Norfloxacin, a Fluoroquinolone Antibacterial Agent

Classification, Mechanismof Action, and in Vitro Activity

ELLIE J.C. GOLDSTEIN, M.D.

Los Angeles,

California

From the R.M. Alden Research

Laboratory,
Los
Angeles,
California,
and Santa Monica
Hospital
Medical
Center,
Santa Monica,
California.
Requests for reprints should be addressed
to Dr. Ellie
J.C. Goldstein,
R.M. Alden Research
Laboratory,
11980 San Vicente Boulevard,
Suite 103, Los Angeles, California,
90049.

Norfloxacin is an orally absorbed fluoroquinolone antibacterial with

a fluorine at position 6 and a piperazine ring at position 7. These
changes have resulted in a marked enhancement (compared with
that of the older quinolones) of in vitro antibacterial activity. Specifically, the antibacterial spectrum of norfloxacin fncludes Pseudomonas aeruginosa, as well as enteric pathogens. Norfloxacin is also
active against both penicillin-susceptibfe
and penicillfn-resistant
strains of Neisseria gonorrhoeae. Relative to its activity against
gram-negative bacteria, norfloxacin is somewhat less active against
gram-positive cocci. In general, the staphylococci are more suscep
tibte to the drug than are the streptococci. As with all fluoroquinolones, norfloxacins activity against anaerobic bacteria is
poor. For urinary tract bacterial isolates, the following Bauer-Kirby
disk diffusion zone-size breakpoints have been proposed: greater
than or equal to 17 mm, susceptible; 13 to 16 mm, intermediate; less
than or equal to 12 mm, resistant. Bacteria with minimal inhibitory
concentrations (WCs) less than or equal to 16 pg/ml are considered
susceptible; those with WCs greater than or equal to 32 pgirnl are
considered resistant to norfloxacfn. The mechanism of action of
norfloxacin involves inhibition of the A subunit of the important
bacterial enzyme DNA gyrase, which is essential for DNA replication. Plasmid-mediated resistance to the fluoroquinolones
is not
encountered. Further, although some cross-resistance within the
fluoroquinolone class has occurred, there is little cross-resistance
between norfloxacin and antibiotics of other classes.
The new fluoroquinolone class of antibacterials has received increasing
clinical attention in recent years [1,2]. The infectious disease community
has viewed these orally absorbed, synthetically derived agents with special interest, despite the recent development of numerous beta-lactam
antibiotics (including penicillins, cephalosporins, carbapenems, and monobactams). The newer drugs have a broad antibacterial spectrum that
includes gentamicin-susceptible and gentamicin-resistant strains of
Pseudomonas aeruginosa; other multi-resistant, gram-negative rods;
gram-positive cocci; and beta-lactamase-producing bacteria [3-291. Furthermore, their mechanism of antimicrobial activity differs from that of
other well-known antibiotics. The fluoroquinolones inhibit the activity of
DNA gyrase, an essential bacterial enzyme involved in DNA replication
[30-321; consequently, plasmid-mediated resistance to the fluoroquinolones is not encountered [l].
Norfloxacin, one of these fluoroquinolone antibacterials, was originally
synthesized in 1980 by the Japanese, who were the first to document its

June

26, 1967

The

American

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of Medicine

Volume

62

(suppl 6B)

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

Parent

Nucleus
A. Carboxylic
acid ring
B _ Pyridine ring
X . Carbon or nitrogen
R - Side chain

Naphthyridine

Quinolone

Cinnoline

Pyrido-Pyrimidine

Derivatives
Enoxacin
Nalidixic acid

Derivatives
Ciprofloxacin
Flumequine
Norfloxacin
Oxolinic acid
Pefloxacin

Derivatives
Cinoxacin

Derivatives
Pipemidic

acid

Norfloxacin

Igun, 1. Structure

of norfloxacin

and other quinolone

derivatives.

broad spectrum of antibacterial activity [33]. A quinolone

carboxylic acid derivative, norfloxacin (1-ethyl6-fluoro1,4-dihydro-4-0x0-7-(1 -piperazinyl)S-quinoline carboxylic
acid) is characterized by the addition of a fluorine at position 6 and a piperazine ring at position 7 (Figure 1). These
structural changes have resulted in a marked enhancement (compared with the older quinolones) of its antibacterial spectrum.
This article reviews (1) the classification of norfloxacin
and other fluoroquinolones; (2) the proposed mechanism
of action of the fluoroquinolones; and (3) published reports in the international literature of the in vitro antibacterial activity of norfloxacin.

Figure 1, it has a bicyclic, heteroaromatic system made up

of a carboxylic acid ring (A) and a substituted pyridine
nucleus (6) with nitrogen atoms at positions 1 and 6. The
prototype naphthyridine antibacterial, nalidixic acid, has
pronounced activity against gram-negative bacteria (excluding P. aeruginosa) and relatively modest activity
against gram-positive organisms. Thus, in 1963, this
agent was introduced in the United States for the treatment of urinary tract infections.
In 1966, Turner et al [35] reported the synthesis of
oxolinic acid, which has an antibacterial spectrum similar
to that of nalidixic acid. It became commercially available
in 1972. By substituting a carbon for nitrogen at position 8
(Figure l), oxolinic acid became the first quinolone and
the prototype for this class of antibacterials. Unlike the
naphthyridine derivatives, which have two nitrogen atoms
(position 1 of ring A and position 8 of ring B), true quinolone antibacterials have only a single nitrogen atom at
position 1 (ring A).
Cinoxacin, released in 1975, was reported by Wick et al

CLASSIFICATION

In a study of new antibacterial agents, Lesher and associates [34] prepared a number of 1 ,&naphthyridine carboxylic acid derivatives; nalidixic acid was considered the
outstanding compound in this series. As can be seen in
4

