Voi.
14,1995
Use of Norfloxacin for
Prevention of Symptomatic
Urinary Tract Infection in
Chronically Catheterized
Patients
O.T. R u t s c h m a n n l * , A . Z w a h l e n 2
Thirty.four elderly inpatients with long-term urethral
catheters were randomly assigned to receive either
norfloxacin (200 mg/day) or placebo in a double-
blind study with cross-over after three months.
Twenty-three patients completed the entire study.
Norfloxacin treatment was associated with a
Persistent decrease in gram-negative isolates
(P < 0.005) and the acquisition of gram-positive
norftoxacin-resistant flora. It also resulted in a
highly statistically significant reduction of sympto-
matic urinary tract infections (1 vs. 12, p < 0.02), a
decrease in catheter-associated local complica-
tions, obstructions and leakage (p < 0.05) and an
improvement in the patients' general condition
(P < 0.001). In conclusion, within the conditions of
the present study, long-term suppression of gram-
negative bacteriuria by norfloxacin reduced the in-
Cidence of catheter-related urinary tract infection
and associated morbidity.
The rate of urethral catheterization in nursing
homes ranges from 7 to 10 % (1). This represents
an important problem, since the presence of an
indwelling catheter is associated with chronic
bacteriuria and increased morbidity (2, 3). Al-
most all nosocomial urinary tract infections
(UTIs) are associated with indwelling bladder
catheters. In previous studies, prophylactic treat-
ment with various antibiotic regimens failed to
prevent bacteriuria and its complications and was
followed by the emergence of bacterial resistance
(4-8). Using fluoroquinolones, recent trials have
shown a reduction of bacteriuria and sympto-
matic UTIs associated with postsurgical cathe-
terization (9-11). However, the potential benefit
of chemoprophylaxis with a quinolone in long-
epartment of Medicine,Division of Infectious
I D •
Daseases,
.
University Host~ital, CH-t211 Geneva 14, Switzerland.
2Departme"nt o(Medicine, H6pital de Zone de Saint-
Loup/Orbe, CH-1318 Pompaples, Switzerland.
Notes 441
term catheterized patients has not been defined.
The aim of this study was to determine the clinical
effectiveness of suppressive doses of norfloxacin
in preventing UTIs and other complications as-
sociated with long-term urethral catheterization
in elderly patients.
Patients and Methods. Thirty-four elderly in-
patients (23 women and 11 men, median age 82.5
years) living in seven nursing homes were en-
rolled in this study. Urethal catheterization had
lasted for a mean period of 18 months at the time
of randomization. Indications for catheterization
were incontinence (59 %), dementia (24 %),
pressure sore (24 %), urethral obstruction (21%),
cerebral stroke (21%) and neurogenic bladder
(15 %). Sixty percent of the patients had mod-
erate to severe mental status alterations and 37 %
had sequellae of cerebral stroke. Informed con-
sent was obtained from the patients and/or their
close relatives.
Patients were assigned to receive either norfloxa-
cin (200 mg/day) or placebo for three months,
using a double-blind randomization with cross-
over after three months. Randomization (12) and
preparation of capsules containing either placebo
or norfloxacin were carried out by Dr. Pannatier,
Department of Pharmacy, Centre Hospitalier
Universitaire Vaudois, Lausanne. Catheter man-
agement was standardized using closed sterile
drainage, replacement of the catheter at the
beginning, at cross-over, and at the end of the
study, as well as in case of obstruction; no local an-
tiseptic was used (13).
Urine cultures were obtained once monthly by
aspiration from the catheter using standard asep-
tic techniques. Results of culture were trans-
mitted only after completion of the study to the
principal investigator, who oversaw the collection
of clinical data. Antibiotic susceptibility was de-
termined by the Kirby-Bauer disk diffusion
method (Becton-Dickinson, Switzerland) using
the definitions of sensitivity and resistance used
by the manufacturer. Strains with intermediate
susceptibility were considered resistant. Erythro-
cyte and leucocyte counts were obtained and liver
and renal function tests performed at the begin-
ning, at cross-over and at the end of the study.
Episodes of UTI, catheter-related local complica-
tions (obstruction, encrustations, leakage, supra-
pubic pain, inflammation of meatus, hematuria)
and side effects of treatment were evaluated
weekly (14). Symptomatic UTI was defined as
bacteriuria >l(P cfu/ml associated with a
temperature of > 38.5°C for two consecutive days
442 Notes Eur. J. Clin. Microbiol. Infect. Dis.

