The impact of antimicrobial drug consumption and alcohol-based hand
rub use on the emergence and spread of extended-spectrum β-lactamase (ESBL)-producing strains – A time series analysis
Klaus KaierUwe Frank
Elisabeth Meyer No. 31 – Oktober 2008
The impact of antimicrobial drug consumption and alcohol-
based hand rub use on the emergence and spread of
extended-spectrum β-lactamase (ESBL)-producing strains –
A time series analysis
Department of Environmental Health Sciences, University Medical Center Freiburg and
Research Center for Generational Contracts, Freiburg University
Department of Environmental Health Sciences, University Medical Center Freiburg
Research Center for Generational Contracts, Freiburg University
Institute of Hygiene and Environmental Medicine, Charité University Medicine Berlin,
Keywords: ESBL; antibiotic use; time series analysis.
∗ Corresponding author: Kaier, Klaus; Department of Environmental Health Sciences, University Medical
Center Freiburg, Breisacher Straße 115b, D-79106 Freiburg, Germany; Phone +49(0)761/270 8272, Fax
+49(0)761/270 8253, Email firstname.lastname@example.org
Background: Extended-spectrum β-lactamase (ESBL)-producing strains have become a
major public health threat worldwide. The aim of this study was to explore the temporal relationship between the consumption of different antibiotics, alcohol-based hand disinfection and the incidence of nosocomial ESBL.
Methods: Time series analysis was performed based on monthly data available from 01/2005 to 10/2007 on antibiotic consumption and on the use of alcohol-based hand rub. The incidence of nosocomial ESBL (cases per 1000 patient days) was regressed on the different antibiotic agents and the monthly volume of alcohol-based hand rub orders.
Antibiotic consumption was defined as monthly defined daily doses (DDD) per 1000 patient days, while alcohol based hand rub was quantified in litres per 1000 patient days. A multivariate regression model was built using a polynomial distributed lag (PDL) model.
Results: The multivariate analysis showed that using alcohol-based hand rub for hand disinfection had a significant influence on the ESBL incidence (p=0.002). A higher volume of alcohol-based hand rub use was subsequently associated with a lower incidence of
ESBL-producing strains. Additionally, the model showed that temporal increase in the use of third-generation cephalosporins (p=0.022) and fluoroquinolones (p=0.001) is, after a time lag of up to three months, followed by temporal variations in the incidence of nosocomial ESBL. Furthermore, the incidence of patients admitted with ESBL was also
shown to have an influence on the incidence of nosocomial ESBL (p<0.001). The analysis shows that a higher incidence of patients admitted with ESBL was followed by a higher incidence of nosocomial ESBL. The final model explained 75 % of the monthly variations in
the incidence of nosocomial ESBL.
Conclusions: The analysis identifies selective pressure caused by the use of different antimicrobial agents as a driving factor in the emergence and spread of ESBL. Furthermore,
the study confirms that hand disinfection is key to the prevention of nosocomial ESBL.
The emergence and spread of extended-spectrum β-lactamase (ESBL)-producing strains is
still an unresolved problem both in Germany and worldwide.1-3
During the past two decades, consumption of broad spectrum cephalosporins has
increased worldwide and a large number of ESBL positive strains have emerged since the initial description of ESBL production by K. pneumoniae isolates in Germany in 1983.4 Generally, seriously ill patients with prolonged hospital stay and invasive devices are at risk for acquisition of ESBL-producing pathogens.5
Antibiotic consumption is also a well known risk factor, and several studies have found a
positive relationship between third-generation cephalosporin, other β-lactam or
fluoroquinolone use and the acquisition of ESBL-producing organisms.6-8
The epidemiology of ESBLs has changed dramatically since the year 2000.9 Until recently, most infections caused by ESBL producing bacteria have mostly been described as
nosocomially acquired, often in specialist units. The enzyme variants found were mostly TEM or SHV. Now the CTX-M enzymes have replaced the mutants. Infections due to ESBL producers are increasingly being found in non-hospitalised patients, but the mode of
transmission is not exactly clear.10, 11 Livermore concludes that at present "the opportunities for control (of ESBLs) are disturbingly small".9
The statistical technique of time series analysis has proven to be a powerful tool to determine the relationship between antibiotic use and the occurrence and spread of
methicillin-resistant Staphylococcus aureaus (MRSA).12-14 Two recent studies included the use of antiseptic hand rub in their analysis.15, 16 This gives a more complete picture of the dynamics of resistance, since the influence of both selective pressure and the transmission
of resistant strains is analysed.
