REVIEW ARTICLE

Drugs 2001; 61 (3): 353-364

0012-6667/01/0003-0353/$27.50/0
Adis International Limited. All rights reserved.

An Update on the Role of Nitrofurans

in the Management of Urinary
Tract Infections
David R. Guay
University of Minnesota, Institute for the Study of Geriatric Pharmacotherapy, and College of
Pharmacy and Partnering Care Senior Services, HealthPartners, Minneapolis, Minnesota, USA

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)

Fig. 1. Chemical structures of nitrofurazone and nitrofurantoin.

The first nitrofuran available for clinical use

was nitrofurazone (nitrofural), which gained recognition as a useful antibacterial agent in the care
of war wounds in Europe during World War II.[1]
While several thousand nitrofuran compounds
have been synthesised since then,[2] only 2 derivatives have become established in clinical use:
nitrofurazone and nitrofurantoin. Throughout the
years, these 2 nitrofurans have remained clinically
useful against a wide spectrum of Gram-positive
and Gram-negative bacteria,[2-4] including many
strains of common urinary tract pathogens.[4,5] Today, the primary use of nitrofurantoin is as an oral
antibacterial agent for the treatment of genitourinary infections. Nitrofurazone is primarily used as
a topical antibacterial agent in patients with burns
and skin grafts, and recently was approved for the
prophylaxis of catheter-associated urinary tract infection (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.
The objective of this paper is to review key aspects of the nitrofurans currently available for clinical use (nitrofurantoin and nitrofurazone). Although the nitrofurans have been an important
component of the antimicrobial armamentarium
for approximately 50 years, there have been few
recent reviews of the nitrofurans in the literature,
and none include recently available data on the use
of nitrofurazone in the prevention of CAUTI.
Therefore, in an era when concern about bacterial
resistance to many anti-infective agents is growing,
it is important to provide a current overview of the
nitrofurans, especially considering that these agents
may be active against organisms that have devel Adis International Limited. All rights reserved.

oped resistance to other antibacterials, and that

emergence of resistance to the nitrofurans has not
appreciably occurred after several decades of clinical use.[2,3,6] The nitrofurans may be unique among
common antibacterial agents in this regard.
In this paper, after a brief discussion of the structure, mode of action, and pharmacological properties of nitrofurantoin and nitrofurazone, the literature
on the antimicrobial activity, bacterial resistance,
clinical use and adverse reactions of the nitrofurans
is reviewed.
1. Structure, Mechanism of Action
and Chemistry
Nitrofurantoin and nitrofurazone are synthetic antibacterial nitrofuran derivatives which are chemically related. Chemical structures are provided in
figure 1.
Studies indicate that the presence of enzymes
capable of reducing nitrofurantoin is crucial for its
activation.[6,7] Activated nitrofurantoin and nitrofurazone have been shown to similarly inhibit a
number of bacterial enzymes.[2,4,6,8-12] It appears that
the nitrofurans act by inhibiting bacterial enzymes
involved in DNA and RNA synthesis, carbohydrate
metabolism, and other metabolic enzyme proteins.[13]
Organic matter (e.g. blood and serum) slightly reduces the antibacterial activity of nitrofurazone in
vitro, but this small reduction is not likely to be
clinically important in patients with burns or other
surface wounds containing blood or serum.[14]
Aminobenzoic acid also has an inhibitory effect on
the antibacterial activity of nitrofurazone.[3]
Nitrofurazone and nitrofurantoin exist as lemon
yellow, odourless, crystalline powders, which are
very slightly soluble in water and in alcohol. The
Drugs 2001; 61 (3)