in the absence of other clinical sources of infec-
tion. Flank pain, unexplained mental disturbance
and abdominal discomfort were also considered
as signs of UTI (6, 13, 15). Symptomatic UTIs
were treated by amoxicillin/clavulanate for ten
days. Prophylaxis was stopped during this period
and resumed thereafter. Before opening of the
randomization code, the nursing staff was asked
to evaluate each patient's general condition as un-
changed during the entire study or improved
during one or the other period. Criteria included
well-being of the patient, appreciation of his or
her social involvement, awareness, need for nurs-
ing care and functional status.
Wilcoxon's matched-pairs signed-rank test was
used for statistical analysis.
Results and Discussion. Eleven patients did not
complete the study: six died of non-infectious
causes (3 during placebo and 3 during norfloxacin
period), one died of septic shock (placebo period)
and in four patients the catheter was withdrawn.
Thus, we further analyzed the results of the 23
patients who completed the entire study.
Of the 161 urine cultures, 146 grew > 103 cfu/ml
and were considered positive according to the cri-
teria defined by van der Wall et al. (11), Negative
cultures were more frequent during the norfloxa-
cin than during the placebo period (13 vs. 2,
p < 0.05). Norfloxacin was associated with a sig-
nificant reduction of the average number of
bacterial isolates per patient (1.5 isolates/patient
at the beginning of the study, 1.8 at the end of
placebo and 0.96 at the end of the norfloxacin pe-
riod, p < 0.03). Gram-negative rods were predom-
inant before treatment and at the end of the
placebo period. Norfloxacin prophylaxis dramati-
caUy reduced the number of gram-negative isolates
(p < 0.005) and was associated with a moderate
increase in the number of gram-positive isolates
(p > 0.5, NS) (Table 1).
The microbial resistance pattern at randomiza-
tion and at the end of the placebo period was sim-
ilar, i.e. 25 % of the strains were resistant to
norftoxacin (10 % of the gram-negative and 50 %
of the gram-positive isolates). After three months
of norfloxacin treatment, 90 % of the urine iso-
lates were resistant to both norfloxacin and ci-
profloxacin; however, they remained susceptible
to other antibiotics (sensitivity to amoxicil-
Iirdclavulanate 85 vs. 100 %, ceftriaxone 80 vs.
90 %, cotrimoxazole 60 vs. 75 %, before and after
norfloxacin treatment, respectively).
Although norfloxacin prophylaxis failed to prevent
asymptomatic bacteriuria, it reduced sympto-
matic UTI: one episode occurred in the norfloxacin
arm compared to 12 in the placebo arm (p < 0.02)
(Figure I). Infections other than UTIs (mainly
respiratory tract infections) were not influenced
by norfloxacin, since six episodes occurred during
both periods. Encrustations (visual assessment)
and blockage of the catheter were reduced during

Table 1: Bacteria isolated from urine before and after three months of placebo or norfloxacin therapy.

No. of strains (no. sensitive to norfloxacin)

Type of organism
Before study After placebo After norfloxacin

Gram-negativebacteria 21 (20) 31 (28) 5" (1)

Escherichiacoli 11 (11) 16 (15) 0
Proteus mirabilis 4 (4) 4 (3) 1 (0)
Proteus vulgaris 2 (2) 1 (1) 0
Proteus morganii 0 2 (2) 0
Klebsiellapneumoniae 1 (1) 1 (0) 3 (0)
Klebsiella oxytoca 0 1 (1) 0
Pseudomonasaeruginosa 3 (2) 4 (4) 1 (1)
Citrobacterfreundii 0 2 (2) 0

Gram-positivebacteria 12 (7) 10 (5) 17b (1)

Enterococcusfaecalis 4 (4) 7 (5) 4 (1)
Staphylococcusaureus 4 (1) 2 (0) 3 (0)
Staphytococcusepidermidis 4 (2) 1 (<3) 8 (0)
Alpha-hemolytic streptococci 0 0 1 (0)
Beta-hemolytic streptococci O 0 1 (O)

Total no, ofstrains 33 (27) 41 (33) 22 c (2)

