Infection DOI 10.1007/s15010-014-0693-2
ORIGINAL PAPER
Implementing an intensified antibiotic stewardship programme targeting cephalosporin and fluoroquinolone use in a 200-bed community hospital in Germany J. P. Borde • S. Litterst • M. Ruhnke • R. Feik • J. Hu¨bner • K. deWith • K. Kaier W. V. Kern
•
Received: 28 June 2014 / Accepted: 10 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Background Prescription of third-generation cephalosporins and fluoroquinolones has been linked to an increasing incidence of gram-negative bacteria producing extended-spectrum beta-lactamases, methicillin-resistant Staphylococcus aureus and nosocomial infection with Clostridium difficile. Antibiotic stewardship (ABS) programmes offer evidence-based tools to control antibiotic prescription rates and thereby influence the incidence of nosocomial infection and contain the development of multidrug-resistant bacteria, but there is limited experience with such programmes at community hospitals. Methods We implemented an ABS programme at a 200-bed community hospital and aimed at a [ 30 % reduction of cephalosporin and fluoroquinolone consumption within 1 year. Pharmacy data were obtained to estimate hospital-wide drug use density expressed in WHOATC-defined daily doses (DDD) or hospital-adapted
recommended daily doses (RDD) per 1,000 patient days. The effect of the ABS intervention on drug use density was analysed using interrupted time-series analysis for the periods between January 2011 and March 2013 as preintervention, and between April 2013 and March 2014 as post-intervention period. The CDI incidence was calculated based on microbiology laboratory data. Results Cephalosporin use (measured in RDD/1,000 patient days) decreased by 33 %, and fluoroquinolone use decreased by 31 %, respectively. Interrupted time-series analysis confirmed significant changes in the drug use density trends for both cephalosporins and fluoroquinolones after the intervention as well as for total antibiotic use that decreased by 11 % while no significant effect was noted for CDI incidence rates. Conclusion ABS programmes can be effective in community hospitals and may help establish ecologically advantageous antibiotic strategies when needed.
K. Kaier and W. V. Kern have equally contributed. J. P. Borde (&) M. Ruhnke Ortenauklinikum Achern, Medizinische Klinik, Sektion Infektiologie, Josef-Wurzler-Straße 7, 77855 Achern, Germany e-mail: [email protected] S. Litterst Ortenauklinikum Offenburg-Gengenbach, Pharmacy Service, Ebertplatz 12, 77654 Offenburg, Germany R. Feik Ortenauklinikum Achern, Medizinische Klinik, 77855 Achern, Germany
K. deWith Universita¨tsklinikum Carl Gustav Carus, Zentralbereich Infektiologie, Fetscherstraße 74, 01307 Dresden, Germany K. Kaier Center for Medical Biometry and Informatics, University Medical Center, 79106 Freiburg i.Br., Germany W. V. Kern Division of Infectious Diseases, Department of Medicine, University Medical Center, 79106 Freiburg i.Br., Germany
J. Hu¨bner Division of Pediatric Infectious Diseases, Department of Pediatrics, von Haunersches Kinderspital, 80337 Munich, Germany
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J. P. Borde et al.
Keywords Antibiotic stewardship Interrupted timeseries analysis Cephalosporins Fluoroquinolones Secondary setting Community non-teaching hospital
Background The 2014 publication ‘‘Antimicrobial resistance and global surveillance’’ of the World Health Organization (WHO) is alarming [19]. Emergence and spread of multidrug-resistant bacteria are of growing concern in global healthcare and are limiting effective treatment of life-threatening infections. In the last decades, it has been shown that antimicrobial resistance is driven by the increasing trend of overall antibiotic consumption [2]. Notably, the prescription of third-generation cephalosporins [1] and fluoroquinolones [1, 2] has been linked to a growing incidence of gram-negative bacteria producing extended-spectrum beta-lactamases (ESBL) [3, 4], methicillin-resistant Staphylococcus aureus (MRSA) [5] and Clostridium difficile [6–8]. Cephalosporins and fluoroquinolones remain among the most frequently prescribed antibiotics in Germany, both in the outpatient as well as hospital setting. It is therefore, not surprising to observe increasing numbers of third-generation cephalosporin-resistant Escherichia coli isolates in this country [9]. Hospital antibiotic stewardship (ABS) programmes offer several evidencebased tools to control prescription rates of antimicrobial drugs, to influence incidence of nosocomial infections and to contain the development of multidrug-resistant bacteria [10–12]. However, most ABS studies have been made in the setting of large tertiary referral hospitals or academic teaching hospitals [12]. The recently published systematic Cochrane review included only few interventional trials which reported community non-teaching hospitals with \250 beds [12]. In Germany, infectious disease management and hospital ABS programmes have faced special problems, in particular the lack of specialists and positions outside referral university medical centers, and the frequently outsourced microbiology laboratories and infection control teams. A recently published German–Austrian ABS guideline [20] now recommends one fulltime equivalent infectious disease physician position for hospitals with 250–500 beds. So far, however, almost no German hospital of this size has implemented such a programme. We here show that an ABS intervention in a small German community hospital provided that an appropriate infrastructure is available, can be very effective in targeting and reducing broad-spectrum antibiotic use.
