by patients. vancomycin-resistant E. faecium. Despite less clinical As shown in the Table 1, most patients were only colo- relevance of VRE compared to infections caused by nized by non-invasive VRE-isolates, which were isolated methicillin-resistant Staphylococcus aureus (MRSA), from screening cultures (faeces or rectal swab, followed management of invasive VRE infections is challenging by skin swab, oropharyngeal swab). Among 87 patients because of limited treatment options. Furthermore, en- with proven VRE-infection, 18 patients developed VRE terococcal bacteraemia was associated with increased bacteraemia with E. faecium. risk of death in allogeneic haematopoietic stem cell A total of 201 patients were admitted to inpatient transplant recipients [15]. During a 7-year surveillance wards, 52 patients to intensive care units and 13 were study, a dynamic relationship was identified between outpatients. The specialties most frequently involved antimicrobial use of glycopeptides, fluoroquinolones, Table 1 Hospital-wide trends in colonizing and invasive vancomycin-resistant Enterococcus (VRE) species during the study period 2011 through 2012 Species Annual total no. (%) patients with VRE Annual no. (%) patients only colonized with VRE Annual no. (%) patients infected with VRE 2011 2012 2011 2012 2011 2012 Any Enterococcus sp. 123 (100) 143 (100) 87 (71) 92 (64) 36 (29) 51 (36) E. faecium 123 (100) 140 (98) 87 (71) 90 (63) 36 (29) 50 (35) E. faecalis 3 (2.4) 4 (2.8) 3 (2.4) 2 (1.4) 0 2 (1.4) E. raffinosus 1 (0.8) 0 1 (0.8) 0 0 0 In case of isolation of more than one Enterococcus spp. in one patient, the patient was only counted once for the category any Enterococcus sp. Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 4 of 7 a higher incidence of VRE-bloodstream infection and previ- ous hospital use of other, non-glycopeptide, antimicrobials Surgical units such as the third-generation cephalosporin ceftriaxone BMT unit [17]. In a recent systematic review it was not possible to General medical units Cardiothoracic surgery conclusively determine a potential role for reduction of Nephrology vancomycin use in controlling VRE [18]. But, in a retro- Haematooncology spective case–control study in a university hospital of Gastroenterology Korea, vancomycin use significantly prolonged the duration Urology Infectious Diseases of VRE carriage among intensive care patients already colo- Dermatology nized with vancomycin-resistant E. faecium [19]. However, Transplant unit because of the high tenacity of VRE in the environment, Trauma unit measures other than reduction of glycopeptide use, such as Neurology Psychiatry isolation of patients and enforced environmental cleaning, Paediatrics are necessary to control its spread [20]. Patients who are at Emergency risk are consequently screened at admittance and isolated Otorhinolaryngology in single rooms. We also hypothesize that in our hospital Gynaecology Ophthalmology the departments most frequently involved treat patients with chronic diseases for a long period of time, and VRE Total no. patients with VRE emerge due to glycopeptide use. Fig. 1 Specialty-specific isolation of VRE in the General Hospital of Vancomycin and teicoplanin are used therapeutically in Vienna during the two-year study period our hospital to treat invasive infections with gram-positive multi-drug resistant microorganisms or as empirical and extended-spectrum cephalosporins and an increase therapy in severe sepsis or septic shock in intensive care in the incidence of VRE, with average delays between 2 and immunosuppressed patients. During the period 2000 and 6 months [13]. In contrast, other studies do not report through 2011, vancomycin was used most frequently in such a direct relationship between glycopeptide use and our institution as first-line treatment in patients with VRE isolation [16] but have shown an association between MRSA bacteraemia, followed by teicoplanin [21]. Defined daily doses of antibiotics 0 10000 20000 30000 40000 Surgical units BMT unit General medical units Cardiothoracic Surgery Nephrology Haematooncology Gastroenterology Urology Infectious Diseases Dermatology Transplant unit Trauma unit Neurology