A major aim of the analysis presented here was to apply the methodology used in these recent analyses on the incidence of ESBL. Thus, the temporal relationship is shown
between the incidence of nosocomial ESBL, in-hospital consumption of different antimicrobial agents, the amount of alcohol-based hand rub used and the incidence of patients admitted with ESBL.
The analysis took place at University Medical Center Freiburg, a 1600 bed tertiary care hospital with approximately 54,000 inpatient admissions annually.
For the study period (01/2005 – 10/2007), monthly quantities of all antimicrobial drugs delivered to each hospitalization unit were exported from the pharmacy information system. Antimicrobial use was expressed in defined daily doses (DDD) following the
definition of the WHO ATC index, in order to allow a comparison of the different antimicrobial agents used. Data on the use of alcohol-based hand rub was derived from the orders placed by each hospitalization unit, expressed in litres. The number of monthly nosocomial ESBL cases was exported from an existing database at the Department for
Infection Control. An ESBL case was defined as nosocomial if detected more than 48 h after admission. Infected and colonized cases were included. Data on ESBL were only available from 2005, whereas all the other parameters were available from the beginning of 2003
and were integrated in conformance with the lagged structure of the model from August 2004 through October 2007. All the variables were normalized in values per 1000 patient days.
A two step time-series approach was carried out to explore the influence of antimicrobial use and hand disinfection on the incidence of nosocomial ESBL. All the variables were
logarithmically transformed. All of the observed series were highly volatile. Carbapenems were not included in the analysis, because their application may be a result rather than a cause of ESBL.17
In the first step, the relationship between each explanatory variable (the different
antimicrobial drug consumption and the alcohol-based hand rub series) and the explained variable (the ESBL series) was explored by separately running simple ordinary least squares regressions for each independent variable. The purpose of these univariate regressions
was to quantify the relationship between the independent variables and ESBL, and to identify lag structures for the final multivariate regression model.18 Furthermore, we tested
for stationarity with the Augmented Dickey Fuller test which is provided by the Eviews statistical package with which the whole analysis was conducted (Eviews 5.0, Quantitative Micro Software, Irvine, California, USA). All the relevant variables (the explained variable
and explanatory variables) are stationary at the ten percent level.
In the second step, a multivariate model to explain the correlation between ESBL incidence, consumption of the different antimicrobials and use of alcohol-based hand rub were built. To address the fact that for some variables more than one lag were identified as
being statistically significant, a polynomial distributed lag (PDL) modelling approach was used for the multivariate regression analysis. For the final model, we started integrating variables with the strongest relationship, but finally tested all variables for relevance.
Furthermore, we integrated the incidence of patients admitted with ESBL as an additional explanatory variable in the multivariate model.
The Akaike Information criterion was estimated to inform about the optimal lag length and
the goodness of the overall analysis, as well as the determination coefficient, R2, which informs about how much percentage of variance of the ESBL series is explained by the model.
Incidence of ESBL
From January 2005 to October 2007, a mean of 0.135 nosocomial ESBL cases were
documented per 1000 patient days at University Medical Center Freiburg. The mean of patients admitted with ESBL was 0.116. Overall, 54 % of all the ESBL cases were nosocomial and the biggest proportion (78 %) of these nosocomial cases were infections. A peak for
the nosocomial cases was observed in late summer 2007, while in two periods (04/2005, 01/2007) no cases of nosocomial ESBL were observed at all (Figure 2).
Antibiotic use and the use of alcohol-based hand rub
Trends in the use of each class of antimicrobials and in alcohol-based hand rub are presented in Table 1. The overall monthly use of antimicrobials was 631.8 DDD/1000 patient days and showed a significant ascending trend (p=0.02, based on regressions of
the series on time). Also, consumption of most antibiotic classes remained constant, significant (p<0.05) increasing trends were observed in the use of fluoroquinolones,
macrolides, third-generation cephalosporins, imidazoles, carbapenems, combinations of sulfonamides and trimethoprim, other antimicrobials as well as in alcohol-based hand rub. Descending trends were observed in the use of penicillins with extended spectrum and
For the incidence of nosocomial ESBL, a multivariate model was estimated including four
explanatory variables. Fluoroquinolones and third-generation cephalosporin consumption was identified as having a statistically significant influence on the incidence of nosocomial ESBL. Accordingly, temporal variations in the use of fluoroquinolone or third-generation cephalosporins are followed by temporal variations in the incidence of nosocomial ESBL.