123
Materials and methods Setting The intervention took place at a community-based 200-bed hospital in southern Germany. The 100-bed-sized general medical service is divided into several clinical sections: cardiology, angiology, gastroenterology and, newly established, infectious diseases––each section is led by a board certified specialist. More than 130 cardiac devices are implanted per year––including cardiac resynchronization therapy (CRT) devices and implanted cardiac defibrillators (ICD). The surgical service is focused on general surgery, traumatology with 500 prosthetic joint implantations per year and spinal surgery. The hospital includes an interdisciplinary 10-bed ICU as well as an obstetrics and gynaecology division. ABS programme The hospital had no specific ID resources before the intervention. The ABS intervention started with the appointment of one ID specialist for the newly established clinical section ‘‘infectious diseases’’. The aim of the ABS programme was to reduce the unnecessary prescribing of third-generation cephalosporins and fluoroquinolones. The use of narrow-spectrum or broad-spectrum penicillins was encouraged as alternative if needed and possible. An infectious disease physician was newly appointed to revise the local practice guideline accordingly, to communicate the new recommendations, to initiate consultations and give feedback on ward- and hospital-wide evolution of antibiotic use. The infectious disease physician dedicated 25 % of his time to the programme and worked 75 % in general internal medicine. The intervention was started in April 2013. The programme included daily (weekdays) rounds on the interdisciplinary intensive care unit and a bacteremia service (unsolicited infectious disease consultations in patients with bloodstream infection). The internal guidelines were consented in all clinical divisions and sections and were made available in written pocket-sized formats to the house staff. Before the intervention, ceftriaxone had been one of the most frequently prescribed antibiotics in the treatment of community-acquired pneumonia (CAP). The new guideline recommended ampicillin/ sulbactam as first-line therapy for CAP. This replacement strategy is in-line with the IDSA recommendation for the treatment of admitted patients with CAP [13]. Besides the use of flucloxacillin for S.aureus bacteremia (SAB), we promoted the use of narrow-spectrum penicillins especially for skin–soft tissue infections (SSTI) most likely caused by streptococci spp. like erysipelas.
Implementing an intensified antibiotic stewardship programme
Data acquisition
level effect or a slope effect. As our data indicate a change in the slope rather than a level change, our regression model to analyse the use of antibiotic Y over time t in a single setting was specified accordingly:
Quarterly antibiotic use data were obtained from the hospital pharmacy and were expressed as WHO-ATC-defined daily doses (DDD) and dose definitions adapted to local guidelines (recommended daily doses, RDD) to account for major discrepancies between DDD and RDD for penicillins, normalised per 1,000 patient days. All DDD and RDD calculations/transformations are based on the ADKA-if national surveillance program and definitions [22]. The data were administered using MicrosoftÒ Excel software. The DRG case mix index, patient days, data on length of stay and on hospital deaths were obtained from the administration. Cases of Clostridium difficile infection were obtained from the hospital hygiene database and from the hospital DRG controlling service. Laboratory diagnosis of C. difficile infection is made on the basis of the IDSA/SHEA guidelines regarding this infection [14]. In detail, our laboratory performs C. difficile toxin-ELISA and GLDHantigen tests. Each case was reviewed to verify the infection and to define whether the infection was nosocomially acquired (onset of symptoms and verified diagnosis [48 h after hospital admission). The incidence was then calculated in cases per 1,000 patient days.
Yt ¼ b0 þ b1 timet þ b2 time after interventiont þ ut In detail, b0 determines the baseline level of the respective antibiotic use in January 2011, b1 determines the overall linear trend in the use of the respective antibiotic over the entire study period. b2 determines the change in post-intervention trend, where the time after intervention is a continuous variable indicating the number of months after the start of the intervention and is coded as zero before the intervention. ut represents the error term. All analyses were carried out using Stata 12 (StataCorp, College Station, TX, USA). We applied linear regressions with Newey-West standard errors with a maximum lag of 2 to be considered in the autocorrelation structure.