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SYMPOSIUM

[36] to have equivalent antibacterial activity along with

superior pharmacological properties compared with nalidixic acid. It differed from oxolinic acid in the substitution
of nitrogen at position 2, thereby forming the cinnoline
ring [37]. Some researchers consider cinoxacin the prototype cinnoline; others consider it a nalidixic acid analogue
(naphthyridine family) with a cinnoline system [37].
Subsequently, researchers throughout the world modified these two six-membered rings and, by 1977, more
than 1,000 variants had been created [371. In current
usage, the term quinolone is often loosely applied and
used generically to refer to all members of the naphthyridine (nalidixic acid), quinolone (oxolinic acid), cinnoline (cinoxacin), and pyrido-pyrimidine (pipemidic acid)
classes of antibacterials.
Norfloxacin was recently synthesized by attaching a fluorine at position 6 and a piperazine ring at position 7 to the
quinolone nucleus [33]. Other fluorinated, piperazinyl analogues of the naphthyridine and quinolone families have
also been synthesized and several of these are currently
in clinical development [36].
The relationship between structural substitutions and
antibacterial activity has previously been reviewed [37,
361. Any substitution on the quinolone nucleus is an important determinant of a quinolones in vitro activity. The A
ring is considered responsible for the intrinsic effect of
all analogues and most substitutions within this ring result
in a loss of activity [37]. One exception is the substitution
of a nitrogen at position 2, as in cinoxacin, which resulted
in improved pharmacokinetics with little change in antibacterial activity [36]. Most quinolones have a methylsubstituted pyridine nucleus for ring B. However, this may
be replaced by a variety of other aromatic and heterocyclic rings without losing antibacterial activity [37]. Substitutions with nitrogen at positions 5, 6, 7, or 6 of the pyridine
B ring will, however, decrease or abolish the activity of
these compounds [36]. For example, the 6/8-dinitrogen
in pipemidic acid decreases antibacterial activity but enhances absorption. Hence, the basic structure of nalidixic
acid, the quinolones, and related compounds is a bicyclic,
heteroaromatic ring (A-B) system, with one of these having the characteristics of the A ring.
In addition to substitutions within the ring, numerous alterations of the ring itself have been attempted and have
produced varying degrees of activity. Most compounds,
including norfloxacin, have an ethyl (C2Hs) substituent at
position 1. This moiety appears to be essential for good
antibacterial activity. For example, ciprofloxacin has a
three-membered ring, spatially constructed to form a similar configuration as an ethyl group at position 1. Another,
as-yet-to-be-named quinolone has a 4-fluorophenol group
at position 1. Both have maintained antibacterial activity
[38]. Modification at position 2, however, does not appear
to be beneficial, and, consequently, very few such compounds have been studied. A carboxylic acid (COOH) and
a ketone moiety are usually attached to positions 3 and 4,
June

26, 1987

ON NORFLOXACIN-GOLDSTEIN

respectively. These positions are rarely modified, as the

link between the carboxylic acid and the ketone moiety
seems to be necessary for binding of these compounds to
DNA gyrase, [38] and, therefore, for the antibacterial activity of these agents.
Whereas modification at position 5 does not seem to
improve antibacterial efficacy, substitutions at positions 6
and 7 do result in marked enhancement of such activity.
For example, the norfloxacin nucleus has a fluorine at
position 6 and a piperazinyl ring at position 7. Other halogens (e.g., chlorine, bromine, and iodine) have been substituted at position 6. However, only the fluorine atom has
produced a dramatic increase in general antibacterial activity [38], while the piperazine ring at position 7 confers
antipseudomonal activity on norfloxacin and other similar
compounds. Finally, modifications at position 8 (with either fluorine or short one- to three-atom chains) appear to
alter, and possibly enhance, activity against gram-positive
and anaerobic organisms [38].
MECHANISM

OF ACTION

The fluoroquinolone antibacterials in general, and norfloxacin in particular, are bactericidal. These agents are
thought to specifically inhibit the A subunit of the enzyme
DNA gyrase, a type II topoisomerase [30,31], which appears to be essential for DNA replication. However, the
exact mechanism by which the fluoroquinolones cause
cell death remains to be demonstrated [30].
DNA gyrases have been found in numerous bacteria
and have been studied in Escherichia coli, Micrococcus
luteus, P. aeruginosa, and Bacillus subtilis [Sl]. The enzyme is composed of two A subunits (with a molecular
weight of 100,000 to 150,000 daltons each) and two B
subunits (with a molecular weight of 90,000 to 95,000 daltons each). It has equal amounts of each subunit and requires all four entities of both types to be active. Whereas
novobiocin and coumermycin Al inhibit the activity of the
B subunit, the fluoroquinolones inhibit the A subunit. Since
this enzyme is multifunctional, there are several alternative theories regarding the mechanism of action of these
agents [31,39].
Cozzarelli [40] and Gellert [41] have reviewed the activities of DNA gyrase and have found the functions of this
enzyme to include the following: (1) Supercoiling of DNA.
This process involves the sign inversion model (i.e., the
breaking and resealing of DNA strands) and is coupled
with energy transduction. Although both novobiocin and
the fluoroquinolones inhibit supercoiling, each interferes
at a different sequence in the process [31]. (2) Binding of
gyrase to DNA. This is site specific and is not inhibited by
either novobiocin or the fluoroquinolones. (3) Relaxation
of supercoiled DNA. This activity is inhibited by the fluoroquinolones but not by novobiocin. (4) Cleavage of DNA.
Neither the fluoroquinolones nor novobiocin interferes
with this step in the sequence. (5) Hydrolysis of adenosine
triphosphate (ATP) (to adenosine diphosphate [ADP]) and
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6B)

