Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . .
1. Structure, Mechanism of Action and Chemistry
2. Pharmacokinetic Properties . . . . . . . . . . .
3. Spectrum of Antibacterial Activity . . . . . . . .
4. Bacterial Resistance . . . . . . . . . . . . . . . .
5. Clinical Use . . . . . . . . . . . . . . . . . . . . .
6. Adverse Reactions . . . . . . . . . . . . . . . . .
7. Conclusion . . . . . . . . . . . . . . . . . . . . .
Abstract
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353
354
355
355
357
358
361
362
There have been few recent reviews of the nitrofurans in the literature, and
none include recently available data on the use of nitrofurazone (nitrofural) in the
prevention of catheter-associated urinary tract infection (CAUTI). Nitrofurazone
and nitrofurantoin are the only nitrofurans that have become established in clinical use in the 20th century. These 2 nitrofurans have remained clinically useful
against a wide spectrum of Gram-positive and Gram-negative bacteria, including
many strains of common urinary tract pathogens. Today, the primary use of nitrofurantoin is as an oral antibacterial treatment for genitourinary infections.
Nitrofurazone is primarily used as a topical antibacterial agent in burns and skin
grafts and recently was approved for the prophylaxis of CAUTI. The recent development of a nitrofurazone-impregnated catheter as a novel modality in the
prevention of CAUTI reflects a renewed interest in the effectiveness of nitrofurans. In an era when concern about bacterial resistance to many anti-infective
agents is growing, the nitrofurans have continued to be active against organisms
that have developed resistance to antibacterials. The presence of multiple mechanisms of action for the nitrofurans might be expected to reduce the ability of
bacteria to develop resistance. Considering that an emergence of resistance to the
nitrofurans has not appreciably occurred after several decades of clinical use, the
nitrofurans may be unique among common antibacterial agents in this regard.
354
Guay
O
O2N
CH
O
NNHCONH2
O2N
CH
O
N
NH
O
Nitrofurazone (Nitrofural)
(5-nitro-2-furaldehyde semicarbazone)
Nitrofurantoin
(1 - [(5-nitrofurfurylidene) amino] hydantoin)
355
356
Two specific pathogens, diphtheroids and Bacillus fluorescens, quickly disappeared after application and did not interfere with any clinical response, resulting in successful skin grafting.[20]
Subsequently, Shipley and Dodd[21] reported on
the efficacy of nitrofurazone in the management of
bacterial wound infections. Healing of wounds after nitrofurazone soluble dressing application was
classified as brilliant, good, questionable, and
no effect. They reported that 77% of wound healings were considered brilliant or good. Grampositive cocci and diphtheroids were the predominant isolates, constituting 71% of total isolates.
Altogether, 63% of isolates were eradicated during
therapy, with a wide range of times to eradication.
In some cases, isolates were not eradicated and yet
wounds either healed or improved.[21] 18 years after his first study, Shipley[22] conducted a followup study using nitrofurazone, documenting the
continued highly effective antibacterial activity of
the agent.[22]
After many years of nitrofurazone use in the
treatment of SSSI, the lack of development of bacterial resistance led to a new use for the drug in the
prevention of CAUTI. Fifty years after the nitrofurans were first introduced, a report by Johnson et
al.[5] demonstrated that nitrofurazone, as a component of a nitrofurazone-matrix catheter, inhibited
the in vitro growth of most bacterial strains implicated in CAUTI, including many Gram-negative
bacilli. In this study, 70 strains of urinary pathogens were studied in order to: (i) determine the activity of nitrofurazone and of the nitrofurazone matrix catheter against bacteria causing CAUTI; (ii)
demonstrate whether a correlation existed between
susceptibility to nitrofurazone and susceptibility to
inhibition by the nitrofurazone-matrix catheter;
and (iii) determine the validity of using the nitrofurantoin minimum inhibitory concentration (MIC)
as a surrogate for the nitrofurazone MIC. The urinary
pathogens studied included coagulase-negative
staphylococci, Staphylococcus aureus, Enterococcus
spp., Serratia spp. and Proteus spp., Corynebacterium minutissimum, Escherichia coli, Enterobacter
spp., Klebsiella spp., Proteus mirabilis, Citrobacter
Adis International Limited. All rights reserved.