Results The overall antibiotic use density remained stable over the pre-intervention as well as post-intervention period if expressed in DDD/1000 while there was a slight decrease (-11 %) when the RDD/1,000 data format was used. Remarkable changes, however, were observed in the use density for defined antibiotic classes. As expected, there was a major change in the prescribing of cephalosporins, fluoroquinolones and also of penicillins between pre- and post-intervention. The drug use density levels for cephalosporins decreased by 33 %, measured in RDD/1,000 patient days, and there was a reduction by 30 % in the use
Statistical analysis The effect of the intervention on drug use density was analysed using interrupted time-series analysis for the periods between January 2011 and March 2013 as preintervention, and between April 2013 and March 2014 as post-intervention period. Interrupted time-series analysis allows accounting for two effects of the intervention: a Table 1 Mean quarterly antibiotic use densities before (January 2011 through March 2013, n = 9 quarters) and after the ABS programme (April 2013 through March 2014, n = 4 quarters)
Substance
Cephalosporins Third-generation Other Penicillins Piperacillin ± BLI Aminopenicillin ? BLI Narrow Spectrum Carbapenems FQ
DDD/1,000 patient days
RDD/1,000 patient days
Before
After
Change in %
Before
170.9
126.8
-26
121.0
81.1
-33
48.7
29.8
-39
47.8
29.0
-39
122.3
96.9
-21
73.2
52.1
-29
187.5
273.7
46
99.8
120.1
20
17.6
17.7
1
20.5
20.7
1
155.7 14.2
186.3 69.6
20 392
73.4 5.9
79.6 19.8
9 233
8.0
4.9
-38
5.8
3.3
-43 -31
After
Change in %
64.7
43.1
-33
45.3
31.4
Aminoglycosides
1.2
2.2
88
0.9
2.0
117
Glycopeptides
5.8
5.2
-10
5.8
5.2
-10
39.0
32.0
-18
23.9
26.6
11
3.4
3.4
2
1.8
1.7
-6
480.4
491.3
2
304.3
271.3
-11
Macrolides/Clindamycin Tetracyclins Total
123
123
13
295.7 (0.000)***
-14.98 (0.014)*
p \ 0.001 ***
p \ 0.01, **
p \ 0.05, *
13 13 13 N
p-values in parentheses
13 13
8.470 (0.000) 1.241 (0.012) 42.07 (0.000) 5.996 (0.000) Baseline level
The baseline trends and the post-interventional trends are shown for each drug class. All consumptions are data expressed in RDD/1,000 patient days
13
2.499 (0.003) 20.95 (0.000)
0.326 (0.346)
** ***
0.0422 (0.979)
***
1.429 (0.442) -0.138 (0.254) 0.539 (0.343) -0.440 (0.139)
0.252 (0.731) 0.781 (0.002)
* ***
-7.843 (0.000) -0.747 (0.039) Post-interventional trend
***
**
-0.0885 (0.180) 0.713 (0.107)
*** *
-0.0608 (0.698) Baseline trend
Total Antiinfectives Tetracyclins Macrolids Clindamycin Glycopeptides Amino glycosides Fluoroquinolones
13 13 13 N
52.03 (0.000)***
-4.941 (0.004)
Baseline level
78.42 (0.000)***
-4.369 (0.008) -9.310 (0.001)
130.4 (0.000)***
Post-interventional trend
-0.886 (0.102)
** **
-1.194 (0.018)*
**
-2.079 (0.013)* Baseline trend
1/2 Gen. Cephalo sporins Total Cephalo sporins
Table 2 Interrupted time-series analysis of quarterly consumption data
The present work demonstrates that it is feasible and effective to introduce an ABS programme in a small community hospital that previously had no resources for stewardship activities and intensified infectious disease expert consultations. The programme itself was based on core ABS activities earlier described in international and national guidelines [11]. The resources were essentially the appointment of an infectious disease physician who worked part time in the stewardship programme and part time in general internal medicine. The endpoints measured here were limited to overall and antibiotic class use density over time as well as crude outcome data (hospital deaths and length of stay). We controlled for disease severity using the German DRG case mix index that remained stable between pre- and post-intervention. Given the relatively low C. difficile infection incidence pre-intervention (compared with the national estimate of 0.4 cases per 1,000 patient days) [21], we were unable to show a significant reduction in the nosocomial C. difficile infection over time in this hospital, but a longer follow-up period and time-series analysis rather than level change analysis will be needed to fully assess a possible association. Apart from the demonstrated reduction in the overall antibiotic use and the use of cephalosporins and fluoroquinolones, we believe that there were other favourable effects associated with the intervention, e.g. improved management of bloodstream infection. Data from this
3 Gen. Cephalo sporins
Discussion
Carbapenems
1.720 (0.503)
2.235 (0.109)
13 13 13 13
63.67 (0.000)***
-0.775 (0.746) 0.0625 (0.965)
18.62 (0.000)*** 84.02 (0.000)***
1.522 (0.311)
1.746 (0.045)* 0.271 (0.645) 2.983 (0.000)***
Total Penicillins
Piperacillin ? BLI
Aminopen. ? BLI
Narrow Spectrum Penicillins
of fluoroquinolones. Conversely, penicillin consumption increased (20 % measured in RDD/1,000), in particular for narrow-spectrum penicillins (Table 1). Time-series analysis confirmed that the changes in the use of cephalosporins and fluoroquinolones, in fact, represented significant trend changes in the post-intervention period (Table 2). It also showed that the decreased overall antibiotic consumption was significant while the increase in penicillins was statistically not significant. We also calculated trend changes for other antibiotic classes and found a significantly decreasing trend for carbapenems, an increasing trend for aminoglycosides, and no trend changes for glycopeptides, macrolides, and tetracyclines. In the post-intervention period, the DRG case mix index, length of stay and in-hospital deaths remained stable compared with pre-intervention levels (these data are available on request from the author). The mean (quarterly) incidence of nosocomial Clostridium difficile infection in the pre-intervention period was 0.26 ± 0.18 cases per 1,000 patient days. Post-intervention the incidence decreased to 0.18 ± 0.06 cases per 1,000 patient days, but this 30 % difference was not statistically significant.
