l hternationM Journal of Antimicrobial Agents 1 (1991) 29-46 29

1991 Elsevier Science Publishers B.V. 0924-8579/91/$ 03.50

ANTAGE00002

Review

Pefloxacin
E. B e r g o g n e - B r r r z i n
Department of Microbiology, Bichat-Claude Bernard Universi~ Hospital, Paris, France

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Introduction cal properties, antimicrobial activity, clinical pharmacology,

clinical indications and adverse effects of pefloxacin as com-
pared to that of the parent compound, nalidixic acid.
Discovered in 1962 during chloroquine synthesis, nalidixic
acid, the progenitor of 4-quinolones, offered an unexpected
activity against gram-negative aerobic bacteria and has been Chemistry
used successfully in the clinical management of urinary tract
infections. Well tolerated, it has also proved useful in the treat-
ment of enteric infections such as dysentery due to Shigella The chemical name of pefloxacin is 1-ethyl-6-fluoro-7- (4-
spp. But the clinical use of nalidixic acid remained limited due methyl- 1-piperazinyl)-4-oxo- 1,4- dihydro-3-quinolone carbo-
to its narrow spectrum of antibacterial activity and restricted xylic acid and the dihydrate mesylate salt is used for the tablet
pharmacokinetic characteristics. Several further compounds and injection formulations (Fig. 1). Its molecular formula is
synthetized in the 1970s such as pipemidic acid, oxolinic acid, C17H2oFN303, C H 4 0 3 8 , 2H20, and its molecular mass is
cinoxacin, flumequin, exhibited very little improvement with 465.50 kDa. This methyl-4-piperazinyl fluorinated quinolone
the same indications and the same limitations as that of the has been synthetized in Laboratoire Roger Bellon, 94140 A1-
parent compound, nalidixic acid. A significant improvement fortville, France; initially developed as 1589 RB, pefloxacin
in quinolone development occurred with the introduction of a has been in clinical use in France since 1985 and was marketed
fluorine in position 6 and furthermore of a piperazine substitu- under the national approved name Peflacine; the international
ent in position 7 of the basic nucleus of quinolone molecule: nonproprietary name is pefloxacin (mesylate dihydrate). Pe-
this has resulted in the synthesis of the series of the new fluoro- floxacin's physical appearance is that of a whitish crystalline
quinolones which evolved since the early 1980s [98]. Among powder, easily soluble in water, slightly soluble in 95% alco-
them the earliest compound was pefloxacin which was ini- hol and totally insoluble in chloroform (Table 1); the drug is
tially designed for treating urinary tract infections but which stable as a powder as well as in aqueous solution; when 1.00 g
proved surprisingly active against a wide range of Gram-nega- of pefloxacin mesylate dihydrate is dissolved in 100 ml of
tive and Gram-positive bacteria, including staphylococci and
Pseudomonas aeruginosa [43, 44]. Moreover, pefloxacin and TABLE 1
further fluorinated quinolones exhibited favourable pharma- Solubility of pefloxacin at room temperature
cokinetic properties which permitted their introduction in the Solvents Amount of pefloxacin dissolved (mg/l)
treatment of systemic bacterial infections [99]. Marketed in
Water 580: easily soluble
1985 for oral and parenteral use, pefloxacin has proved an
Chloroform 0.32: very slightly soluble
extremely useful addition to the physicians' antibacterial ar- Methanol 6.21: slightly soluble
mamentarium. The purpose of this work is a review of chemi- Alcohol 1.83: slightly soluble
Acetone 0.05: quite non-soluble
Correspondence to." E. Bergogne-Brrrzin, Dept. of Microbiology, Bichat- Dimethylformamide 4.48: slightly soluble
Claude Bernard University Hospital, 46 Rue Huchard, 75877 Paris Cedex 18, Ether 0.03: non-soluble
France. Ethyl acetate 0.016: non-soluble
30
/ NF
CH3-- N
\ /
C17H20N303F
Fig. 1. Mesylatedihydratepefloxacin.
water, the pKa is 6.3, corresponding to carboxylic function;