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

Norfloxacin

.I
I
AZ
E
c?T

3
Time

June

26, 1967

The

American

Journal

(Hours)

the associated release of energy. This step is inhibited by

novobiocin, but not by the fluoroquinolones. (6) Catenation and decatenation of DNA. Catenation refers to the
interlocking of duplex DNA rings and the resolution of
these rings into component circles. This step is inhibited
by both the fluoroquinolones and novobiocin. Thus, in
general, the fiuoroquinolones inhibit those reactionse.g., supercoiling, relaxation, catenation, and decatenation-that
require the breaking and reuniting of DNA
strands.
DNA was recognized as a constituent of chromosomes
more than 70 years ago. However, it was not until Watson
and Crick elucidated the double-helix structure of DNA
that the field of molecular biology and microbial genetics
was revolutionized [42]. This technologic advance made it
possible to analyze the antibacterial activity of the fluoroquinolones on a molecular level, knowledge of which
since 1952 has come primarily from work with E. coli [42].
As the repository of genetic information, DNA directs
the manufacture of cellular proteins. Information from
DNA is transcribed by messenger RNA (mRNA) and carried to the ribosomes where it is translated, with the assistance of transfer RNA (tRNA), into specific proteins.
DNA exists as two long slender strands of covalently
bonded polymers, which are composed of four nucleotide
bases: adenine, guanine, thymidine, and cytosine. These
two polymers are twisted about each other into a righthanded helix and held together by weak hydrogen bonds
linking complementary base pairs. The double helix
makes a complete turn every 34 angstroms and is capable of assuming many forms and reacting in many ways
[43]. The topographic supercoiled state of DNA, which is
controlled by topoisomerase enzymes such as DNA gyrase, is the natural state of bacterial genetic material.
Thus, the supercoiling of DNA is an important element in
the process of DNA replication, transcription, and genetic
recombination [41].
6

(1.0 mg/L)

of Medicine

Volume

Figure 2. The effects of norfloxacin upon

DNA, RNA, arid protein synthesis were
monitored by measuring the incorporation of rtilthymidine,
rH]uridine,
or
r5S]methionine
administered
in fiveminute pulses at the times indicated after
commencement of treatment with norfloxacin at 7.0 mglliter. l = RNA; 0 =
protein;
0 = DNA. Reproduced
with
permission from PO].

E. coli have one chromosome composed of doubiestranded DNA in a circular shape [42]. Ttiis chromosome
is long and large and, in order to fit within the confines of
the cell nucleus, it must twist the helix upon itself, i.e.,
become sup&coiled. The DNA gyrase enzyme promotes the energy-dependent supercoiling and uncoiling of
DNA; the A and B subunits of DNA gyrase are involved in
different steps of the supercoiling process [31].
In the simple bacterial cell, mRNA sequentially copies
various regions of DNA. For DNA replication to occur,
breaks must be present in the circular strands of DNA and
each strand must act as a template for itself. There must
also be exposure of the two single DNA strands in order
for mRNA to gain access to the parent DNA strand and
form a complementary strand. This is accomplished by
relaxation of the supercoiled strands, which are coiled in a
direction opposite from that of the double helix itself [31].
Replication also requires separation of the complementary parent DNA strands: these functions are accomplished by DNA gyrase. Once replication is completed,
there must be separation of catenated (intertwined) rings
for distribution of genetic material to daughter cells. DNA
gyrase also helps accomplish this.
Wolfson and Hooper [44] have recently published a
minireview of the mechanisms of action of the fluoroquinolones, i.e., as inhibitors of DNA gyrase. Alternative
theories regarding the mechanism of antibacterial action
of the fluoroquinolones have also been postulated. For
example, Zweerink and Edison [32] studied the activity of
11 of the fluoroquinolones, including norfloxacin, on M.
luteus DNA gyrase. They noted that the potency of the
fluoroquinolones as DNA gyrase inhibitors did not always
correlate with their antimicrobial potency [32]. This suggested that other factors, such as penetration of the drug
into the bacterial cell, were important for fluoroquinolone
activity. Conversely, Wright and associates (391 suggested that the fluoroquinolones might exert their antibac62 (suppl

6B)

SYMPOSIUM

terial effect by inhibiting another class of enzymes, the

. tRNA synthetases.
Crumplin and associates [30], who examined the effects of norfloxacin on E. coli K12 and mutant derivatives,
noted that the agent was bactericidal, specifically inhibited
DNA gyrase activity, and precipitated a range of metabolic sequelae. They suggested that the death of norfloxacin-treated E. coli required competent RNA activity and
protein synthesis (Figure 2). In fact, the addition of protein
inhibitors, e.g., rifampicin or chloramphenicol, to norfloxacin-treated E. coli in vitro prevented bacterial killing in
their study (Figure 3). This phenomenon has also been
observed with several of the other fluoroquinolones
[30,31]. Whether this observation has any in vivo clinical
relevance remains to be seen, however. Crumplin et al
[30] also reported that norfloxacin-treated E. coli had less
enterotoxin in the periplasmic space; since local enterotoxins probably produce tissue inflammation, this may
reduce patient symptoms prior to ceil death.
IN VITRO ANTIBACTERIAL

E. co/i

10

KU6

+ Norfloxacin

(b) RNA

30
Time

June

26,1987

(2.5 mg/L)