0.966 (0.046)*
J. P. Borde et al.
Implementing an intensified antibiotic stewardship programme Intervention
340 320 300 280
60
260 40
20
0 2011
2012
2013
2014
Fig. 1 Trends in the quarterly antibiotic use densities (expressed as RDD per 1,000 patient days) for overall antibiotic use (black line, right scale), third-generation cephalosporin use (blue line, left scale), fluoroquinolone use (red line, left scale) and narrow-spectrum penicillin use (green line, left scale) pre- and post-intervention. The increase in overall antibiotic consumption before the start of the intervention in 2013 might be related to the over-average flu activity in this time period [23]
hospital indicate that the outcomes of patients with Staphylococcus aureus bacteremia, for example, improved with the introduction of a bacteremia service [15]. Other endpoints for patients with other disease entities might also have improved with the programme and need to be considered in cost-effectiveness estimations. In a recent large analysis, infectious disease consultations appeared to be life saving and cost effective [16]. A recently published work from Germany estimated net yearly cost savings associated with stewardship activities of at least 500 € per hospital bed [17]. The effects on antibiotic class use density were relatively rapidly observed. The changes in the level of cephalosporin and fluoroquinolone use were remarkable -30 % or more within 1 year. Similar or even more excessive reductions in the use of specific drug classes have been observed by other investigators, and according to a recent metaanalysis, *50 % reductions in the use of cephalosporins or fluoroquinolones are associated with a roughly *50 % reduction in the incidence of C. difficile infections [18]. Our programme with a roughly 30 % reduction in cephalosporin (Fig. 1) and fluoroquinolone use was possibly associated with a roughly 30 % CDI reduction although this association could not be proven. Carefully planned ABS programmes, thus, may be a powerful instrument to influence the frequency and pattern of healthcare-associated infection and increase patient safety. It is of note that we did not observe potentially unfavourable effects of the programme on increased use of second-line antibiotics such as carbapenems or glycopeptides. We emphasise that both for the primary endpoint as well as for secondary
possibly untoward effects, the evaluation of trend changes by interrupted time-series analysis rather than of level changes is important. A limitation of the present study, however, remains the relative short 1-year post-intervention period with four time points only. As a conclusion, the results of this study show that ABS programmes can be easily implemented in small community hospitals in Germany and, are also likely to be cost effective in this setting. They can be used to rapidly change antibiotic strategies if needed and to improve patient outcomes. Conflict of interest On behalf of all the authors, the corresponding author states that there is no conflict of interest. Ethical statement The ethics committee was notified about the trial––formal approval was not required, because the project is based on epidemiological data. Research involving human subjects, human material, specific human or personalised data was not carried out.
References 1. Dancer SJ, Kirkpatrick P, Corcoran DS, Christison F, Farmer D, Robertson C. Approaching zero: temporal effects of a restrictive antibiotic policy on hospital-acquired Clostridium difficile, extended-spectrum b-lactamase-producing coliforms and meticillin-resistant Staphylococcus aureus. Int J Antimicrob Agents. 2013;41:137–42. 2. Livermore DM, Hope R, Reynolds R, Blackburn R, Johnson AP, Woodford N. Declining cephalosporin and fluoroquinolone nonsusceptibility among bloodstream Enterobacteriaceae from the UK: links to prescribing change?. Chemother: J. Antimicrob; 2013. 3. Aldeyab MA, Harbarth S, Vernaz N, Kearney MP, Scott MG, Darwish Elhajji FW et al. The impact of antibiotic use on the incidence and resistance pattern of extended-spectrum beta-lactamase-producing bacteria in primary and secondary healthcare settings. Br. J. Clin. Pharmacol. 2012;74:171–9. 4. Petrikkos G, Markogiannakis A, Papaparaskevas J, Papapareskevas J, Daikos GL, Stefanakos G, et al. Differences in the changes in resistance patterns to third- and fourth-generation cephalosporins and piperacillin/tazobactam among Klebsiella pneumoniae and Escherichia coli clinical isolates following a restriction policy in a Greek tertiary care hospita. Agents: Int. J. Antimicrob; 2007. 5. LeBlanc L, Pe´pin J, Toulouse K, Ouellette M-F, Coulombe M-A, Corriveau M-P, et al. Fluoroquinolones and risk for methicillinresistant Staphylococcus aureus. Canada. Emerg. Infect. Dis. 2006;12:1398–405. 6. Kaier K, Hagist C, Frank U, Conrad A, Meyer E. Two time-series analyses of the impact of antibiotic consumption and alcoholbased hand disinfection on the incidences of nosocomial methicillin-resistant Staphylococcus aureus infection and Clostridium difficile infection. Epidemiol: Infect. Control Hosp; 2009. 7. Pe´pin J, Saheb N, Coulombe M-A, Alary M-E, Corriveau M-P, Authier S et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin. Infect. Dis. [Internet]. 2005;41:1254–60. 8. Talpaert MJ. Gopal Rao G, Cooper BS, Wade P. Impact of guidelines and enhanced antibiotic stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of