Psychiatry Paediatrics Emergency Otorhinolaryngology Gynaecology Opththalmology Glycopeptides Fluoroquinolones 3rd gen cephalosporins Fig. 2 Specialty-specific usage of glycopeptides, fluoroquinolones and third generation cephalosporins in the General Hospital of Vienna during the period June 2010 to June 2012 Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 5 of 7 Fig. 3 Non-linear relationship between the usage of glycopeptides (a), fluoroquinolones (b) or third generation cephalosporins (c) and VRE-rate per 10 000 patients. The points indicate observations and the solid line the fit of the Poisson regression model Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 6 of 7 Furthermore, in patients with moderate to severe colitis References 1. Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin caused by Clostridium difficile, oral glycopeptides can resistance. Nat Rev Microbiol. 2012;10:266–78. promote acquisition of gastrointestinal VRE [22], whereas 2. Rivera AM, Boucher HW. Current concepts in antimicrobial therapy against the use of other oral antimicrobial agents against C. select gram-positive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. difficile, such as fidaxomicin, decrease the risk of VRE Mayo Clin Proc. 2011;86:1230–43. acquisition [23]. 3. Centers for Disease Control and Prevention. National Nosocomial Infections A limitation of our study was that we could not assess Surveillance (NNIS) System report, data summary from January 1990-May 1999. Am J Infect Control. 1999;27:520–32. the impact of oral versus intravenous use of glycopep- 4. McCracken M, Wong A, Mitchell R, et al. Molecular epidemiology of tides on the incidence of VRE separately. During the ob- vancomycin-resistant enterococcal bacteraemia: results from the Canadian servation period, only the intravenous formulations of Nosocomial Infection Surveillance Program, 1999–2009. J Antimicrob Chemother. 2013;68:1505–9. vancomycin and teicoplanin were provided for oral use, 5. European Centre for Disease Prevention and Control. Antimicrobial resistance because no oral formulations were available. surveillance in Europe 2011. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2012. 6. Patel R. Clinical impact of vancomycin-resistant enterococci. J Antimicrob Conclusions Chemother. 2003;51 Suppl S3:iii13–21. We demonstrated a positive non-linear relationship be- 7. Novais C, Freitas AR, Silveira E, Antunes P, Silva R, Coque TM, et al. Spread of multidrug-resistant Enterococcus to animals and humans: an underestimated tween the specialty-specific isolation of VRE and glycopep- role for the pig farm environment. J Antimicrob Chemother. 2013;68:2746–54. tide, fluoroquinolone or third generation cephalosporin 8. European Centre for Disease Prevention and Control. Antimicrobial resistance usage in the University Hospital of Vienna. Although VRE surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2014. incidence is increasing in our institution, the increase re- 9. Fehringer K. Annual Report 2011 Vienna General Hospital – Medical mains moderate, and is probably controlled by infection University Campus. http://www.akhwien.at/default.aspx?did=61147. control measures. Nevertheless, to minimize the spread of Accessed October 31, 2013. 10. European Committee on Antimicrobial Susceptibility Testing. glycopeptide-resistant Enterococcus species in the hospital Antimicrobial susceptibility testing EUCAST disk diffusion method. Vers. setting, the implementation of a program for prudent use 5.0, 2015 January 26. http://www.eucast.org/ast_of_bacteria/ of glycopeptides, fluoroquinolones and third generation disk_diffusion_methodology/. 11. Swenson JM, Patel JP, Jorgensen JH. Special phenotypic methods for cephalosporins is warranted. detecting antibacterial resistance. In: Murray PR et al. (eds.), Manual of th Clinical Microbiology, 9 edition, 2007; 1:21173–92. Competing interests 12. World Health Organization. Collaborating centre for drug statistics The authors declare that they have no competing interests. methodology. ATC/DDD Index 2013. http://www.whocc.no/atc_ddd_index/. Accessed December 20, 2012. 