Nitrofurans in the Management of UTIs

drugs are slightly soluble in propylene glycol and

polyethylene glycol mixtures, which are frequently used as vehicles in commercial preparations.
Nitrofurazone cream and ointment are yellow,
opaque, and water-miscible; the topical solution is
a light yellow, clear, somewhat viscous liquid with
a faint characteristic odour, which is miscible with
water.[3] Nitrofurantoin is currently commercially
available as capsules, tablets and oral suspension.[15]
Both nitrofurazone and nitrofurantoin darken
slowly upon exposure to light, although discoloration does not affect the potency of the drug.[2,3]
Nitrofurazone is stable in solutions with a pH of 4
to 9. Nitrofurantoin is a weak acid with a pKa of
7.2.[13,15] Both may be autoclaved with little loss
of antibacterial activity. Preparations of nitrofurazone and nitrofurantoin should be stored and dispensed in tight, light-resistant containers, avoiding
all exposure to direct sunlight, strong fluorescent
light, prolonged excessive heat, and alkaline materials.[2,3]
2. Pharmacokinetic Properties
Nitrofurantoin dual-release capsules contain 2
forms of nitrofurantoin: 25% is macrocrystalline
nitrofurantoin, which has a slower dissolution and
absorption rate than nitrofurantoin monohydrate;
75% is nitrofurantoin monohydrate that forms a gel
matrix once gastrointestinal fluids come into contact with the monohydrate. This gel matrix allows
the dissolution of nitrofurantoin over time. Another oral capsular form available is nitrofurantoin
macrocrystals, which again provide delayed release and decreased bioavailability compared with
microcrystaline preparations e.g. tablets, oral suspension. In the presence of normal renal function,
nitrofurantoin has a terminal disposition half-life
of approximately 20 minutes with 40% of the drug
being excreted into the urine in the therapeutically
active unchanged form.[13,15,16]
When taken orally for urinary tract infection
(UTI), nitrofurantoin is rapidly metabolised in renal tissues and is rapidly excreted into the urine via
glomerular filtration and tubular secretion. There
Adis International Limited. All rights reserved.

355

is a lack of systemic accumulation except in the

presence of impaired renal function; patients receiving long term therapy should be monitored periodically for changes in renal function.[16] It is the
rapid absorption and excretion by the kidneys that
gives nitrofurantoin its therapeutic value as a urinary antibacterial drug.[13] Since nitrofurantoin is
a weak acid, more of the drug is reabsorbed from
the renal tubules if the urine is acidic. If the urine
is alkaline, then little of the drug is reabsorbed and
instead is excreted in the urine. When taken with
food, the bioavailability of nitrofurantoin is enhanced by approximately 40%.[15,16]
As a topical antiseptic, nitrofurazone soluble
dressing contains 0.2% nitrofurazone in a watersoluble base of polyethylene glycols. As a urinary
antibacterial, nitrofurazone is impregnated into the
external surface and inner lumen of a Foley silicone catheter; there is 10.2g (2.0) of nitrofurazone per mm2 surface area of the catheter.
Nitrofurazone elutes into the urethral-catheter
boundary producing local antibacterial activity.
Nitrofurazone is not significantly absorbed systemically through the urethra over 12 to 24
hours.[17] Earlier studies also demonstrate that nitrofurazone is not absorbed systemically from the
urethra or vagina.[18,19]
3. Spectrum of Antibacterial Activity
Throughout the years, the nitrofurans have remained clinically useful against a wide spectrum
of Gram-positive and Gram-negative bacteria,[2,4]
including many strains of common urinary tract
pathogens.[4,5]
One of the earliest reports of the effectiveness
of nitrofurans against the majority of organisms
responsible for skin and skin structure infections
(SSSI) was published in 1945. Snyder et al.[20] reported the efficacy of 5-nitro-2-furaldehyde semicarbazone against 159 bacterial strains from 10
cases of SSSI. Strains of Staphylococcus, Streptococcus, diphtheroids, and Bacillus species were
studied. Results showed that all streptococcal and
staphylococcal isolates were sensitive to the drug
in vivo and rapidly disappeared from the wounds.
Drugs 2001; 61 (3)

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
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Guay