Guay
357
Acinetobacter calcoaceticus
[mg/L (%)]
[mg/L (%)]
50 (5)
100 (5)
200 (26)
Citrobacter spp.
<50-100
50 (90)
100 (100)
Enterobacter spp.
50->300
50(11)
100 (68)
Escherichia coli
8-512
50 (100)
Klebsiella pneumoniae
50 (31)
Proteus mirabilis
100->300
Proteus spp.
50->300
Providencia spp.
Pseudomonas aeruginosa
>200
Serratia marcescens
200 (95)
100 (74)
200 (96)
100 (28)
400 (98)
50 (6)
100 (50)
300 (80)
50 (8)
100 (25)
200 (88)
50 (3)
100 (3)
300 (5)
50 (3)
100 (3)
300 (63)
358
Guay
5. Clinical Use
UTIs can be divided into a number of categories,
including acute uncomplicated cystitis in women,
acute uncomplicated pyelonephritis in women,
complicated UTI (e.g. anatomical or functional
disorder within the urinary tract), and special circumstances (e.g. UTI in children, pregnancy, immunocompromised patients, etc.).
Nitrofurantoin has been used as a definitive
therapy for uncomplicated cystitis and as a prophylactic agent for recurrent uncomplicated cystitis.[15] Numerous studies have demonstrated its effectiveness in eliminating both Gram-negative and
Gram-positive pathogens from the urinary tract in
adults and children and in catheterised patients. Today, nitrofurantoin may still be reasonably considered a first-line therapy for acute uncomplicated
cystitis in women with a dosage regimen of dualrelease capsules 50 to 100mg every 6 hours or
100mg every 12 hours for 7 days. A recent practice
guideline from the Infectious Diseases Society of
America does not support 3-day therapy with nitrofurantoin.[31]
Evidence of the efficacy of nitrofurantoin against
specific microorganisms has accumulated throughout its 50 years of use.[13,15,25,32,33] In 1979, a review
by Gleckman and colleagues[15] demonstrated that
the cure rate in UTI caused by E. coli was approximately 75% in adults and 90% in children. For
recurrent UTI caused by E. coli, nitrofurantoin resulted in an 80 to 100% cure rate in adults and
approximately 90% cure rate in children.
Adis International Limited. All rights reserved.
1992
1993
1994
1995
1996
E. coli
(n = 567)
all
(n = 653)
E. coli
(n = 931)
all
(n = 1081)
E. coli
(n = 967)
all
(n = 1127)
E. coli
(n = 691)
all
(n = 807)
E. coli
(n = 580)
all
(n = 674)
Ampicillinb
26
29
29
32
31
33
32
34
34
38
Cefalotinb
20
20
25
24
38
37
32
32
28
28
Ciprofloxacin
0.2
0.3
0.2
0.1
0.3
0.2
0.3
Gentamicin
0.4
0.4
Nitrofurantoin
22
21
25
24
26
24
25
22
27
26
Cotrimoxazoleb
10
12
12
18
16
Trimethoprimb
10
10
12
12
18
16
Sulfamethoxazole
358
Table II. Percentages of urinary isolates from women with acute uncomplicated cystitis resistant to selected antibacterial agentsa (reproduced from Gupta et al.,[30] with permission)
0.2
Percentages reflect the number of isolates tested with each agent; this may be less than the total number for each column.
There was a significant increasing linear trend in resistance from 1992 to 1996 for Escherichia coli and all isolates for ampicillin (p < 0.002), cefalotin (p < 0.001), trimethoprim
(p < 0.001), and cotrimoxazole (trimethoprim-sulfamethoxazole) [p < 0.001] using the 2 test for linear trend.