~p < 0.005 for the number of strains before study versus the number at the end of placebo period.
p = not significant for the number of strains before study versus the number at the end of placebo period.
Cp < 0.03 for the number of strains before study versus the number at the end of placebo period.
Vol. 14, 1995
p<0.02
O 5 10
l p<O.05
0 5 10
111)
0 5 10
Weeks of treatment
Figure 1: Effect of noflloxacin 200 mgfday versus
Placebo on symptomatic UT~ (p < 0•02), encrusta-
tions/blockages of the urethral catheter (p < 0.05) and
other catheter-related complications (p < 0.005) dunng a
12-week period.
norfloxacin prophylaxis compared to placebo (4
vs. 19, p < 0.05, and 2 vs. 8, p < 0.05, respectively).
Other local complications such as leakage, in-
flammation of meatus, suprapubic pain, hema-
turia and need for catheter replacement were not
significantly reduced. However, the trend to re-
duction observed for each parameter in the
norfloxacin arm was expressed by a significant re-
duction in the total number of adverse events
(596 in norfloxacin arm vs. 744 in placebo arm,
P < 0.005, Figure 1).
The general condition of individual patients was
classified as improved in 12 cases during norfloxa-
ein prophylaxis and in one case during the
placebo period; no change was noted in the other
Notes 443
ten patients (p < 0.001). None of the patients had
to be withdrawn from the study because of side ef-
fects of the treatment, and no biological toxicity
was noted. Seven episodes of moderate, transient
diarrhea were observed during norfloxacin pro-
phylaxis and six during the placebo period. We
did not observe persistent diarrhea, alteration of
liver function tests, hypersensitivity reactions or
alteration in mental status attributable to the
quinolones.
The efficacy and safety of quinolone prophylaxis
has been clearly demonstrated in patients under-
going urologic and gynecologic surgery (9, 16).
Prophylactic regimens containing ciprofloxacin
or norfloxacin plus amphotericin B were shown
to prevent gram-negative bacteriuria and cathe-
ter-associated UTI in surgical patients needing
short-term urethral catheterization (10, 11). In
contrast, chemoprophylaxis in long-term cathe-
terized patients failed to prevent bacteriuria and
favored the emergence of bacterial resistance (4,
5). This led to the widely accepted recommenda-
tion that antibiotics should not be used prophy-
lactically in long-term catheterized patients.
However, none of the previous studies has ana-
lyzed the long-term effect of the newer
quinolones or examined the clinical rather than
the bacteriological outcome of prophylaxis.
Our study confirmed that chronic bacteriuria in
untreated (placebo) patients is characterized by a
polymicrobial flora (2 to 5 different strains in
more than 50 % of cases) that changes over time
(4). In accordance with previous observations, we
noted that norfloxacin failed to prevent bacteri-
uria in long-term catheterized patients and
favored the emergence of quinolone-resistant or-
ganisms (5-8). However, norfloxacin prophylaxis
was associated with a striking decrease in gram-
negative isolates, and this persisted throughout
the three months of treatment. Although gram-
positive norfloxacin-resistant organisms became
predominant in the urine, these strains remained
sensitive to cotrimoxazole and amoxicillin/clavu-
lanate, thus permitting effective treatment of
symptomatic UTI in norfloxacin-treated patients•
Surprisingly, a rapid reacquisition of gram-nega-
tive norfloxacin-sensitive strains was observed
after the cessation of prophylaxis.
In control experiments we determined the MICs
for fecal strains of Escherichia coti, Klebsiella spp.
and Enterococcus faecalis isolated from ten
patients in order to detect enteric cross-infection
with resistant strains in treatment-free patients as
well as selection of resistant strains during
444 Notes
norfloxacin prophylaxis. No shift of MICs was ob-
served during the placebo period; this absence of
documented cross-infection is probably due to
the small proportion of patients receiving
norfloxacin (5 %) among the total population of
our nursing homes. In contrast, norfloxacin treat-
ment was associated with the acquisition of re-
sistant Klebsiella spp. and highly resistant Entero-
coccus faecalis that persisted in the stools three
months after the cessation of norfloxacin treat-
ment (data not shown). These observations con-