spp. and Pseudomonas and Xanthomonas spp. All

strains (except for Pseudomonas spp.) were inhibited by <64g of nitrofurazone per ml. However, 5
strains of Serratia spp. and Proteus spp. that were
inhibited by <64g of nitrofurazone were resistant
to nitrofurantoin. In contrast, no nitrofurantoinsusceptible strains were resistant to nitrofurazone.
The MICs of nitrofurazone and nitrofurantoin correlated significantly, but nitrofurazone MICs were
significantly lower than nitrofurantoin MICs, both
overall and specifically among Gram-negative bacilli (other than Pseudomonas spp.). This would
suggest that most Gram-negative bacteria are actually more susceptible to nitrofurazone than to nitrofurantoin. The nitrofurazone-matrix catheter inhibited the growth of 75% of all strains [notable
exceptions: Serratia spp. (2 of 3 not inhibited),
Proteus spp. (4 of 6 not inhibited), Enterobacter
spp. (1 of 7 not inhibited), and Pseudomonas spp.
(all 10 not inhibited)]. The bacterial strains that
were not inhibited account for 30% of CAUTI. It
was concluded that the nitrofurazone-matrix catheter inhibited the in vitro growth of most bacterial
strains responsible for CAUTI, including Gramnegative bacilli.[5]
Since 1953, nitrofurantoin has been used as an
oral antibacterial agent in the treatment and prophylaxis of UTI. E. coli strains are very sensitive
(96%) to nitrofurantoin, as are other coliform bacteria (overall 68%).[23] Shah and Wade[13] recommended in 1989 that nitrofurantoin should be used
to treat UTI caused by E. coli, Enterococcus faecalis
and S. aureus in general practice, where these organisms account for 90 to 95% of UTI cases. They
reported that the susceptibility of these 3 microorganisms to nitrofurantoin was 92, 96, and 100%,
respectively.
Data regarding inhibitory activity of nitrofurantoin at various concentrations have been reviewed
by Atkinson and are provided in table I.[24] Although
nitrofurantoin appears to be a relatively weak antibacterial, extensive renal elimination (vide supra)
allows its use in the management of UTI. The National Committee on Clinical Laboratory Standards (NCCLS) breakpoints for intermediate susDrugs 2001; 61 (3)

Nitrofurans in the Management of UTIs

357

Table I. Cumulative inhibition of bacterial strains by various concentration of nitrofurantoin[24]

Pathogen

MIC range (mg/L)

Acinetobacter calcoaceticus

Cumulative % of strains inhibited by various concentrations

[mg/L (%)]

[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)

MIC = minimum inhibitory concentration.

ceptibility (64 mg/L) and resistance (128 mg/L)

to nitrofurantoin are based on achievable urinary
drug concentrations, not blood concentrations. In
this regard, it is similar to norfloxacin and nalidixic
acid but unlike most other agents used for UTI.
Thus, for UTIs with a significant tissue component, such as pyelonephritis, nitrofurantoin cannot
be recommended.
4. Bacterial Resistance
A primary reason for a renewed interest in the
nitrofurans is that bacterial resistance to them has
not appreciably evolved after decades of clinical
use.[2,3,6] The presence of multiple mechanisms of
action for the nitrofurans might be expected to reduce the ability of bacteria to develop resistance.
Whereas resistance to the nitrofurans has not
evolved after many years, bacterial resistance to
other commonly used antibacterial agents that attack only one or 2 targets has occurred in recent
years.[6]
The similar modes of action of nitrofurantoin
and nitrofurazone have given rise to the general
assumption that co-resistance should occur. However, Breeze and Obaseiki-Ebor[9] demonstrated
that nitrofurantoin-resistant mutants were easier to
obtain and showed a higher degree of resistance
than nitrofurazone-resistant mutants. These authors suggested that there is a mechanism for nitrofurantoin resistance in E. coli K12 that does not
confer resistance to nitrofurazone.[9]
Adis International Limited. All rights reserved.

Improper use of antibacterial agents and increased personal-to-person contact especially in

high density settings (e.g. daycare, hospitals, nursing homes), have increased the number of resistant
bacterial strains, including ampicillin-resistant
Klebsiella, trimethoprim-resistant E. coli, and
vancomycin-resistant Enterococci.[25] However,
numerous studies have demonstrated that the nitrofurans are highly effective against these and other
urinary pathogens, except most strains of Pseudomonas aeruginosa; the nitrofurans do not inhibit
fungi or viruses. Maartens and Oliver[26] reported
that only 35% of all urinary pathogens were susceptible to amoxicillin whereas 90% were susceptible to nitrofurantoin.
The microbial species causing hospital-acquired
UTI have always differed from those causing community-acquired UTI. E. coli causes 80% or more
of UTI in outpatients in contrast to <50% of nosocomial UTIs.[27] Although E. coli is the most frequently isolated urinary pathogen, it accounts for
only 25% of isolates during short term catheterisation.[28] Still, it has been estimated that 30% of
community-acquired strains and 50% of nosocomialacquired strains of E. coli show multiple antibacterial resistance.[29] A number of studies have demonstrated that in recent years E. coli resistance has
increased to ampicillin, sulfamethoxazole, and trimethoprim.[25] The nitrofurans, however, have continued to be effective against these E. coli strains.
Drugs 2001; 61 (3)

358

In a recent 5-year study (1992 to 1996) of 4342

urinary isolates taken from 4082 patients, E. coli
accounted for 85% of pathogens.[30] Results indicated that more than 20% of E. coli isolates were
resistant to ampicillin, cefalotin (cephalothin), and
sulfamethoxazole. However, only 0 to 2% of E. coli
isolates, and less than 10% of all isolates, were resistant to nitrofurantoin. The percentages of urinary isolates from women with acute uncomplicated cystitis resistant to selected antibacterial
agents appear in table II.[30]

Guay

Landscape table II to be placed here.