Guay
359
Supporting this rationale for an antibacterialimpregnated catheter is the prevalence of catheterisation and CAUTI in hospitalised patients. It is
estimated that 10 to 15% of hospitalised patients
are managed with indwelling catheters, and the
prevalence of urinary catheter use has increased
over the last 2 decades.[27] In 1996, Burke and
Riley[27] reported that 70 to 80% of UTI in acute
care hospitals are caused by indwelling catheters.
CAUTI occurs within 24 to 48 hours after catheter
insertion,[43,44] developing most commonly as a result of the patients own flora, superimposed upon
other factors such as underlying disease, poor catheter insertion techniques and care, and duration of
catheterisation.[28]
Tambyah and co-workers[43] were the first to report on the pathogenesis of CAUTI in 1497 catheterised patients. Results indicated that 235 new
CAUTI occurred, with females (23.2%) having a
higher incidence of infection than males (8.9%).
The majority of CAUTI were acquired extraluminally (66%) rather than intraluminally (34%). The
majority of CAUTI were unimicrobial (94%) rather
than polymicrobial (6%). CAUTI were most often
associated with Enterococci and Gram-negative
bacilli, with 13% caused by E. coli and 26% by
Klebsiella, Enterobacter and Citrobacter species,
P. aeruginosa and other resistant nosocomial Gramnegative bacilli. 34% were caused by enterococci
and staphylococci and 27% by Candida species.
These data are summarised in table III. Investigators found that enterococci, staphylococci and
yeasts gained access to the bladder extraluminally,
whereas Gram-negative bacilli gained access intraluminally. These investigators suggested that a
nitrofurazone-impregnated catheter would significantly decrease the frequency of infections caused
by Gram-negative bacilli.
In recent years, researchers have reported on the
benefits of the nitrofurazone-impregnated catheter
in the prevention of CAUTI. In 1993, as summarised in section 3, Johnson et al.[5] demonstrated
in vitro that nitrofurazone-impregnated catheter
segments inhibited the growth of the majority of
70 urinary bacterial isolates from patients with inDrugs 2001; 61 (3)
360
Guay
Table III. Mechanisms of catheter-associated urinary tract infection (CAUTI), stratified by pathogen group (reproduced from Tambyah et al.,[43]
with permission)
Mechanism
Gram() bacilli
[no. (%)a]
yeasts
[no. (%)a]
all species
115
Extraluminal
44 (79)
37 (54)
34 (69)
Earlyb
11 (20)
11 (16)
9 (18)
31
Later
33 (59)
26 (38)
25 (51)
84
Intraluminal
12 (21)
31 (46)
15 (31)
58
Indeterminate
29
29
19
77
Total infections
85
97
68
250
Percentages refer to 173 of 250 organisms (69.2%) in which the mechanism of infection was determinable. For the determinable cases,
overall 2 = 8.18 (2 degrees of freedom), p = 0.017. For a comparison of yeasts and Gram-positive cocci versus Gram-negative bacilli,
p = 0.007.
361
% calculated
frequency
Pulmonary
acute
subacute
1138
0.00094
22
0.00002
chronic
281
0.00023
miscellaneous
283
0.00023
Hepatic
312
0.00026
Neurological
847
0.00070
Haematological
500
0.00041
362
Guay
fairly low intrinsic antibacterial activity, therapeutically relevant antibacterial activity occurs only
within the urinary tract. Selection pressure for the
development of resistant strains in other parts of
the body should be negligible (with the possible
exception of gastrointestinal tract). Nitrofurantoin
has an established role in the treatment of acute
uncomplicated cystitis in women and long term
prophylaxis (in selected cases of female adults/
children) of uncomplicated UTI. To that may be
added the knowledge that another nitrofuran, nitrofurazone, after many decades of effectiveness in
the treatment of wounds and burns, promises to be
of clinical utility in the short term prevention of
CAUTI.
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