(a) Protein

ACTIVITY

Since 1980, numerous publications and literature reviews

have compared the in vitro activity of norfloxacin with that
of other quinolones, beta-lactams, and aminoglycosides
[3-38,44,45]. These studies have used a variety of media,
test conditions, and methodologies. The susceptibility of
clinical isolates in general, and of pathogens isolated from
specifically infected sites (e.g., the urinary tract [10,22251, the gastrointestinal tract [26-291, the ocular area [20],
and sites affected by venereal diseases [8,13]), have
been reported. In many of these studies, isolates were
chosen that were resistant to multiple other antibiotics,
including nalidixic acid.
The activity of norfloxacin against a wide spectrum of
bacterial pathogens (more than 9,500 strains) has been
reported in these studies and is shown in Tables I through
VI. Additionally, several authors have published multiple
reports on the comparative in vitro activity of norfloxacin;
when it was not possible to discern whether entirely different isolates had been included in a report, only one of that
authors (or groups) reports is cited.
In general, norfloxacin was active against a wide variety
of aerobic gram-positive and gram-negative bacteria. Furthermore, there was little cross-resistance between norfloxacin and agents of other antibiotic classes. Nalidixic
acid-resistant strains remained susceptible to norfloxacin,
but were significantly less susceptible than nalidixic acidsusceptible strains [4,33,44]. The minimal inhibitory concentration of norfloxacin against 90 percent (MI&) of
1,282 strains of E. coli was less than 0.02 @ml. Additionally, norfloxacin was active against all the Enterobacteriaceae and other gram-negative rods, with MI&,-, values as
follows: Klebsiella species, 2 pglml (696 strains); Enterobatter species, 0.5 pg/ml (556 strains); Proteus mirabilis,
0.1 pg/ml (571 strains); and other Proteus species, 0.4
pg/ml (421 strains).

ON NORFLOXACIN-GOLDSTEIN

60

90

(Minutes)

L
f Vgura

3. Logarithmic phase cultures of E. co/i strain KL76

were treated with norfloxacin at 2.5 mglliter and incubated at
37%. At the times indicated, either chloramphenicol or rifampicin were added to sample cultures. Samples were removed at 1B-minute intervals for viable counting. l = RNA;
Cl = protein. Reproduced with permission from [30].

Norfloxacin was also active (MI& of 2 pg/ml) against

1,325 gentamicin-susceptible strains of P. aeruginosa.
Against 97 gentamicin-resistant strains, norfloxacin had a
MI&, of 1 w/ml and a Ml& of 8 &ml [9,16,22]. It ap
peared to be active against Citrobacter species, Serratia
marcescens, Morganella species, and Providencia species. Some Providencia species, non-aeruginosa Pseudomonas species (including Pseudomonas maltophilia
and Pseudomonas cepacia), and Acinetobacter calcoaceticus var. anitratus had higher MIC& values. Occasionally,
these organisms were resistant to norfloxacin.
A variety of enteric pathogens were also susceptible to
norfloxacin; these included Salmonella species, Shigella
species, toxogenic E. coli, Campylobacter fetus species
jejuni, Vibrio cholerae, Yersinia enterocolitica, Aeromonas
species, and Plesiomonas shigelloides. The agent had
poor activity against Clostridium difficile, however.
One study found strains of Listeria monocytogenes to
be relatively resistant to norfloxacin [6]. Other studies,
however, found the agent to be active against both penicillin-susceptible and penicillin-resistant strains of Neisseria gonorrhoeae [7,8,13]. In fact, Crider et al [B] noted that
98 percent of the gonococci isolated from servicemen in
the Philippines were inhibited by 0.125 &ml of norfloxatin. They did not detect a difference in susceptibility to
norfloxacin between penicillinase-producing and nonpenicillinase-producing strains of N. gonorrhoeae.
The American

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82 (euppl6B)

SYMPOSIUM

TABLE

ON NOAFLOMCIN-GOLDSTEIN

Summary

of Published

in Vitro Activity

of Norfloxacin

Number

Staphylococcus
aureus
Methicillin susceptible

(or not specified)

Methicillin-resistant

Staphylococcus
(coagulase

negative)

Staphylococcus
Streptococcus

saprophyticus
agalaqtiae

Streptococcus
Enterococci
Streptococcus

bovis
faecalis

Not specified

Streptococcus
pneumoniae
Penicillin susceptible

Penicillin

resistant

Streptococcus

Streptococcus

June

26,1987

pyogenes

viridans

The

American

Journal

of Medlclne

of

against

Gram-Positive

Cocci
Maximal
MIC

MK50

MN&

strains

bwml)

MW)

50
115
26
16
22
30
35
15
20
100
14
34
30

1
1
0.6
2
1
2
2
1
0.2
1.6
1
2
0.5

2
2
6.3
4
4
2
2
1
0.5
3.1
2
4
1

4
4
6.3
4
6
4
2
2
0.5
6.3
4
32
1

25
25
30
15
16
50
9
13
20
20
50
15
20
9
10
25
10
15

0.5
1
0.5
0.2
1.6
1
1
1
2
1
1
2
4
1.6
2
2
4
2

1
1
1
0.5
3.1
2
1
2
4
2
3.1
2
6
6.3
2
4
4
16

2
4
1
1
12.5
6
2
4
4
2
12.5
2
6
6.3
4
4
4
16

26
125
20
52
50
30
25
50
20
19
16
20

4
4
3.1
6
3.1
1
2
4
2
2
2
2

4
a
12.5
6
6.2
2
4
a
4
4
a
4

a
16
12.5
16
6.2
2
4
6
4
4
16
4

10
16
20
20
10
10
20
16
20
22

2
6
2
4
4
2
2
1.6
4
6

4
16
6
16
4
2
32
6.3
4
25

4
16
16
32
6
4
32
6.3
32
25

Volume

82 (suppl6B)

Reference

[31
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PI

1161
(241
v41

PaI
1101
[71
[191
[41
171
131
131
[41
171

1101
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1241
v41

1161
(171

1181
1191
1101
[31

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[lOI
P41

1181

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1141

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TABLE II

Summary of Published in Vitro Activity of NorfIoxacin against Qram-Negative Bacilli

Acinetobacter
A. anitratus

species

A. lwoffi
Not specified

Citrobacter

Escherichia

species

coli

Nalidixic acid susceptible

Nalidixic resistant
Ampicillin susceptible
Ampicillin resistant

Hemophilus

Klebsiella
Natidixic
Nalidixic

influenzae

species
acid susceptible
resistant

15
60
16
23
35
5
46
20
45
11
33
6
35
23
5
20
99
25
158
204
24
21
56
40
38
54
100
53
200
25
40
40
100
126
50
103
56
27
40
13
53
50
10
20
100
32
40
23
27
16
20
20
24
43
199
7
26
40