the pKb is 7.6, corresponding to the nitrogen atom of the 4-
methyl-I- piperazinyl function of the molecule. The above
mentioned physicochemical characteristics indicate that pe-
floxacin is poorly liposoluble and predominantly hydrosol-
uble (all data on physicochemical properties went from Roger-
Bellon and Rh6ne-Poulenc data- on-file, and investigator's
brochure; unpublished data).
Microbiology
Spectrum of antibacterial activity
In terms of structure-activity relationship, the marked
enhancement of antibacterial activity of pefloxacin as com-
pared to the parent compound, nalidixic acid, is to be related to
the presence of the fluorine at position 6 and of the piperazine
moiety at position 7 of the molecule of pefloxacin. The
spectrum of antibacterial activity of pefloxacin is shown in
Table 2.
Enterobacteriaceae Pefloxacin, as other fluoroquinolo-
nes, is highly active against the Enterobacteriaceae (Citro-
bacter, Enterobacter, Klebsiella, Morganella, Proteus); the
minimal inhibitory concentrations (MICs) ofpefloxacin for all
genus and species of this family of bacteria ranges usually
between 0.03 and 4 or 8 mg/l (15, 45, 49, 99); against Salmo-
nella, Shigella and Yersinia (data not shown in Table 2) the
MIC50/MIC90 were lower: 0.12/1.0, 0.06/0.06, 0.12/0.25 mg/1,
respectively [56]. As shown in Table 2, for most species of
Enterobacteriaceae, pefloxacin was significantly more active
than nalidixic acid.
Gram-negative aerobic bacteria Although moderate sus-
ceptibility to pefloxacin is noted for some Gram- negative aer-
obic bacilli such as Pseudomonas aeruginosa, Acinetobacter
spp., Alcaligenes, Pseudomonas spp. including Xanthomonas
maltophilia [89], the MICs of pefloxacin for these bacteria
O
II
~ . COOH
~ ~N / CH3SO3H,2H20
I
C2H5 M.M.=465,5
when ranging from 1 to 4 mg/1 are somewhat compatible with
its in vivo achievable concentrations. Among Pseudomonas
and Acinetobacter, many strains have become resistant to pe-
floxacin and other fluoroquinolones [5]. Among other Gram-
negative aerobic bacteria, some gastrointestinal pathogens
such as Aeromonas sp., Campylobacter spp. [87] and genital
pathogens such as N. gonorrhoeae or H. ducreyi [93] are very
susceptible to pefioxacin whereas Gardnerella vaginalis is
inhibited by higher MIC50/MIC90 (4/8 mg/l); among Gram-
negative respiratory pathogens, Haemophilus influenzae in-
cluding ~l-lactamase producers [15,73] andBranhamella (Mo-
raxella) catarrhalis are very susceptible to pefloxacin.
Gram-positive cocci Staphylococci including S. aureus
and coagulase-negative staphylococci even resistant to other
antibiotics are susceptible or moderately susceptible to peflo-
xacin, with MICs in the range 0.125-0.5 rag/1. Initially methi-
cillin-resistant strains (MRSA) were as susceptible to peflo-
xacin as methicillin-sensitive (MET-S) staphylococci [15];
changes as a function of time have occurred and an overall
resistance of 41.2% of S. aureus to pefloxacin was evaluated
recently (96.8% among MRSA and 10.1% among MET-S
strains) (personal communication, 1990). The streptococci of
groups A, B, C and G, enterococci, Streptococcus pneumo-
niae, and non haemolytic streptococci (not shown in Table 2)
[45,73] are resistant to pefloxacin with MICs in the range 4 to
16 mg/1.
Miscellaneous The MICs of pefloxacin for Legionella
pneumophilaweremoderatelylow(MIC50/MIC90:1.0/1.0mg/
1) [98]; for Eikenella corrodens, Vibrio cholerae, the MICs
were very low whereas Helicobacter pylori, Listeria monocy-
togenes and Nocardia astero'ides were resistant to pefloxacin,
with MIC50 of 8 mg/1 or more [56]. Mycobacteria (Table 2)
[33, 48] are moderately or not susceptible to pefloxacin and
most anaerobes including Bacteroi'des, Clostridium and Fuso-
bacterium spp are resistant to pefloxacin [31]. Mycoplasma
spp and Chlamydiae are poorly susceptible to pefloxacin
(MIC50/MIC90: 2/8 mg/l) whereas Rickettsia conori and Cox-
iella burneti are susceptible at therapeutically achievable con-
centrations [56].
 31

