Fluoroquinolone consumption and resistance in haematologyoncology ...
Fluoroquinolone consumption and resistance in
haematology–oncology patients: ecological analysis
in two university hospitals 1999–2002
Winfried V. Kern1
*, Michaela Steib-Bauert1
, Katja de With1
, Stefan Reuter2,3
, Hartmut Bertz4
and Heike von Baum6
Center for Infectious Diseases and Travel Medicine, Department of Medicine, 4
Department of Haematology-
Oncology and 5
Institute of Environmental Medicine and Hospital Epidemiology, University Hospital, Hugstetter
Strasse 55, D-79106 Freiburg; 2
Section of Infectious Diseases and Clinical Immunology and 3
Haematology-Oncology, University Hospital and Medical Center; 6
Section of Hospital Hygiene, Department of
Medical Microbiology and Hygiene, University of Ulm, Ulm, Germany
Received 26 July 2004; returned 21 September 2004; revised 3 October 2004; accepted 23 October 2004
Objectives: To compare rates of in vitro ﬂuoroquinolone resistance of bacterial isolates obtained from
inpatients of two haematology–oncology services with high and low ﬂuoroquinolone consumption.
Methods: Two hospitals with consistently high (A) and low (B) ﬂuoroquinolone use in their haemato-
logy–oncology services between the years 1999 and 2002 were identiﬁed in a hospital antibiotic use
surveillance project. Rates of in vitro resistance to ﬂuoroquinolones in inpatients of the services were
determined for Escherichia coli and coagulase-negative staphylococcal bloodstream isolates, and also
for Pseudomonas aeruginosa and Staphylococcus aureus isolates from any site.
Results: Fluoroquinolone resistance of E. coli was signiﬁcantly higher in hospital A than in hospital B,
but there was no such correlation between ﬂuoroquinolone use and resistance rates for P. aeruginosa
Conclusion: The impact of antibiotic consumption on the prevalence of resistance may differ widely
between different pathogens. Interventions using ecological analyses of the relationship between hos-
pital antibiotic use and resistance need to consider pathogen-speciﬁc dynamics in the emergence and
control of bacterial resistance.
Keywords: antibiotic use, Escherichia coli, ﬂuoroquinolone resistance, antibiotic policy, drug utilization, febrile
neutropenia, resistance epidemiology, staphylococci
Fluoroquinolones were introduced into clinical practice in the
hope of slowing down the development of resistance due to the
extremely low likelihood of transferable plasmid-mediated
resistance. Fluoroquinolone resistance, however, is now common
among many bacterial pathogens worldwide.1–3
the most important risk factor for ﬂuoroquinolone resistance
appears to be previous ﬂuoroquinolone use.4–7
lone use through interventions might offer opportunities to
reduce the prevalence of bacterial resistance to this class of anti-
biotics. Planning such interventions requires information about
the relationship between the volume of quinolone use and the
prevalence of resistance in different health care settings, patient
populations, and drug–pathogen pairs.
In a recent hospital antibiotic use surveillance project, we
identiﬁed two hospitals with consistently high and low ﬂuoroqui-
nolone consumption levels in haematology–oncology services
over several years. We evaluated the rates of resistance of clinical
isolates from inpatients of these services in order to obtain esti-
mates for pathogen-speciﬁc variations in resistance prevalence as
a baseline before intervention. Unexpectedly, there was no corre-
lation between unit-wide ﬂuoroquinolone consumption and resist-
ance among staphylococci and Pseudomonas aeruginosa, while
*Corresponding author. Tel: +49-761-270-1819; Fax: +49-761-270-1820; E-mail: firstname.lastname@example.org
Journal of Antimicrobial Chemotherapy
DOI: 10.1093/jac/dkh510 JAC
Page 1 of 4
JAC q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
Advance Access published December 1, 2004
ﬂuoroquinolone resistance of Escherichia coli correlated well
with consumption data.
Materials and methods
Two university hospitals with large differences in ﬂuoroquinolone
consumption in the haematology–oncology service were identiﬁed
after evaluation of antibiotic use data obtained from the hospital
pharmacies. This ﬁnding was related to the extensive use of oral
ﬂuoroquinolones (>90% levoﬂoxacin orally in daily dosages of
1 Â 500 mg in patients with normal renal function) for infection pre-
vention in all haematology patients with neutropenia admitted to
one of the two hospitals (hospital A), while trimethoprim/sulfa-
methoxazole was used as the standard prophylactic regimen for
cancer patients with neutropenia in the second hospital (hospital B).