13. Kritsotakis EI, Christidou A, Roumbelaki M, Tselentis Y, Gikas A. The dynamic Authors’ contribution relationship between antibiotic use and the incidence of vancomycin-resistant CF, EP and WG designed the protocol of the study. DM, TW and MM provided Enterococcus: time-series modeling of 7-year surveillance data in a tertiary-care the microbiological data, the RDA/Archimed/Alert data and data on antimicrobial hospital. Clin Microbiol Infect. 2008;14:747–54. usage. DK performed the statistical analyses. CF prepared the present manuscript. 14. White H. A heteroskedasticity-consistent covariance matrix estimator and a MD, DM, WG and EP were major contributors in writing the manuscript. direct test for heteroskedasticity. Econometrica. 1980;48:817–38. All authors read and approved the final manuscript. 15. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, et al. Enterococcal bacteremia is associated with increased risk of mortality in Acknowledgments recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect The authors thank all colleagues in the Department of Hospital Epidemiology Dis. 2012;55:764–70. and Infection Control who routinely entered the surveillance data of patients 16. Peel T, Cheng AC, Spelman T, Huysmans M, Spelman D. Differing risk factors with positive VRE cultures into the RDA/Archimed Alert System of the General for vancomycin-resistant and vancomycin-sensitive enterococcal bacteraemia. Hospital of Vienna, Austria. Clin Microbiol Infect. 2012;18:388–94. 17. McKinnell JA, Kunz DF, Chamot E, Patel M, Shirley RM, Moser SA, et al. Association between vancomycin-resistant Enterococci bacteremia and Funding ceftriaxone usage. Infect Control Hosp Epidemiol. 2012;33:718–24. This work was supported by internal funding. 18. de Bruin MA, Riley LW. Does vancomycin prescribing intervention affect vancomycin-resistant enterococcus infection and colonization in hospitals? Author details A systematic review. BMC Infect Dis. 2007;7:24. Department of Medicine I, Division of Infectious Diseases and Tropical 19. Yoon YK, Lee SE, Lee J, Kim HJ, Kim JY, Park DW, et al. Risk factors for Medicine, Medical University of Vienna, Währinger Gürtel 18–20 1090, Vienna, prolonged carriage of vancomycin-resistant Enterococcus faecium among Austria. Center for Infectious Diseases and Infection Control, Jena University patients in intensive care units: a case–control study. J Antimicrob Chemother. Hospital, Jena, Germany. Department of Hospital Epidemiology and 2011;66:1831–8. Infection Control, Medical University of Vienna, Währinger Gürtel 18–20 1090, 20. Marcel JP, Alfa M, Baquero F, Etienne J, Goossens H, Harbarth S, et al. Vienna, Austria. Section for Medical Statistics, Medical University of Vienna, Healthcare-associated infections: think globally, act locally. Clin Microbiol Währinger Gürtel 18–20 1090, Vienna, Austria. Division of Clinical Infect. 2008;14:895–907. Microbiology, Department of Laboratory Medicine, Medical University of 21. Forstner C, Dungl C, Tobudic S, Mitteregger D, Lagler H, Burgmann H. Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. Hospital Pharmacy, Predictors of clinical and microbiological treatment failure in patients with General Hospital of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective Center of Medical Statistics, Informatics and Systems Intelligence, Medical cohort study in a region with low MRSA prevalence. Clin Microbiol Infect. University of Vienna, Währinger Gürtel 18–20 1090, Vienna, Austria. 2013;19:E291–7. Received: 15 February 2015 Accepted: 24 May 2015 22. Shin JW, Yong D, Kim MS, Chang KH, Lee K, Kim JM, et al. Sudden increase of vancomycin-resistant enterococcal infections in a Korean tertiary care Forstner et al. Antimicrobial Resistance and Infection Control (2015) 4:25 Page 7 of 7 hospital: possible consequences of increased use of oral vancomycin. J Infect Chemother. 2003;9:62–7. 23. Nerandzic MM, Mullane K, Miller MA, Babakhani F, Donskey CJ. Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection. Clin Infect Dis. 2012;55 Suppl 2:S121–6. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

Journal

Antimicrobial Resistance & Infection ControlSpringer Journals

Published: Jun 15, 2015

There are no references for this article.