2
4
3.1
1
1
4
1.6
~0.06
0.06
0.06
0.1
<O.l
SO.06
0.2
0.1
0.08
0.1
=0.06
SO.08
0.06
0.5
SO.06
10.06
0.1
0.05
0.06
0.05
~0.06
0.01
0.06
0.1
0.06
0.05
0.1
0.1
0.1
0.2
0.06
0.06
0.1
SO.06
0.2
0.1
0.03
0.1
0.1
=0.06
0.02
0.03
0.06
0.4
0.1
0.1
0.06
0.06
2
SO.06
0.2

4
6
12.5
4
4
8
6.3
0.25
0.2
2
0.4
0.2
0.1
0.5
0.5
0.03
3.1
0.12
CO.06
0.12
8
50.08
SO.06
0.2
0.2
0.1
0.2
0.1
0.2
0.1
0.2
0.5
0.2
0.5
0.2
0.1
0.4
0.1
0.5
0.2
0.5
0.2
0.5
0.2
0.8
1
10.06
0.02
0.12
0.06
1.8
0.1
0.2
0.2
0.1
8
0.1
0.5

4
32
12.5
4
4
8
50
1.0
2
2
0.8
0.2
32
1
0.5
0.06
100
0.25
2
8
16
SO.06
0.5
2
3.1
4
1
1
2
0.1
2
2
0.8
4
8
0.25
1.6
0.1
0.2
0.5
32
1
0.5
8
50
4
SO.06
0.02
0.12
0.06
3.1
0.1
2
0.2
2
8
0.12
0.5

[31
141

El
141
I141
WI

1191
131
141
[51

PI

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1161
1241
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[lOI

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131
[51
141
[41

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PI
171

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(241

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[251
1171

WI
[lOI
131
141

PI
151
[iI

[181
[241
1171

WI
(191

WI
131

PI
I141

1181
1191
El
151
141
141

WI

June 26,1987 The Amwkan Joumd of Medicine Volume 82 (ruppl8B)

SYMPOSlUMON

NORFLOXACIN-GOLDSTEIN

TABLE

Summary

II

of Published

in Vitro Activity

of Norfloxacin

Number of Strains
K. pneumoniae
K. oxytoca

38
13
38
53
100
20
100
19
22
44
31
10
40
20
18
10
61
25
31
125
20
18
40
50
36
20
20
98
60
24
10
10
9
70
53
25
20
20
181
9
14

Listeria monocytogenes
Morganella
species

Proteus

mirabilis

Naiidixic
Natidixic

Other

acid susceptible
resistant

Proteus

Providencia
Natidixic
Natidixic

Pseudomonas
Gentamicin

Gentamicin

Gentamicin

species

species
acid susceptible
resistant

aeruginosa
susceptible

resistant

susceptibility

(Table II Is continued
10

24
12
31
22
20
11
59

not noted

on page 11)

MGAI Wml)

Gram-Negative
Mb0 bmU

0.1
0.1
0.1
0.1

0.4
0.4
2

0.5

0.1
0.1
0.1

0.2
0.5
6.3
0.1

0.06
0.05
0.1
co.1
0.1
~0.06
0.06
0.01

0.2
0.5
0.5
2
12.5

0.2
0.06
0.2
0.5
10.1

0.2
0.1
0.1
0.06

0.1

0.5
0.03
0.2
~0.06
0.1
0.06
0.5
0.1

0.06
10.06
0.06
0.1

0.03
50.06
0.1

0.06
0.06
0.05
0.3
so.1
0.03

8
0.4
0.06
so.1
0.1

0.2

18
56
31
25
54
18
50
424
67
40
100

0.5
0.5
0.5

100

0.5

50
48
120

2
2

June 26, 1987 The American Journal of Medicine

against

4
0.5
0.5
0.8
0.5
0.1

Volume 82 (suppl 66)

Bacilli

(continued)

Maximal MIC

Reference

0.8
1.6
4
2
8
4
1.6
0.5
0.5
8
12.5
2
2
0.4
0.5
1
2
0.2
0.1
0.5
2

161

PI

1211
1161
I241
[I71

[191
[181
[2,51

PO1
PI
131
141

PI
[\!I
12,51
131
[51
[41
[41

PI

0.1
0.1

0.1
0.1

0.2

[161

2
4
2

0.1

0.1

[181

0.2
0.2
0.1
0.1
0.06
0.4
0.06
~0.06
0.5

0.4
2

[2,51

WI

0.1

0.1
0.1
3.1

0.1

0.06
0.4
0.3

0.2
0.1
0.4
0.25
0.1

0.6

(71
1241
1171

1191
[31
[51

El
141
[161
1241
1171

1181
1191
PI

so.1

[lOI

0.2
16
3.1
0.5
0.5
0.5
4

1
16

[41
141

2
2
4
8
8
2
2
3.1
2
0.8
4
2
4
16

32
8
8
r32
8
4
>32

so.1

PI

6.3
0.5
2
2
4

1251

[=I

100

4
10
32
2
16
32

171

[lOI

1161

PI
P61
P21

PI
1161
[31
141

El
[71
[231
DOI
iI41
1241
t151

SYMPOSIUM

TABLE

II

Summary

of Published

in Vitro Activity
Number

of Norfloxacin

of Strains

M&0

16

26
5

cepacia
maltophilia

Pseudomonas

species

Serratia

TABLE

susceptible

species

Ill

Summarv

of Published

in Vitro
Number

Aeromonas

Activity

fetus

species

Clostridium
Escherichia

difficile
coli (toxogenic)