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.

Drugs 2001; 61 (3)

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

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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

Drugs 2001; 61 (3)

Nitrofurans in the Management of UTIs

In a recent 18-year study of the efficacy and

safety of long term nitrofurantoin use in preventing
UTI,[32] female patients (n = 219) received nitrofurantoin at various doses and times of day: 50mg
every 12 hours (n = 43), 100mg at bedtime (n =
110), or 50mg at bedtime (n = 66). All patients were
instructed to take the drug with food since its bioavailability is enhanced with meals. The majority
of patients were aged <40 years (61%) and radiological abnormalities were noted in 24% of patients. Brumfitt and Hamilton-Miller[32] concluded
that there was a decreased frequency of UTI recurrence in 84% of patients after using nitrofurantoin
for a mean of 9.9 months (range 3 to 12 months,
median and mode 12 months). Only 9 strains of
bacilli causing breakthrough infections were resistant to nitrofurantoin [E. coli (2 resistant strains),
Klebsiella pneumoniae (3 resistant strains) and
others (4 resistant strains)]. In addition, singledose nitrofurantoin is useful as postcoital UTI prophylaxis.[34]
Whereas the primary use of nitrofurantoin has
been in the management of UTI, nitrofurazone has
had a broad range of antibacterial use. Historically,
the predominant use has been as a topical agent in
wound infections, burns, and skin grafts, but it has
also been of clinical utility in vaginal surgery,[35]
external ocular infections,[36] insect bites,[37] stasis
ulcers,[38] bacterial ear infections,[39] and middle ear
surgery.[40]
More recently, nitrofurazone has been developed
for use in combination with a Foley catheter to prevent CAUTI.[5,41] The catheter is impregnated intraand extraluminally with nitrofurazone with the rationale that nitrofurazone, like nitrofurantoin, is effective against many multidrug-resistant pathogens, including the most common uropathogens.
The notion that an antibacterial such as nitrofurazone could be used in conjunction with a catheter to prevent UTI was first reported in 1985:
[The] development of a biomaterial that inhibits
bacterial adherence and does not allow upstream
colonisation of bacteria on the catheter drainage
system would significantly influence the rate of
catheter-acquired urinary tract infection.[42]
Adis International Limited. All rights reserved.

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

Infecting pathogen group

Gram(+) cocci
[no. (%)a]

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.

At time of catheter insertion.

dwelling catheters. Johnson et al.[5] concluded that

the nitrofurazone-matrix catheter inhibited the
growth of most bacterial types, including many
Gram-negative bacilli, which would prevent such
bacteria from migrating extraluminally along the
external surface of the catheter into the bladder.
In 1997, Maki and Holcomb[41] reported results
of a randomised, double-blind, controlled clinical
trial that compared the antibacterial properties of a
nitrofurazone-impregnated catheter with that of a
standard silicone catheter in 344 patients undergoing short term catheterisation. The vast majority
(91.5%) of patients were catheterised for 7 days or
less. Over a period of 11 months, patients who were
managed with the nitrofurazone-impregnated catheter had a 3-fold reduction in the incidence of bacterial CAUTI compared with patients managed
with a standard silicone catheter (2.4% incidence
vs 6.9% incidence, respectively; p = 0.07). Bacterial CAUTI was defined as the presence of 103
colony-forming units of organisms/ml urine (single organism or total for mixed population). The
difference in time of actual occurrence of bacterial
CAUTI between the 2 groups was statistically significant (p = 0.007, Kaplan-Meier survival, Breslow
logrank statistic) for the first 5 days of use, with
CAUTI occurring earlier in patients managed with
a standard catheter.[17,41] On the basis of this study,
this impregnated catheter has received US Food
and Drug Administration approval for short term
Adis International Limited. All rights reserved.