TABLE 2
The in vitro activity of pefloxacin as compared to that of nalidixic acid (data compiled from references 15, 31, 45, 48, 49, 73, 87)
Organism Antibiotic Range MIC (m/l)
(no. of isolates)
MIC 50 MIC 90

Enterobacteriaceae
E. coli (45) pefloxacin 0.03-8 0.125 2
(102) pefloxacin 0.03-4 0.06 0.25
(102) nalidixic acid 1- 128 2 4
Klebsiella spp. (45) pefloxacin 0.06-4 0.25 2
(75) pefloxacin 0.015-8 0.125 2
(75) nalidixic acid 0.125-> 128 4 128
Citrobacter (20) pefioxacin 0.03-0.25 0.06 0.125
(22) pefloxacin 0.06-2 0.125 0.5
(22) nalidixic acid 2-32 4 8
Enterobacter (35) peftoxacin 0.06-16 0.125 2
(80) pefloxacin 0.06-2 0.125 0.5
(80) nalidixic acid 2-32 4 8
Serratia (25) pefloxacin 0.06-1 0.25 1
(20) pefloxacin 0.06-0.5 0.125 0.25
(20) nalidixic acid 1-16 2 16
Proteus mirabilis (40) pefloxacin 0.06-1 0.25 1
(59) pefloxacin 0.03-4 0.25 0.5
(59) nalidixic acid 1-> 128 8 8
Proteus vulgaris (25) pefloxacin 0.125-0.25 0.125 0.25
(9) pefloxacin 0.125-0.25 0.125 0.25
(9) nalidixic acid 4 4 4
Morganella morganii (20) pefloxacin 0.06-1 0.125 0.25
(18) petloxacin 0.125-4 0.25 0.25
(18) nalidixic acid 2-> 128 4 8
Proteus rettgeri (20) pefloxacin 0.03-0.5 0.25 0.5
(3) pefloxacin 0.03-0.5 0.25 128
(3) nalidixic acid 0.5-128 4 4
Gram-negative anaerobes
Acinetobacter (35) pefloxacin 0.03-2 0.25 1
(25) pefloxacin 0.06-4 0.25 2
(25) nalidixic acid 1-64 4 32
Alcaligenes (6) pefloxacin 0.06-4 0.25 2
nalidixic acid 1-64 4 32
Pseudomonas spp. (35) pefloxacin 0.06-4 2 4
(9) pefloxacin 0.06-4 1 4
(9) nalidixic acid 4-64 16 32
P. aeruginosa (35) pefloxacin 1-8 1 8
(56) pefloxacin 0.5-16 1 8
(56) nalidixic acid 32-> 128 64 >128
Aeromonas (10) pefloxacin 0.008-0.03 0.016 0.016
(10) nalidixic acid 0.008-0.12 0.12 0.12
Campylobacter spp (20) pefioxacin 0.12-1 0.25 0.5
(100-200) pefloxacin 0.31-0.62 0.31 0.62
(15) pefloxacin 0.12-0.5 0.25 0.5
(15) nalidixic acid 2-8 2 4
H. influenzae (20) pefloxacin 0.008-0.06 0.03 0.06
(46) peftoxacin < 0.0075-0.5 0.06 0.06
(46) nalidixic acid 0.5-8 1 2
G. vaginalis (20) petloxacin 2-8 4 8
(20) nalidixic acid 64-512 256 512
B. catarrhalis (20) pefloxacin 0.125-0.25 0.125 0.25
(20) nalidixic acid 4-8 4 8
32

TABLE 2 (continued)
The in vitro activity of pefloxacin as compared to that of nalidixic acid (data compiled from references 15, 31, 45, 48, 49, 73, 87)

Organism Antibiotic Range MIC (m/l)

(no. of isolates)
MIC 50 MIC 9(/
N. gonorrhoeae (40) pefloxacin 0.016-0. 125 0.016 0.06
(40) nalidixic acid 0.5-2 1 2
Gram-positive cocci
S. aureus (30) pefloxacin 0.25-1 0.5 0.5
(90) pefloxacin O. 125-8 0.25 0.5
(90) nalidixic acid 16-> 128 64 128
S. epidermidis (15) pefloxacin 0.25 -0.5 0.5 0.5
(30) pefloxacin 0.25-2 0.5 0.5
(30) nalidixic acid 32-> 128 64 128
13-haemolytic streptococci groups A, C and G
(40) pefloxacin 4-128 8 16
group A (9) pefloxacin 4-8 8 8
group B (16) pefloxacin 4-16 8 16
group G (3) pefloxacin 4-8 4 8
groups A, B, G nalidixic acid > 128 > 128 > 128
Strept. pneumoniae (20) pefloxacin 4-16 8 8
(23) pefloxacin 2-16 4 t6
Enterococci (44) pefloxacin 2-8 4 4
(20) pefloxacin 2-8 4 8
Anaerobes
B. fragilis (99) pefloxacin 4-32
(30) pefloxacin 4-32 16 32
(30) nalidixic acid 128-512 512 512
B. melaninogenicus (40) pefloxacin 2-16 8 16
Peptostreptococcus spp. (20) petloxacin 1-8 2 8
Peptococcus spp. (20) pefloxacin 1-32 4 8
Clostridium spp. (20) pefloxacin 1-32 4 8
(25) nalidixic acid 8->512 512 >512
C. difficile (105) pefloxacin 16-32
Fusobacterium spp. (10) pefloxacin 1-64 16 32
Veillonella spp. (10) pefloxacin 0.25-2 1 2
Mobiluncus spp. (20) pefloxacin 4-16 8 16
Mycobaeteria
M. tuberculosis pefloxacin 4 8
M. avium pefloxacin 16 >16
M. bovis pefloxacin 2.5 4.8
M. xenopi pefloxacin 8 16
M. kansasii pefloxacin 2 8
M. fortuitum pefloxacin 1 4