Plesiomonas

shigelloides

jejuni

species

Vibrio
Vibrio

cholerae
parahaemolyticus

Vibrio vulnificus
Yersinia enterocolitica

MIC

12.5

12.5
16
2
16

16

WI
PI
PI
[71
[31
[51

[lOI
t141

PI
t31
141
141

4
6.3
4
2
4
0.5
2
10
2

0.8

4
0.5
4
0.1
2
3.1
0.1
12.5
0.1

against

P51
(1 ai

32
16
32
32
12.5
2

12.5
0.5
0.2
4

1'31
P21
171

1101
1161
1241
j231
11ai

1191

100

0.2

Enteric

28
11

50
4
17
7
50
19
27

0.01
0.1

0.06
0.06
so.5
0.05
0.01
0.03
0.01
0.01

a0
21

40
20
25
40
26
22

0.008
0.1

0.66
co.05
0.06
co.5
~0.06
0.06

10
9
19
14
la

25

26,1967

The American

[51

Pathogens

0.02

0.2
0.5
so.5
2
0.5
1

0.1

so.5
1
0.2
0.5
128
0.00s

co.5
~0.06

SO.5
~0.06

1
1

so.5
0.1
0.06

171

w
PI
1261

P91
[El
[51

WI
El

0.2
0.06

[!ii]
[la]
BJI

1
0.1
1
1

0.06
0.1
co.5
0.1
0.06
0.03
0.03
0.01
0.01
0.2
0.06
SO.05
0.06
so.5
~0.06
0.03

P4
PI

0.2
0.1
0.03
0.03
0.25

[!I

P91
VI
WI
WI
WI
[=I

0.01

0.2
0.2
SO.05
0.25
so.5
~0.06
0.03

of Medicine

Volume

Reference

PI
wi
WI
WY

128
1
0.01

so.05

Journal

Reference
v71
[191

>12a

0.2
0.5
2

0.05
50.06
so.5
so.5
0.06
0.25
64
SO.05
0.004
so.5
~0.06
0.06
co.5
0.05

6
30
36

June

Maximal

Maxlinal MIC

27
species

(conf~nuedj

6.3
4
2
2
25
12.5

of Strains

ia
20

Shigella

Bacilli

2128

of Norfloxacin

28

Salmonella

4
0.5

0.8
0.1

al

Campylobacter

2
0.2
0.5

so.1

species

1.6

12.5
0.1
0.1
4
0.4
2
0.1
2
0.1
0.2
0.4

33
40
6
14
10
100
20
100
20

(not specified)

0.8

,128

38

Gentamicin

6.3

10
31
93
19
39
4
25
32
5

Serrafia marcescens
Nalidixic acid susceptible
Nalidixic acid resistant

MICgo MVml)

0.5

12.5

19

(not specified)

Gram-Negative

b.aW

20
106
59

Pseudomonas
Pseudomonas

against

ON NORFLOXACIN-GOLDSTEIN

(271

[=I
V61
1291

62

(suppl 66)

11

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

TABLE IV

Summary of Published in Vitro Activity of Norfloxacin against Anaerobic Bacteria

Number of

MN&

Strains
Bacteroides

Other

fragilis

Bacteroides

group

species

Clostridium
perfringens
Other Clostridium
species
(Non-perfringens,
nondiiicile)

Fusobacterium

species

Peptostreptococcus

species

bo/mU

Maximal
MIC
>lOO
128
512
32
128
128
>lOO
512
128
12.5

mll

ho/ml)

24
13
20
1st
10
12
12
26
17
17

6.3
32
128
16
16
32
25
8
8
1.6

25
32
256
32
128
128
>lOO
128
64
1.6

17
9
18
13
6
10
2

16
32
32
8
8
2
2

32
128
128
32
16
16
4

64
2128
128
128
16
128
-

RefefOllC@

PI
WI
1121
1121
1141

1181

WI
WI
P41

WI
P21
1141

Ifs1
P21
1141
1141

US1

Other 8. fragilis group.

+B. fragilis group.

TABLE V

Summary of Published in Vitro Activity of Norfloxacin against Neisserla gonorrhoeaa

Numberot

Neisseria
gonorrhoeae
Beta-lactamase
negative

Beta-lactamase

TABLE VI

(or not specified)

positive

Streins

ma

wa

bo/mU

Wml)

50
14
5
52
56
48
17
48
58
16

SO.06

SO.06

0.05
0.03
0.03
0.15
0.01
0.01
0.05
0.06
so.1

0.1
0.06
0.1
so.1
0.01
0.03
1.0
0.1
0.3

~0.06
0.1
0.06
0.1
0.3
0.01
0.03
1.0
0.5
0.3

Reference
131
PI
Is:
1131
P41

WI

WI
PI
1131

Summary of Published in Vitro Activity of Notfloxacin against Mycobacteria

Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium

tuberculosis
fortuitum
avium complex
chelonas
kansasii

Numberof
Ntrainr

MlCp
Wml)

20
20
20
20
20

4
0.5
16
16
16

Whereas norfloxacin is extremely active against gramnegative pathogens, it is relatively less active against
gram-positive cocci. However, Staphylococcus species,
including methicillin-susceptible and methicillin-resistant
S. aureus, Staphylococcus saprophyticus, and other co-

12

Maximal
MC

June 26,19S7

The American Journal of Mdlclne

Mb0
bolml)
8
2
>16
>16
>16

Maximal
MtC
8
>16
>16
>16
>16

Reference
1471
1471
[47l
[47l
[47l

agulase-negative staphylococci, are susceptible to norfloxacin. In general, staphylococci are more susceptible to
norfloxacin than are streptococci. For example, the MIC&
of norfloxacin for enterococci, including many Streptococcus faecalis, is 8 m/ml, and, in a multicenter study, enter-

Volume 82 (suppl6B)