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Clostridium difficile infection. J Antimicrob Chemother. 2011;66:2168–74. Meyer E, Schwab F, Schroeren-Boersch B, Gastmeier P. Dramatic increase of third-generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance 2001 to 2008. Crit Care. 2010;14:R113. Mondain V, Lieutier F, Hasseine L, Gari-Toussaint M, Poiree M, Lions C, et al. A 6-year antifungal stewardship programme in a teaching hospital. Infection. 2013;41:621–8. Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein R a, Burke JP et al. 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. 2007;44:159–77. Davey P, Brown E, Charani E, Fenelon L, Gould IM, Holmes A et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane database Syst. Rev. 2013 4:CD003543. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious
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diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431–55. Borde JP, Batin N, Rieg S, Feik R, Reimling C, Kern WV et al. Adherence to an antibiotic stewardship bundle targeting Staphylococcus aureus blood stream infections at a 200-bed community hospital. Infection 2014. Schmitt S, McQuillen DP, Nahass R, Martinelli L, Rubin M, Schwebke K, et al. Infectious diseases specialty intervention is associated with decreased mortality and lower healthcare costs. Dis: Clin. Infect; 2014. Borde JP, Kaier K, Steib-Bauert M, Vach W, Geibel-Zehender A, Busch H, et al. Feasibility and impact of an intensified antibiotic stewardship programme targeting cephalosporin and fluoroquinolone use in a tertiary care university medical center. BMC Infect Dis. 2014;14:201. Feazel LM, Malhotra A, Perencevich EN, Kaboli P, Diekema DJ, Schweizer ML. Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and metaanalysis. Chemother: J. Antimicrob; 2014. http://www.who.int/drugresistance/en/. S3-Leitlinie Strategien zur Sicherung rationaler Antibiotika-Anwendung im Krankenhaus AWMF-Registernummer 092/001, 2013. http://www.nrz-hygiene.de/surveillance/kiss/cdad-kiss/. http://www.antiinfektiva-surveillance.de/32-0-Allgemeine-Infor mationen.html. https://influenza.rki.de/Diagrams.aspx?agiRegion=0.
ORIGINAL PAPER
Implementing an intensified antibiotic stewardship programme targeting cephalosporin and fluoroquinolone use in a 200-bed community hospital in Germany J. P. Borde • S. Litterst • M. Ruhnke • R. Feik • J. Hu¨bner • K. deWith • K. Kaier W. V. Kern
•
Received: 28 June 2014 / Accepted: 10 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Background Prescription of third-generation cephalosporins and fluoroquinolones has been linked to an increasing incidence of gram-negative bacteria producing extended-spectrum beta-lactamases, methicillin-resistant Staphylococcus aureus and nosocomial infection with Clostridium difficile. Antibiotic stewardship (ABS) programmes offer evidence-based tools to control antibiotic prescription rates and thereby influence the incidence of nosocomial infection and contain the development of multidrug-resistant bacteria, but there is limited experience with such programmes at community hospitals. Methods We implemented an ABS programme at a 200-bed community hospital and aimed at a [ 30 % reduction of cephalosporin and fluoroquinolone consumption within 1 year. Pharmacy data were obtained to estimate hospital-wide drug use density expressed in WHOATC-defined daily doses (DDD) or hospital-adapted
recommended daily doses (RDD) per 1,000 patient days. The effect of the ABS intervention on drug use density was analysed using interrupted time-series analysis for the periods between January 2011 and March 2013 as preintervention, and between April 2013 and March 2014 as post-intervention period. The CDI incidence was calculated based on microbiology laboratory data. Results Cephalosporin use (measured in RDD/1,000 patient days) decreased by 33 %, and fluoroquinolone use decreased by 31 %, respectively. Interrupted time-series analysis confirmed significant changes in the drug use density trends for both cephalosporins and fluoroquinolones after the intervention as well as for total antibiotic use that decreased by 11 % while no significant effect was noted for CDI incidence rates. Conclusion ABS programmes can be effective in community hospitals and may help establish ecologically advantageous antibiotic strategies when needed.
K. Kaier and W. V. Kern have equally contributed. J. P. Borde (&) M. Ruhnke Ortenauklinikum Achern, Medizinische Klinik, Sektion Infektiologie, Josef-Wurzler-Straße 7, 77855 Achern, Germany e-mail: [email protected] S. Litterst Ortenauklinikum Offenburg-Gengenbach, Pharmacy Service, Ebertplatz 12, 77654 Offenburg, Germany R. Feik Ortenauklinikum Achern, Medizinische Klinik, 77855 Achern, Germany
K. deWith Universita¨tsklinikum Carl Gustav Carus, Zentralbereich Infektiologie, Fetscherstraße 74, 01307 Dresden, Germany K. Kaier Center for Medical Biometry and Informatics, University Medical Center, 79106 Freiburg i.Br., Germany W. V. Kern Division of Infectious Diseases, Department of Medicine, University Medical Center, 79106 Freiburg i.Br., Germany
J. Hu¨bner Division of Pediatric Infectious Diseases, Department of Pediatrics, von Haunersches Kinderspital, 80337 Munich, Germany
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J. P. Borde et al.