The two haematology–oncology services were similar with respect
to the number of beds and number of admissions per year with
de novo diagnosed acute leukaemia. The number of stem cell or
bone marrow transplant recipients was slightly higher in hospital B
(yearly number, $ 70 versus 100, respectively). This subgroup of
hospital B haematology–oncology service patients received cipro-
ﬂoxacin (in daily dosages of 2 Â 500 mg) for infection prevention
during the neutropenic period following the conditioning regimen.
In both hospitals, ﬂuoroquinolones were not recommended as ﬁrst-
or second-line empirical therapy of neutropenic fever.
The two hospitals are located in different regions of the federal
state of Baden-Wu¨rttemberg where ﬂuoroquinolone consumption in
the community has been comparatively low.8,9
Antibiotic use was expressed as deﬁned daily doses per 100
patient days (DDD/100) according to the World Health Organization
(WHO)/Anatomical Therapeutic Chemical (ATC) classiﬁcation
(http://www.whocc.no). We also used a different deﬁnition of daily
doses [prescribed daily doses (PDD), consistent with local guide-
lines] since the WHO/ATC classiﬁcation usually overestimates
antibiotic consumption due to its often low deﬁned daily doses com-
pared with truly prescribed doses in hospital practice. For example,
the WHO/ATC DDD for levoﬂoxacin (according to the WHO/ATC
2001 classiﬁcation guidelines) is 250 mg, whereas the dose usually
prescribed (and also used according to local guidelines in hospital
A) was 500 mg per day.
Yearly rates of in vitro resistance to ﬂuoroquinolones (cipro-
ﬂoxacin and/or levoﬂoxacin) in E. coli, other Enterobacteriaceae,
P. aeruginosa, other non-fermentative bacilli, Staphylococcus
aureus and coagulase-negative staphylococci (CoNS) were retrieved
from the microbiology laboratories of the two institutions. Suscepti-
bility testing was done according to established guidelines using
microbroth dilution tests. Identical breakpoints for resistance were
used in the two institutions. Copy strains (isolates from the same
patient during a given admission) were excluded. For E. coli and
other Enterobacteriaceae, resistance to trimethoprim/sulfamethoxa-
zole was also evaluated.
We evaluated isolates obtained from any site versus bloodstream
isolates separately. We ﬁnally only included groups of isolates in
this analysis if their mean annual number (tested non-copy isolates)
was at least 10 at both institutions. Thus, bloodstream isolates of
P. aeruginosa and S. aureus had to be excluded from analysis, and
in hospital A, inadequate numbers of staphylococci had been tested
for susceptibility to ﬂuoroquinolones in 1999. Also, meaningful
comparison of resistance rates in Enterobacteriaceae other than
E. coli and in non-fermentative Gram-negative bacilli other than
P. aeruginosa was not possible due to major differences in the num-
bers of isolates at the two hospitals: there were many more Entero-
bacteriaceae isolates from hospital B patients, and conversely, there
were many more isolates of non-fermenters in hospital A patients,
suggesting distinctive effects of antibiotic use on the spectrum of
signiﬁcant pathogens and presumably patient endogenous ﬂora.
Pearson’s correlation coefﬁcient r was used to describe the
association between yearly department-wide resistance rates and
Results and discussion
Hospital A haematology–oncology service showed a ﬂuoroqui-
nolone use density of 75 DDD/100 (4-year average, 1999–2002;
range, 53.2–92.8) which was signiﬁcantly higher than at hospital
B (4-year average, 12 DDD/100; range, 9–13.2) (Figure 1).
Applying the alternative daily dose deﬁnition (prescribed daily
doses, PDD) to consumption data from the two hospitals, ﬂuoro-
quinolone use in hospital A was still much higher than in hospi-
tal B (4-year averages, 37.9 versus 10.7 PDD/100) while total
consumption of antibiotics was similar in the haematology–
oncology services of the two hospitals (81.9 versus 81.4
PDD/100) (Figure 1). Since trimethoprim/sulfamethoxazole was
used as a standard prophylactic drug in neutropenic patients in
hospital B, consumption of this agent was higher in hospital B
than in hospital A (6.3 versus 15.5 PDD/100).