SYMPOSIUM

TABLE

Vii

Quality Control
with Norfioxacin

Limits, Proposed
against Urinary

interpretive
Zone Standards,*
Bacterial isolates

Organism

Susceptible
Moderately
Resistant
ATCC
*10-w

and MiCs for Susceptibility

25922
25923
27853

28-36
17-28
22-29

Zone
47 mm
13-16
mm
512 mm

susceptible

Testing

OualityControl
limits (mm)

ATCCNumber

Escherichia
coli
Staphylococcus
aureus
Pseudomonas
aeruginosa

ON NORFLOXACIN-GOLDSTEIN

516

MC
pg/ml

232

pglml

= American
Type Culture Collection.
disk standards
derived from [46,48].

ococci and group D non-enterococci accounted for a large

percentage of the norfloxacin-resistant strains [46].
The activity of ail fluoroquinoione antibacteriais against
anaerobic bacteria is poor [6,12,14,18,19]. Most studies
have not differentiated between Bacteroides fragilis and
other members of the B. fragiiis group (e.g., Bacteroides
distasonis, Bacteroides vuigatus, and Bacteroides
thetaiotaomicron, among others); Goldstein and Citron
[12], however, did speciate anaerobic isolates. They
noted that B. fragilis strains were somewhat more susceptible to norfloxacin than were other B. fragilis group strains
[12]. With the exception of Bacteroides ureolyticus, Ciostridium perfringens, and some Eubacterium species, the
majority of anaerobes (including gram-positive cocci and
rods and gram-negative rods) were relatively resistant to
norfioxacin. Some variation in results from study to study
may be related to methodoiogic and technical considerations, as well as to the lack of anaerobic speciation in
many of the trials.
Gay and associates [47] studied the activity of norfloxatin against 100 isolates of mycobacteria. They noted that
the range of MiCs for individual isolates of each species
varied widely. isolates of Mycobacterium tuberculosis and
Mycobacterium fortuitum were usually more susceptible
to norfloxacin (MI&, values of 8 pg/ml and 2 pg/ml, respectively) than were isolates of Mycobacterium avium
complex, Mycobacterium kansasii, and Mycobacterium
cheionei (MI&-, values greater than 16 pg/mi) [47].
Preliminary studies have found norfioxacin to be active
against isolates of Campyiobacter pyioridis. it was not active against Chlamydia trachomatis [48-501. However,
Meier-Ewert et al [49] tested norfioxacin against five
strains of C. trachomatis and found that although 5 pg/ml
reduced iodine-stainable inclusions by at least 50 percent, 20 pg/mi was required for inhibition of replication.
The proposed quality control limits and interpretive
standards for disk diffusion testing and determination of
MiCs for norfioxacin are shown in Table Vii. Using a
lo-pg disk, Shungu et al [46,51] proposed the following

June 26,1987

interpretive zone-size breakpoints for urinary tract bacterial isolates: greater than or equal to 17 mm, susceptible;
13 to 16 mm, moderately susceptible (intermediate): less
than or equal to 12 mm, resistant. Because of differences
in antibacterial spectra and pharmacokinetic properties,
the use of a class disk for the fluoroquinolones seems
inappropriate. it has been proposed, however, that isolates with MlCs less than or equal to 16 pg/ml be considered susceptible, whereas those with MlCs greater than
or equal to 32 pg/ml be considered resistant to norfloxatin. (When reconstituting norfioxacin from standard laboratory powder, it must first be soiubilized in O.lN sodium
hydroxide and then diluted in sterile water or broth. if a
steers-type replicator is used, one must be careful of drug
carryover. Additionally, the head should be changed between runs.)
A number of studies have evaluated the effect of different environmental test conditions on the activity of norfloxacin [6,14,17,44,52-551. in general, these findings apply
to all members of the fluoroquinolone class of antibacterials [44].
Tolerance (minimal bactericidal concentration (MBC)/
MIC ratio greater than or equal to 32 mglml) does not
seem to occur with norfioxacin. Furthermore, studies have
shown that for norfloxacin, MiCs are similar to MBCs
[14,52]. Although the MiCs of aerobic bacteria are not
markedly affected by inoculum size [4,17,44,52], an inoculum effect is observed with some anaerobic bacteria [56].
Similarly, early studies suggested that pH and the composition of the testing media had little or no effect on the
activity of norfioxacin [44,52]. For example, Shah et al [53]
compared the activity of nalidixic acid, cinoxacin, and norfloxacin against 302 urinary tract pathogens in DST
(Oxoid) agar and pooled human urine agar (pH 5.4 to 5.8)
[53]. They found that all three compounds lost activity in
urine agar, an effect confirmed by other investigators [4].
They suggested that this finding was due to low urinary
pH, especially if the level was less than 5.0 [45,54,55].
However, Greenwood and associates [54], using a dy-

The

American

Journal

of Medicine

Volume

82

(suppl 8B)

13

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

l
A

l
l

i
A

Proteus

+
Acinetobacter

Hafnia
E. coli

Serratia
+
Klebsiella

namic bladder model to simulate clinical cystitis, noted

that this effect has little clinical relevance since the urine
concentrations of norfloxacin still greatly exceed those
necessary to inhibit growth even under the most unfavorable conditions. Lacey et al [55] noted a similar decrease
in the activity of norfloxatiin in urine having an acid pH.
Despite this, when comparing norfloxacin with other antibiotics, the rate of killing of cultures in urine was second
only to gentamicin.
Lacey et al [55] also reported a reduction in the activity
of norfloxacin at high, as opposed to low, urine concentrations (90 pg/ml), a phenomenon called the paradoxical

14

June

28, 1987

The American

Journal

of Medicine

Volume

tf

Figure 4. Frequency (x 10-9 of appearance of resistant variants at M/C x 4

concentrations
of
antibiotic.
l =
nalidixic acid; A = noifloxacin.
Reproduced with permission from [Sl].

or %agle effect. They postulated that this effect was produced by reduced drug solubility at low pH and not by the
pH level itself. Although a paradoxical effect has been
observed with nalidixic acid [57,58], preliminary probe
experiments with E. boli suggest that it does not octiur with
norfloxacin [59].
Neu [80] has recently reviewed the effect of cations
upon the activity of fluoroquinolones, and suggested that
alteration of norfloxa+s activity in urine and Laceys [55]
reported paradoxical effect might be related to the higher
concentrations of magnesium in urine as opposed to broth
or agar media. For the fluoroquinolones, increased mag-

82

(suppl 8B)

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

>105
105-

101.