Positive coefficients were estimated for both fluoroquinolone and third-generation cephalosporin use, which shows a positive relationship between these variables and the incidence of nosocomial ESBL. Furthermore, since all the variables were normalized due to
logarithmical transformation, a one percentage increase in fluoroquinolone consumption, is, according to the estimated coefficient in Table 2, followed by a 4.43 percentage increase in the incidence of nosocomial ESBL after a time lag of one month. Correspondingly, a
reduction of fluoroquinolone use is followed by a decline in the incidence of nosocomial ESBL. A one percent increase in the use of third-generation cephalosporins is followed by a 1.98 percent rise in the incidence of nosocomial ESBL after a time lag of three months.
Conversely, use of alcohol-based hand rub use shows to have a negative influence on the incidence of nosocomial ESBL. A one percentage increase in the use of alcohol-based hand rub is thus able to cause a decrease in the incidence of nosocomial ESBL of 6.73 percent after a time lag of up to four months.
Also, the incidence of patients admitted with ESBL (both colonized and infected) was included in the model, showing that every one percentage change in the incidence of patients admitted with ESBL was followed by a 0.9 percentage change in the incidence of
nosocomial ESBL. Graphical representations between the monthly use of explanatory variables and the monthly incidence of ESBL are displayed in Figure 3.
Additionally, the model included an autoregressive term of order (lag) one and had a R2 of
0.75 and an adjusted R2 of 0.69, which means that up to 75 % of the monthly variations in the ESBL incidence can be explained by the included variables (Figure 4). Also, the F-statistic shows its significance (F=11.54). We can reject the null hypothesis of serial
correlation with the Breusch-Godfrey Test and the null hypothesis of heteroscedacity with the White Heteroscedacity Test.
To our knowledge, this is the first time a time-series analysis using lagged variables shows the inter-temporal impact of imported ESBL cases, antimicrobial consumption and use of alcohol-based hand rub solution on the incidence of nosocomial ESBL cases.
The main aim of this study was to investigate the temporal relationship between certain classes of antimicrobials, hand disinfection and the incidence of ESBL. The final model demonstrates the efficiency of hand disinfection and allows to quantify the impact of
antimicrobial use on the incidence of ESBL. Third-generation cephalosporin and fluoroquinolone consumption were positively correlated with ESBL incidence, which fact can be interpreted that use of these antibiotics has a stimulating effect on the emergence and spread of ESBL in hospital settings. In contrast, the use of alcohol-based hand rub had
a negative impact on ESBL and is therefore able to prevent ESBL transmission in the hospital setting.
The method chosen in this study, i.e. time series analysis, establishes a time-dependant
relationship and allows forecasting future trends and consequences. The approach has already been used to study the cause-effect relationship between antibiotic use, hand disinfection and MRSA,13-16, 19 but not yet for ESBL.
Interestingly, the incidence of nosocomial ESBL cases (0.135, January 2005 – October 2007) at University Medical Center Freiburg lay at almost the same level as the incidence of nosocomial MRSA (0.149, January 2005 – October 2007). This points to the fact that the burden of nosocomial ESBL comes close the burden of the most prominent multiresistant
In previous studies, fluoroquinolone and third-generations-cephalosporin consumption was identified as constituting a risk factor for the selection of ESBL 20-22 Our results are also
in line with the only study so far to employ time series analysis for ESBL resistance and antibiotic use: Hay et al. showed that the incidence of ESBL-producing Klebsiella in an Australian hospital followed the amount of third-generation cephalosporin use lagged by
The negative impact of hand disinfection on the spread of ESBL in the hospital setting
might be small.9 In our study, however, hand disinfection proved to be an effective measure to control ESBL.24 This relationship underlines the importance of infection control practices at hospital admission including screening and isolation.25
The limitations of the study must be considered. No admission screening programme was in place for ESBL. Therefore, it is not possible to state the exact number of imported and nosocomially-acquired resistant pathogens. Second, aggregated data may be distorted by ecological fallacy. The data were produced at a large teaching university hospital (1600
beds) which might not be representative.