Keywords Antibiotic stewardship Interrupted timeseries analysis Cephalosporins Fluoroquinolones Secondary setting Community non-teaching hospital
Background The 2014 publication ‘‘Antimicrobial resistance and global surveillance’’ of the World Health Organization (WHO) is alarming [19]. Emergence and spread of multidrug-resistant bacteria are of growing concern in global healthcare and are limiting effective treatment of life-threatening infections. In the last decades, it has been shown that antimicrobial resistance is driven by the increasing trend of overall antibiotic consumption [2]. Notably, the prescription of third-generation cephalosporins [1] and fluoroquinolones [1, 2] has been linked to a growing incidence of gram-negative bacteria producing extended-spectrum beta-lactamases (ESBL) [3, 4], methicillin-resistant Staphylococcus aureus (MRSA) [5] and Clostridium difficile [6–8]. Cephalosporins and fluoroquinolones remain among the most frequently prescribed antibiotics in Germany, both in the outpatient as well as hospital setting. It is therefore, not surprising to observe increasing numbers of third-generation cephalosporin-resistant Escherichia coli isolates in this country [9]. Hospital antibiotic stewardship (ABS) programmes offer several evidencebased tools to control prescription rates of antimicrobial drugs, to influence incidence of nosocomial infections and to contain the development of multidrug-resistant bacteria [10–12]. However, most ABS studies have been made in the setting of large tertiary referral hospitals or academic teaching hospitals [12]. The recently published systematic Cochrane review included only few interventional trials which reported community non-teaching hospitals with \250 beds [12]. In Germany, infectious disease management and hospital ABS programmes have faced special problems, in particular the lack of specialists and positions outside referral university medical centers, and the frequently outsourced microbiology laboratories and infection control teams. A recently published German–Austrian ABS guideline [20] now recommends one fulltime equivalent infectious disease physician position for hospitals with 250–500 beds. So far, however, almost no German hospital of this size has implemented such a programme. We here show that an ABS intervention in a small German community hospital provided that an appropriate infrastructure is available, can be very effective in targeting and reducing broad-spectrum antibiotic use.
123
Materials and methods Setting The intervention took place at a community-based 200-bed hospital in southern Germany. The 100-bed-sized general medical service is divided into several clinical sections: cardiology, angiology, gastroenterology and, newly established, infectious diseases––each section is led by a board certified specialist. More than 130 cardiac devices are implanted per year––including cardiac resynchronization therapy (CRT) devices and implanted cardiac defibrillators (ICD). The surgical service is focused on general surgery, traumatology with 500 prosthetic joint implantations per year and spinal surgery. The hospital includes an interdisciplinary 10-bed ICU as well as an obstetrics and gynaecology division. ABS programme The hospital had no specific ID resources before the intervention. The ABS intervention started with the appointment of one ID specialist for the newly established clinical section ‘‘infectious diseases’’. The aim of the ABS programme was to reduce the unnecessary prescribing of third-generation cephalosporins and fluoroquinolones. The use of narrow-spectrum or broad-spectrum penicillins was encouraged as alternative if needed and possible. An infectious disease physician was newly appointed to revise the local practice guideline accordingly, to communicate the new recommendations, to initiate consultations and give feedback on ward- and hospital-wide evolution of antibiotic use. The infectious disease physician dedicated 25 % of his time to the programme and worked 75 % in general internal medicine. The intervention was started in April 2013. The programme included daily (weekdays) rounds on the interdisciplinary intensive care unit and a bacteremia service (unsolicited infectious disease consultations in patients with bloodstream infection). The internal guidelines were consented in all clinical divisions and sections and were made available in written pocket-sized formats to the house staff. Before the intervention, ceftriaxone had been one of the most frequently prescribed antibiotics in the treatment of community-acquired pneumonia (CAP). The new guideline recommended ampicillin/ sulbactam as first-line therapy for CAP. This replacement strategy is in-line with the IDSA recommendation for the treatment of admitted patients with CAP [13]. Besides the use of flucloxacillin for S.aureus bacteremia (SAB), we promoted the use of narrow-spectrum penicillins especially for skin–soft tissue infections (SSTI) most likely caused by streptococci spp. like erysipelas.