use in continuous urinary bladder drainage in adult

males and females requiring catheterisation.
In 1999, Johnson and co-workers[45] reported a
comparison of the in vitro antibacterial activity of
sterile catheter segments from a nitrofurazone-containing catheter and from a silver hydrogel catheter.
In an assessment of the inhibitory activity against
86 susceptible and multidrug-resistant isolates, the
nitrofurazone-containing catheter was more broadly
active than the silver hydrogel catheter against the
diverse bacterial types characteristic of CAUTI.
Isolates included at least 4 susceptible and at least
4 multidrug-resistant clinical (predominately from
urine) isolates each of E. coli, K. pneumoniae,
Citrobacter freundii, S. aureus, coagulase-negative
staphylococcus, and Enterococcus faecium. The
nitrofurazone-containing catheter inhibited all susceptible strains tested and all multidrug-resistant
strains of the same species in a comparable fashion
[except for vancomycin-resistant E. faecium). In
contrast, the silver hydrogel catheter inhibited only
23% of strains tested (p < 0.001 between catheter
groups). Although the silver hydrogel catheter inhibited all staphylococci, the inhibition zones for
these were smaller than with the nitrofurazonecontaining catheter (p < 0.001). During serial daily
transfer, the duration of inhibitory activity was
longer with the nitrofurazone-containing catheter
(5 days) compared with the silver hydrogel catheter
(0 to 1 day).[45]
Drugs 2001; 61 (3)

Nitrofurans in the Management of UTIs

An alternative strategy for elimination of asymptomatic bacteriuria in patients catheterised short

term is the use of single dose cotrimoxazole (trimethoprim-sulfamethoxazole) 320 to 1600mg administered after catheter removal. Single-dose
therapy is 81% effective (94% for patients aged
65 years) in this regard.[46]
6. Adverse Reactions
Evidence from clinical studies and daily practice demonstrates that short term nitrofurantoin
therapy is a reasonably well-tolerated treatment for
UTI.[13,16,32] The most common adverse events associated with the use of nitrofurantoin include nausea (8%), headache (6%), and flatulence (1.5%).
Adverse events occurring in less than 1% of patients include diarrhoea, dizziness, pruritus, alopecia, and fever.[16] In an analysis of data obtained
over 18 years (1975 to 1992) at one hospital using
nitrofurantoin prophylactically in women with recurrent UTI, 40% of patients had some form of
adverse event, with nausea being the most common. The overall incidence of adverse events as
well as that of nausea varied according to treatment
regimen. The highest daily dose (100mg microcrystalline taken as 50mg twice daily) was associated with the highest incidence (48.0%), followed
by 100mg macrocrystalline (once daily) [38.2%]
and 50mg macrocrystalline (once daily) [27.2%].
No serious adverse events of any type were reported. The mean period of therapy was 9.9
months.[32] Although rare, serious adverse events
in patients on long term (>6 months), low dose
prophylactic nitrofurantoin therapy have been reported, including chronic pulmonary reactions, hepatic injury, peripheral neuropathy, and hypersensitivity to nitrofurantoin. The occurrence of these
adverse events varies in different countries, possibly due to prescribing and reporting practices.[13]
DArcy[47] has categorised 4 of the major adverse reactions to nitrofurantoin as pulmonary, hepatic, neurological, and haematological based on
121.4 million courses of nitrofurantoin treatment.[13,47] The estimated overall percentage of
these adverse events indicates that the frequencies
Adis International Limited. All rights reserved.

361

Table IV. Worldwide adverse drug reaction data for nitrofurantoin

(reproduced from DArcy,[47] with permission)
Reaction

Treatment courses 121.4 million

total no.

% 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

are very low, as summarised in table IV. Patients

with renal impairment (creatinine clearance <35 to
40 ml/min or clinically significant elevation of serum creatinine) should not receive nitrofurantoin.
Although the chances of hepatic injury are low, liver
function tests should be performed periodically in
patients receiving long term nitrofurantoin therapy. The carcinogenic effects of nitrofurantoin in
humans are not known.
A variety of adverse pulmonary syndromes due
to nitrofurantoin have been described: acute pneumonitis, chronic pulmonary infiltrates and fibrosis,
pulmonary eosinophilia, pulmonary haemorrhage,
and pleural reactions with effusion. Acute pneumonitis, which is most common in the elderly, is
characterised by features of acute respiratory infection with or without pulmonary oedema and
pleuritic chest pain. This reaction, probably secondary to type I or III hypersensitivity, varies in
onset from several hours to 8 to 10 days after commencing therapy and is accompanied by eosinophilia in 20 to 30% of patients. Recovery is usually
rapid when treatment is stopped and rechallenge is
contraindicated as a more aggressive reaction will
result. The chronic diffuse interstitial pneumonitis
reaction characteristically occurs when therapy duration exceeds 6 months and presents with insidiously progressive dyspnoea and dry cough. Roentgenological examination reveals bilaterally patchy
infiltrates or a diffuse reticular pattern and pleural
effusions. While resolution usually follows drug
discontinuation, 8 to 10% of patients will die of
Drugs 2001; 61 (3)