In conclusion, the driving factors of ESBL resistance were the number of ESBL cases imported to the hospital and the extensive use of fluoroquinolones and third-generation
cephalosporins. The key to prevent the spread of ESBL, however, appears to be the use of alcohol-based hand rub.
Financial support: Research on health and economic impacts of antimicrobial resistance by K.K. and U.F. is currently supported by the European Commission (Project BURDEN, Project commissioned by DG SANCO, Grant Agreement N° 2005203; http://www.eu-burden.info).
Potential conflict of interest: No conflict of interest.
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Table 1. Monthly time series of antimicrobial drug use and alcohol-based had rub series
and temporal with ESBL (August 2004 or through October 2007)a
Possible explanatory variables
Average monthly useb Trendc p
631.8 (560.1–714.6) Upward
Second-generation cephalosporins 176.1
Penicillins with extended spectrum
Combinations of penicillins with ß- 45.4 (27.8–56.7)
lactamase inhibitors ß-lactamase-sensitive penicillins 40.3
Combinations of sulfanomides and 21.5(0–56.7) Upward
trimethoprim Glycopeptides 13.5
Other antimicrobialsd 2.5
Alcohol-based hand rub
aData on ESBL were only available from January 2005, whereas all other parameters were available from the beginning of 2003. According to the lagged structure of the model, all possible explanatory variables were integrated in the model from August 2004. bQuantities of antimicrobials are expressed in DDD per 1000 patient days, those of Alcohol-based hand rub in litres per 1000 patient days. cBased on regressions of the series on timedIncluding the sparse use of linezolid, daptomycin, tigecycline and fosfomycin.
Table 2. Multivariate model to explain the monthly number of nosocomial ESBL cases/1000 patient days (R2=0,75)
Third-generation cephalosporinsa 3 1.98
Alcohol-based hand rubb 3-4
Patients admitted with ESBLc 0
Autoregressive termd 1
aIn DDD/1000 patient days.
bIn litres/1000 patient days.
cPatients admitted with ESBL infections or colonisations/1000 patient days.
dThe autoregressive term represents the past incidence of ESBL.
Figure 1. Setting, dates, population, infection control changes, antibiotic policy, isolation policy and definitions; summary table according to the ORION statement.26
Setting: 1600-bed tertiary care teaching hospital in Southern Germany with approximately 54,000
inpatient admissions annually. Infection control department with four hospital epidemiologists and three
full-time infection control nurses.
Dates: January 2005 to October 2007.
Population: A monthly average of 35,898 (range, 30063–39781) patient days were documented. Endemic ESBL (a mean of 0.135 nosocomial ESBL cases per 1000 patient days) with clones of E. Coli, Enterobacter
cloacae, Klebsiella species, Acinetobacter and Citrobacter.
Infection control changes: The monthly use of alcohol-based hand rub for hand disinfection was highly variable during the study period.
Antibiotic policy: Hospital guidelines for antibiotic use. However, no restriction policy.
Isolation policy: Besides standard precautions, contact precautions are recommended for all patients
colonized or infected with ESBL positive bacteria. Barrier precautions include single-room placement or
cohorting. Staff wear gloves and gowns while treating the patient. Furthermore, roommates are screened.
No admission screening. Electronic flagging of patients identified in the past with ESBL who are readmitted
to the hospital has been in place for the whole study period.
Definition of ESBL incidence: Number of nosocomial cases of ESBL (both colonizations and infections) per
1000 patient days.
Figure 2. The number of nosocomial ESBL cases/1000 patient days and number of patients
admitted with ESBL/1000 patient days at Freiburg University Medical Center, January 2005
– October 2007
Nosocomial ESBL cases/1000 patient daysPatients admitted with ESBL/1000 patient days
Figure 3. Graphical explorations of the monthly number of nosocomial ESBL cases/1000
patient days and lagged values of explanatory variables.
Nosocomial ESBL incidence (left
scale); -------- Independent variables used for the final model (right scale): (a) third-generation cephalosporin use (in DDD, lag 3); (b) fluoroquinolone use (in DDD, lag 1); (c) Alcohol-based hand rub use (in DDD,
cumulated lags 3-4); (d) Patients admitted with ESBL. (a)
Continuation Figure 3
Figure 4. The monthly number of nosocomial ESBL cases and monthly sum of lagged
independent variables as identified in the model
Nosocomial ESBL cases (logarithmically transformed, left scale)Sum of lagged variables (logarithmically transformed, right scale)
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