103.
l
l
.
l

102-

l
l
l

10'.

l
l
i
l

O-

Pseudomonas
+
Acinetobacter

Figure 5. Frequency (x 70-3 of appearance of resistant variants at M/C x

16 concentrations
of antibiotic.
l =
nalidixic acid; A = norfloxacin.
Reproduced with permission from [Sl].

nesium concentrations do alter MI&, but increased calcium concentrations do not. It is speculated that magnesium may increase MIC values by impeding ATPase activity or by interfering with the interaction between DNA and
the fluoroquinolones.
Whereas nalidixic acid has been limited in its clinical
usefulness because of the development of bacterial resistance during therapy [61], studies on the frequency,
selection, and development of in vitro resistance to norfloxacin have produced conflicting results regarding the
latters clinical applications [53,54,61-641. Tenney et al
[62] were able to produce resistant strains of E. coli and P.

June

29,1987

ii

iii

Citrobacter
Serratia
+
Klebsiella

Proteus

Hafnia
E. coli

aeruginosa by serial passage with subinhibitory concentrations of norfloxacin. Greenwood et al [54] have also
been able to induce resistance. They noted, however, that
the level of resistance remains within therapeutically
achievable limits. Duckworth and Williams [62] reported
that resistance developed less frequently with norfloxacin
than with nalidixic acid (Figures 4 and 5); they also found
nonfermenting gram-negative bacteria more likely to develop resistance than were enterobacteria. Sanders et al
[63] reported that nalidixic acid was likely to select resistant mutants, but notfloxacin was no more likely to select
for resistant mutants than amikacin. They estimated the

The

American

Journal

of Medicine

Volume

92

(suppl 66)

15

SYMPOSIUM

ON NORFLOXACIN-GOLDSTEIN

mutational frequency to be as low as 1Oe7 to 1Ov8. Crossresistance within the fluoroquinolone class has occurred,
however, although it has not developed between fluoroquinolones and other classes of antibiotics, e.g., the betalactams. One exception is a K. pneumoniae strain that
developed cross-resistance. This unique change suggests an alteration in outer membrane proteins and,
hence, permeability barriers [65,66].

The class of fluoroquinolones as a whole is also bactericidal. The mechanism of action of these drugs involves
inhibition of bacterial DNA gyrase, an essential enzyme
involved in DNA replication. The incidence of cross-resistance within the fluoroquinolone class and between norfloxacin and other antibiotic classes (e.g., penicillins,
cephalosporins, and aminoglycosides) is very low. The
exploration of the in vitro, antibacterial, and pharmacologic properties of norfloxacin has provided a sound rationale for its use as treatment for a number of important
infectious disease syndromes.

COMMENTS

In conclusion, norfloxacin is an interesting new fluoroquinolone antibacterial agent. As a consequence of structural modifications of the quinolone nucleus, it has a
broader spectrum of in vitro antibacterial activity than
does nalidixic acid. This spectrum includes aerobic grampositive and gram-negative organisms; multi-antibioticresistant, gram-negative rods; aminoglycoside-resistant
P. aeruginosa; and beta-lactamase-producing organisms.

ACKNOWLEDGMENT

I would like to thank the following people for various forms

of assistance: Alice E. Vagvolgyi, Judee H. Knight, Diane
M. Citron, Ronald Grun, Gregory Fergueson, and Richard
D. Meyer.

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1.
2.
3.

4.

5.

6.

7.

a.

9.

10.

11.

12.

13.

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Lancet 1984; I: 24-25.
Fass FtJ: The quinolones.
Ann Intern Med 1985; 102: 400-402.
Barry AL, Jones RN, Thornsberry
C, et al: Antibacterial
activities
of ciprofloxacin,
norfloxacin,
oxolinic acid, cinoxacin
and nalidixic acid. Antimicrob
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1984; 25: 633-637.
Bauernfeind
A, Ullmann U: In-vitro activity of enoxacin,
ofloxatin, norfloxacin
and nalidixic acid. J Antimicrob
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1984; 14 (SUPPI c): 33-37.
Body BA, Fromtling
RA, Shadomy
S, Shadomy HJ: In vitro antibacterial activity of norfloxacin
compared
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Chin NX, Neu HC: In vitro activity of enoxacin,
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aminoglycosides,
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Antimicrob
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1983; 24: 754-763.
Corrado
ML, Cherubin
CE, Shulman M: The comparative
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Crider SR, Colby SD, Miller LK, et al: Treatment
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N Engl
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Forward KR, Harding GKM, Gray GJ, et al: Comparative
activities of norfloxacin
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against gentamicin-susceptible
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Pseudomonas
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1983; 24:
602-604.
Hasse D, Urias B, Harding G, Ronald A: Comparative
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Eur J
Clin Microbial
1983; 2: 235-241.
Gombert
ME, Aulicino TM: Susceptibility
of multiply antibioticresistant
pneumococci
to the new quinolone
antibiotics,
nalidixic acid, coumermycin,
and novobiocin.
Antimicrob
Agents
Chemother
1964; 26: 933-934.
Goldstein
EJC, Citron DM: Comparative
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hospitals. Antimicrob
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1985; 27: 657-659.
Khan MY, Siddiqui Y, Gruninger
RP: Comparative
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15.

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19.

20.

21.

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23.

24.

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against Neisseria
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Antimicrob
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King A, Warren C, Shannon
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Journal

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