Implementing an intensified antibiotic stewardship programme
Data acquisition
level effect or a slope effect. As our data indicate a change in the slope rather than a level change, our regression model to analyse the use of antibiotic Y over time t in a single setting was specified accordingly:
Quarterly antibiotic use data were obtained from the hospital pharmacy and were expressed as WHO-ATC-defined daily doses (DDD) and dose definitions adapted to local guidelines (recommended daily doses, RDD) to account for major discrepancies between DDD and RDD for penicillins, normalised per 1,000 patient days. All DDD and RDD calculations/transformations are based on the ADKA-if national surveillance program and definitions [22]. The data were administered using MicrosoftÒ Excel software. The DRG case mix index, patient days, data on length of stay and on hospital deaths were obtained from the administration. Cases of Clostridium difficile infection were obtained from the hospital hygiene database and from the hospital DRG controlling service. Laboratory diagnosis of C. difficile infection is made on the basis of the IDSA/SHEA guidelines regarding this infection [14]. In detail, our laboratory performs C. difficile toxin-ELISA and GLDHantigen tests. Each case was reviewed to verify the infection and to define whether the infection was nosocomially acquired (onset of symptoms and verified diagnosis [48 h after hospital admission). The incidence was then calculated in cases per 1,000 patient days.
Yt ¼ b0 þ b1 timet þ b2 time after interventiont þ ut In detail, b0 determines the baseline level of the respective antibiotic use in January 2011, b1 determines the overall linear trend in the use of the respective antibiotic over the entire study period. b2 determines the change in post-intervention trend, where the time after intervention is a continuous variable indicating the number of months after the start of the intervention and is coded as zero before the intervention. ut represents the error term. All analyses were carried out using Stata 12 (StataCorp, College Station, TX, USA). We applied linear regressions with Newey-West standard errors with a maximum lag of 2 to be considered in the autocorrelation structure.
Results The overall antibiotic use density remained stable over the pre-intervention as well as post-intervention period if expressed in DDD/1000 while there was a slight decrease (-11 %) when the RDD/1,000 data format was used. Remarkable changes, however, were observed in the use density for defined antibiotic classes. As expected, there was a major change in the prescribing of cephalosporins, fluoroquinolones and also of penicillins between pre- and post-intervention. The drug use density levels for cephalosporins decreased by 33 %, measured in RDD/1,000 patient days, and there was a reduction by 30 % in the use
Statistical analysis The effect of the intervention on drug use density was analysed using interrupted time-series analysis for the periods between January 2011 and March 2013 as preintervention, and between April 2013 and March 2014 as post-intervention period. Interrupted time-series analysis allows accounting for two effects of the intervention: a Table 1 Mean quarterly antibiotic use densities before (January 2011 through March 2013, n = 9 quarters) and after the ABS programme (April 2013 through March 2014, n = 4 quarters)
Substance
Cephalosporins Third-generation Other Penicillins Piperacillin ± BLI Aminopenicillin ? BLI Narrow Spectrum Carbapenems FQ
DDD/1,000 patient days
RDD/1,000 patient days
Before
After
Change in %
Before
170.9
126.8
-26
121.0
81.1
-33
48.7
29.8
-39
47.8
29.0
-39
122.3
96.9
-21
73.2
52.1
-29
187.5
273.7
46
99.8
120.1
20
17.6
17.7
1
20.5
20.7
1
155.7 14.2
186.3 69.6
20 392
73.4 5.9
79.6 19.8
9 233
8.0
4.9
-38
5.8
3.3
-43 -31
After
Change in %
64.7
43.1
-33
45.3
31.4
Aminoglycosides
1.2
2.2
88
0.9
2.0
117
Glycopeptides
5.8
5.2
-10
5.8
5.2
-10
39.0
32.0
-18
23.9
26.6
11
3.4
3.4
2
1.8
1.7
-6
480.4
491.3
2
304.3
271.3
-11
Macrolides/Clindamycin Tetracyclins Total
123
123
13
295.7 (0.000)***
-14.98 (0.014)*
p \ 0.001 ***
p \ 0.01, **
p \ 0.05, *
13 13 13 N
p-values in parentheses
13 13
8.470 (0.000) 1.241 (0.012) 42.07 (0.000) 5.996 (0.000) Baseline level
The baseline trends and the post-interventional trends are shown for each drug class. All consumptions are data expressed in RDD/1,000 patient days
13
2.499 (0.003) 20.95 (0.000)
0.326 (0.346)
** ***
0.0422 (0.979)
***
1.429 (0.442) -0.138 (0.254) 0.539 (0.343) -0.440 (0.139)
0.252 (0.731) 0.781 (0.002)
* ***
-7.843 (0.000) -0.747 (0.039) Post-interventional trend
***
**
-0.0885 (0.180) 0.713 (0.107)
*** *
-0.0608 (0.698) Baseline trend
Total Antiinfectives Tetracyclins Macrolids Clindamycin Glycopeptides Amino glycosides Fluoroquinolones
13 13 13 N
52.03 (0.000)***
-4.941 (0.004)
Baseline level
78.42 (0.000)***
-4.369 (0.008) -9.310 (0.001)
130.4 (0.000)***
Post-interventional trend
-0.886 (0.102)
** **
-1.194 (0.018)*
**
-2.079 (0.013)* Baseline trend
1/2 Gen. Cephalo sporins Total Cephalo sporins
Table 2 Interrupted time-series analysis of quarterly consumption data