firmed that long-term quinolone usage may select
particularly resistant strains. Although prolonged
administration of norfloxacin may be associated
with adverse effects, we observed excellent toler-
ance of the drug in our 23 patients (14).
In conclusion, our results demonstrated a striking
effect of norfloxacin prophylaxis in preventing
both symptomatic UTIs and local complications
of indwelling catheters. In addition, the general
condition of more than half of the patients was
improved. These clinical observations suggest
that long-term reduction of gram-negative bac-
teriuria is clinically relevant, which may indicate a
role for endotoxins as a determinant of urinary
catheter-associated morbidity in the elderly. The
results of this study also strongly suggest that at
least some patients with urethral catheterization
may benefit from long-term prophylaxis with
norfloxacin. However, our observations cannot
be extended to hospitalized patients, since the
clustering of individuals receiving quinolones is
known to result in the rapid spread of resistant
strains. Thus, before changing the present con-
sensus recommendation (no treatment), a larger
field trial is required to better define the clinical
indications and ecological conditions in which
quinolone prophylaxis could be used safely.
Acknowledgements
The authors thank R, Auckenthaler, E.C. Bonard, P.
Br6aud, P, Christeler, C. Danthe, C. Dvorak, M.P.
Glauser, E Knobel, L. Pache, A. Pannatier, M. Rossier,
G. Van Melle and P. Vaudaux, as well as Merck Sharp
& Dohme/Chibret Switzerland for financial support.
References
1. Warren JW, Steinberg L, Hebel JR, Tenney JH: The
prevalence of urethral catheterization in Maryland nurs-
ing homes. Archives of Internal Medicine 1989, 149:
1535-1537.
2. Platt R, Polk BF, Murdock B, Rosner B: Mortality as-
sociated with nosocomial urinary-tract infection. New
England Journal of Medicine 1982, 307: 637-642.
Eur. J. Clin. Microbiol. Infect. Dis.
3. Stark RP, Maki DG: Bacteduda in the catheterized
patient. What quantitative level of bacteriuda is relevant?
New England Journal of Medicine 1984, 311: 560-584.
4. Breitenbucher RB: Bacterial changes in the udne
samples of patients with long-term indwelling catheters;
Archives of Internal Medicine 1984, 144: 1585-1588.
5. Warren JW, Anthony WC, Hoopes JM, Muncie HL:
Cephalexin for susceptible bacteriuria in afebdle, long-
term catheterized patients. Journal of the Amedcan Medi-
cal Association 1982, 248: 454-458.
6. Bdtt MR, Garibaldi RA, Miller WA, Herbertson RM, Burke
JP: Antimicrobial prophylaxis for catheter-associated
bacteriuria. Antimicrobial Agents and Chemotherapy
1977, 11: 240-243.
7. Mountokalakis T, Skounakis M, Tselentis J: Short-term
versus prolonged systemic antibiotic prophylaxis in
patients treated with indwelling catheters. Journal of
Urology 1985, 134: 506-508.
8. Brocklehurst JC, Brocklehurst S: The management of
indwelling catheters. British Journal of Urology 1978,
50: 102-105.
9. Cutajar CL: Norfloxacin prophylaxis for endoscopic uro-
logical surgery. British Journal of Urology 1992, 69: 421-
424.
10. Vollaard EJ, Clasener HA, Zambon JV, Joosten HJ, van
Griethuysen AJ: Prevention of catheter-associated gram-
negative bacilluda with norfloxacin by selective decon-
tamination of the bowel and high urinary concentration.
Journal of Antimicrobial Chemotherapy 1989, 23: 915-
922.
11. van der Wall E, Verkooyen RP, Mintjes-de Groot J,
Oostinga J, van Dijk A, Hustinx WNM, Verbrugh HA:
Prophylactic ciproftoxacin for catheter-associated uri-
nary-tract Infection. Lancet 1992, 339: 946-951.
12. Cochran WG, Cox DR: Expedmental designs. John Wiley
& Sons, New York, 1975.
13. Schaeffer AJ: Catheter-associated bacteriuda. Urologic
Clinics of North America 1986, 13: 735-747.
14. Wang C, Sabbaj J, Corrado M, Hoagland V: World-wide
clinical experience with norfloxacin: efficacy and safety.
Scandinavian Journal of Infectious Diseases 1986,
Supplement 48: 81--89.
15. Warren JW, Damron D, Tenney JH, Hoopes JM, Deforge
B, Muncie HL: Fever, bacteremia, and death as com-
plications of bacteduria in women with long-term urethral
catheters. Journal of Infectious Diseases 1987, 155:
1151-1158.
16. Verbrugh HA, Mintjes-de Groot AJ, Andriesse R, Hamer-
sma K, van Dijk A: Postoperative prophylaxis with
norfloxacin in patients requiring bladder catheters.
European Journal of Clinical Microbiology & Infectious
Diseases 1988, 7: 490-494.