362

respiratory failure from this reaction. This reaction

appears to be dose related (increased risk as cumulative dose increases).[13]
Although the type and incidence of adverse effects
associated with nitrofurazone therapy vary according to preparation, dosage and indication, evidence
from clinical studies and daily practice demonstrates
that nitrofurazone is well tolerated as a topical
agent and in a nitrofurazone-impregnated catheter.
As an antibacterial soluble dressing for topical use
as adjunctive therapy for burns and skin grafting,
nitrofurazone is associated with contact dermatitis
allergic reactions, the most common adverse reaction, in approximately 1% of patients. Other reactions include erythema, pruritus and burning, although these are often confused with the condition
that is being treated. More severe reactions include
oedema, vesiculation, denudation, and ulceration.
Although rare, other severe reactions have been reported, including exfoliative dermatitis, autosensitisation, urticaria, and anaphylactoid reactions. All
reactions to nitrofurazone are reversible after therapy ceases.[3]
An extensive literature review of adverse events
associated with nitrofurazone use from 1945 to
1965 was reported by Glascock and co-workers.[40]
The review included data from 136 published articles reporting on 15 162 patients treated with
nitrofurazone. During this era, nitrofurazone was
primarily used as a topical burn and wound agent
and also as an antibacterial in gynaecological, urological, ophthalmological and ear conditions. In the
20 years of clinical use of nitrofurazone reported
in the study, only 1.2% of all patients reported sensitivity reactions. From these data, it may be concluded that nitrofurazone is not a primary irritant
or a potent sensitiser.[40]
The possibility of overgrowth of nonsusceptible
organisms including fungi and Pseudomonas spp.
should be considered in patients undergoing nitrofurazone therapy when the condition does not improve. If superinfection or irritation continues,
nitrofurazone therapy should be discontinued. Nitrofurazone should not be used in patients with significant renal impairment (vide supra). Nitrofura Adis International Limited. All rights reserved.

Guay

zone has been shown to produce mammary tumours

when given in high doses to Sprague-Dawley rats.
However, the relevance of these data to humans is
not known.[3]
Regarding the use of nitrofurazone in the prevention of CAUTI, available data indicate that
nitrofurazone-impregnated catheters are well tolerated and that there are no observable complications
or attributable adverse effects significantly different from those associated with standard catheters.[41]
UTI during pregnancy is associated with maternal and neonatal morbidity.[13] Short term nitrofurantoin therapy during pregnancy has a low
teratogenic potential.[13] The Boston Collaborative
Perinatal Project reported that nitrofurantion did
not increase the relative risk of malformation.[13]
Nitrofurantoin has been detected in human breast
milk in trace amounts; therefore, the importance of
the drug to nursing mothers must be considered
against potential adverse effects to nursing infants
under 1 month of age. The safety of nitrofurazone
for any indication has not been adequately studied
in pregnant women. It is not known whether nitrofurazone is excreted in human milk. As with any
drug, the risks and benefits to both the mother and
child must be weighed when prescribing nitrofurans to pregnant or nursing women.[16,17]
7. Conclusion
Although the prevalence of resistance to many
antibacterial agents has increased among many
pathogens, in particular among uropathogens, such
pathogens generally remain susceptible to the nitrofurans after many decades of clinical use. The
long history of well tolerated and effective use of
nitrofurans, and the continued lack of evolution of
bacterial resistance to these agents led to the development of a nitrofurazone-impregnated catheter
for short term use in the prevention of CAUTI. Evidence reviewed in this paper demonstrates that nitrofurantoin and nitrofurazone are broadly active
against many Gram-positive and Gram-negative
bacteria, including common uropathogens. Because of nitrofurantoins good oral bioavailability
and high degree of renal excretion coupled with its
Drugs 2001; 61 (3)

Nitrofurans in the Management of UTIs

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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Correspondence and offprints: Professor David R. Guay,

University of Minnesota, Institute for the Study of Geriatric
Pharmacotherapy, College of Pharmacy, Weaver-Densford
Hall 7-115C, 308 Harvard St. SE, Minneapolis, MN 55455,
USA.
E-mail: guayx001@tc.umn.edu

Drugs 2001; 61 (3)