The present work demonstrates that it is feasible and effective to introduce an ABS programme in a small community hospital that previously had no resources for stewardship activities and intensified infectious disease expert consultations. The programme itself was based on core ABS activities earlier described in international and national guidelines [11]. The resources were essentially the appointment of an infectious disease physician who worked part time in the stewardship programme and part time in general internal medicine. The endpoints measured here were limited to overall and antibiotic class use density over time as well as crude outcome data (hospital deaths and length of stay). We controlled for disease severity using the German DRG case mix index that remained stable between pre- and post-intervention. Given the relatively low C. difficile infection incidence pre-intervention (compared with the national estimate of 0.4 cases per 1,000 patient days) [21], we were unable to show a significant reduction in the nosocomial C. difficile infection over time in this hospital, but a longer follow-up period and time-series analysis rather than level change analysis will be needed to fully assess a possible association. Apart from the demonstrated reduction in the overall antibiotic use and the use of cephalosporins and fluoroquinolones, we believe that there were other favourable effects associated with the intervention, e.g. improved management of bloodstream infection. Data from this
3 Gen. Cephalo sporins
Discussion
Carbapenems
1.720 (0.503)
2.235 (0.109)
13 13 13 13
63.67 (0.000)***
-0.775 (0.746) 0.0625 (0.965)
18.62 (0.000)*** 84.02 (0.000)***
1.522 (0.311)
1.746 (0.045)* 0.271 (0.645) 2.983 (0.000)***
Total Penicillins
Piperacillin ? BLI
Aminopen. ? BLI
Narrow Spectrum Penicillins
of fluoroquinolones. Conversely, penicillin consumption increased (20 % measured in RDD/1,000), in particular for narrow-spectrum penicillins (Table 1). Time-series analysis confirmed that the changes in the use of cephalosporins and fluoroquinolones, in fact, represented significant trend changes in the post-intervention period (Table 2). It also showed that the decreased overall antibiotic consumption was significant while the increase in penicillins was statistically not significant. We also calculated trend changes for other antibiotic classes and found a significantly decreasing trend for carbapenems, an increasing trend for aminoglycosides, and no trend changes for glycopeptides, macrolides, and tetracyclines. In the post-intervention period, the DRG case mix index, length of stay and in-hospital deaths remained stable compared with pre-intervention levels (these data are available on request from the author). The mean (quarterly) incidence of nosocomial Clostridium difficile infection in the pre-intervention period was 0.26 ± 0.18 cases per 1,000 patient days. Post-intervention the incidence decreased to 0.18 ± 0.06 cases per 1,000 patient days, but this 30 % difference was not statistically significant.
0.966 (0.046)*
J. P. Borde et al.
Implementing an intensified antibiotic stewardship programme Intervention
340 320 300 280
60
260 40
20
0 2011
2012
2013
2014
Fig. 1 Trends in the quarterly antibiotic use densities (expressed as RDD per 1,000 patient days) for overall antibiotic use (black line, right scale), third-generation cephalosporin use (blue line, left scale), fluoroquinolone use (red line, left scale) and narrow-spectrum penicillin use (green line, left scale) pre- and post-intervention. The increase in overall antibiotic consumption before the start of the intervention in 2013 might be related to the over-average flu activity in this time period [23]
hospital indicate that the outcomes of patients with Staphylococcus aureus bacteremia, for example, improved with the introduction of a bacteremia service [15]. Other endpoints for patients with other disease entities might also have improved with the programme and need to be considered in cost-effectiveness estimations. In a recent large analysis, infectious disease consultations appeared to be life saving and cost effective [16]. A recently published work from Germany estimated net yearly cost savings associated with stewardship activities of at least 500 € per hospital bed [17]. The effects on antibiotic class use density were relatively rapidly observed. The changes in the level of cephalosporin and fluoroquinolone use were remarkable -30 % or more within 1 year. Similar or even more excessive reductions in the use of specific drug classes have been observed by other investigators, and according to a recent metaanalysis, *50 % reductions in the use of cephalosporins or fluoroquinolones are associated with a roughly *50 % reduction in the incidence of C. difficile infections [18]. Our programme with a roughly 30 % reduction in cephalosporin (Fig. 1) and fluoroquinolone use was possibly associated with a roughly 30 % CDI reduction although this association could not be proven. Carefully planned ABS programmes, thus, may be a powerful instrument to influence the frequency and pattern of healthcare-associated infection and increase patient safety. It is of note that we did not observe potentially unfavourable effects of the programme on increased use of second-line antibiotics such as carbapenems or glycopeptides. We emphasise that both for the primary endpoint as well as for secondary
possibly untoward effects, the evaluation of trend changes by interrupted time-series analysis rather than of level changes is important. A limitation of the present study, however, remains the relative short 1-year post-intervention period with four time points only. As a conclusion, the results of this study show that ABS programmes can be easily implemented in small community hospitals in Germany and, are also likely to be cost effective in this setting. They can be used to rapidly change antibiotic strategies if needed and to improve patient outcomes. Conflict of interest On behalf of all the authors, the corresponding author states that there is no conflict of interest. Ethical statement The ethics committee was notified about the trial––formal approval was not required, because the project is based on epidemiological data. Research involving human subjects, human material, specific human or personalised data was not carried out.
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