As shown in Figure 2, rates of in vitro resistance to ﬂuoroqui-
nolones were high in hospital A haematology–oncology service
bloodstream isolates of E. coli (range, 64–79%) and relatively
low in hospital B (range, 0–10%), and correlated well with the
consumption data (Pearson’s correlation coefﬁcient, r = 0.95).
Figure 1. Antibiotic use during the years 1999–2002 in the haematology–
oncology services of two university hospitals. DDD, deﬁned daily doses
according to ATC/WHO; PDD, prescribed daily doses according to local
treatment guidelines. Grey bars, ﬂuoroquinolones; black bars, trimethoprim/
sulfamethoxazole; white bars, all other antibacterial agents.
W. V. Kern et al.
Page 2 of 4
The correlation between use and resistance was less clear for
trimethoprim/sulfamethoxazole (r = 0.63) because relatively low
consumption of trimethoprim/sulfamethoxazole in hospital A
(<10 PDD/100) was associated with relatively high resistance
rates in E. coli (range, 33–59%) which were not much lower
than those observed in hospital B, and with trimethoprim/sulfa-
methoxazole resistance rates in E. coli bloodstream isolates ran-
ging between 42 and 76% (Figure 2). A possible explanation for
the higher rate of resistance to trimethoprim/sulfamethoxazole
compared with ﬂuoroquinolones at similar consumption levels is
the more rapid development of resistance to trimethoprim/sulfa-
methoxazole via transferable elements together with a higher
resistance prevalence in the general population.10–12
Rates of ﬂuoroquinolone resistance in the two services were
similar for P. aeruginosa (A, 10–31%; B, 14–29%, Figure 2)
and S. aureus (A, 0–12%; B, 3–17%, data not shown) and
did not correlate with unit-wide ﬂuoroquinolone consumption
(P. aeruginosa, r = À0.05; S. aureus, r = 0.16). Fluoroquinolone
resistance rates for S. aureus reﬂected the MRSA rates in the
two services. In contrast, ﬂuoroquinolone resistance rates were
much higher in CoNS (A, 68–79%; B, 70–79%), but again, did
not correlate with ﬂuoroquinolone consumption (r = À0.05). The
results for hospital B did not change when the bone marrow and
stem cell transplant unit (where ciproﬂoxacin was usually given
as prophylaxis) was excluded from the analysis (data not
These ﬁndings show that pathogen-speciﬁc patterns of
organism–drug interaction obviously depend on organism preva-
lence, clonal turnover, and risks to develop resistance in a par-
ticular species. The ﬁndings are relevant to planning drug use
interventions and interesting for several reasons. First, they show
a uniformly high prevalence of ﬂuoroquinolone resistance
among CoNS even in the low-consumption unit, consistent with
the known rapid development of resistance at no or low ﬁtness
cost in these organisms,13–17
a possible role of methicillin resist-
and, perhaps, frequent patient-to-patient trans-
The ‘low-consumption’ unit showed ﬂuoroquinolone
use of $ 12 DDD/100 which is in the range of that reported for
intensive care units from diverse areas, and thus it is only low
relative to hospital A.23–26
Whether the speciﬁc drug used at hos-
pital B (ciproﬂoxacin) plays a role for the high resistance preva-
lence values in CoNS is possible but cannot be judged from this
study. Second, the data appear to conﬁrm the view that through
restriction of ﬂuoroquinolone use in hospitals, it may be possible
to reduce the prevalence of ﬂuoroquinolone resistance in E. coli
to the level prevalent in the community as suggested by previous
Third, the situation for P. aeruginosa and S. aureus
appears to be different from that for the organisms discussed
above. For unknown reasons, both P. aeruginosa and S. aureus
have become infrequent pathogens in haematological patients.
Low colonization titres and/or infrequent carriage would provide
less chance to select for resistant mutants and enable their trans-
mission. In addition, ﬂuoroquinolone-resistance mutations in
S. aureus and P. aeruginosa may result more frequently in a
relevant loss of ﬁtness. Therefore, interventional programmes
may be less likely to impact on resistance prevalence in these
organisms. This situation may differ in intensive care units with
higher rates of transmission and higher endemic rates of MRSA,
which appear to be more easily selected after exposure to ﬂuoro-
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