Mechanism of action post-replicational repair. This mechanism initially described

The primary target of pefloxacin like that of other quino-
lones is bacterial D N A gyrase (topoisomerase II) which is an
essential bacterial enzyme with a variety of activities
[76,79,98,101] : the DNA gyrase is responsible for the intro-
duction of negative superhelical twists into double-stranded
D N A and for catenation and decatenation of two duplex DNA
circles interlocked like links in a chain; as a result of the quino-
lone activity, most biochemical functions of D N A gyrase on
cell physiology are affected as well as DNA replication and
in E. coli [ 17] has been completely identified and DNA gyrases
have been purified from Pseudomonas aeruginosa, Citrobac-
terfreundii, Staphylococcus aureus and many other organisms
100. Whether pefloxacin binds directly to DNA gyrase or to
DNA, or to the DNA gyrase-DNA complex is still a matter of
debate [76]. Whatever the mechanism, the inhibition of DNA
gyrase by quinolones results in inhibition of bacterial multipli-
cation and the expected effect should be bacteriostatic: in fact
new 4-quinolones and pefloxacin as well are strongly bacteri-
cidal but in a complex manner; the bactericidal effect has been

described as 'biphasic' [100] with a single rapidly killing ef-
fect followed by a paradoxical reduced killing phase in the
presence of increased quinolone concentration; in bacterial
cells incubated with pefloxacin, non-replicative DNA synthe-
sis (DNA repair), termed SOS response, is induced and SOS
response which is thought to protect bacteria from further da-
mage to DNA, prevents replication, blocking cell division and
producing filarnentation [50,100]. Thus the end result of the
SOS response is harmful for the bacteria with morphological
and biochemical disturbances. The expression of such a bacte-
ricidal effect of pefloxacin has been evaluated on the basis of
minimum bactericidal concentration (MBC): the MBC values
have been generally reported as the same as, or within 2 dilu-
tions of the MIC values [2,84,90]; the killing rate of pefloxacin
as measured by time-kill curves was rapid at concentrations
attainable at therapeutic doses and was reported as more rapid
than that of cephalosporins of third generation against Entero-
bacteriaceae and P. aeruginosa; against S. aureus including
methicillin-resistant strains the killing rate of pefloxacin was
at least equivalent to that of pristinamycin ] 11 ].
Resistance mechanisms
Very unusually among antibacterial agents, plasmid-medi-
ated resistance to the 4-quinolones does not occur and enzy-
matic inactivation of pefloxacin by bacteria has not been de-
scribed: resistance to pefloxacin and other quinolones has
been described as developing by bacterial chromosomal mu-
tation [79,98,100]: spontaneous mutations to high-level resis-
tance to nalidixic acid map in the gyr-A locus (which codes for
the two subunits A of the DNA gyrase) in E. coli chromosome;
these mutations can produce cross-resistance but to a lesser
degree to the new fluoroquinolones [17,64,98]; the B subunit
ofDNA gyrase may also interact with the fluoroquinolones but
mutation confers hyper susceptibility to 4-quinolones which
possess a 7-piperazine ring like pefloxacin [79]. The mutations
which affect DNA gyrase, subunit A, occur at a frequency of
10-6 to 10-8; spontaneous single-step mutations conferring re-
sistance to high concentrations of ofloxacin, ciprofloxacin or
pefloxacin have been occasionally reported at a frequency of
about 10-7 [98]. Mutations which may occur in a variety of loci
(nal B, gyr B, pur B, etc...) of the chromosome in E. coli have
been recognized as conferring low levels of resistance to nali-
dixic acid but the effects of these mutations on susceptibility to
fluoroquinolones are unknown. The biochemical mechanism
of resistance in mutants is categorized by reduced permeability
of the porins of Gram-negative bacilli associated with dimin-
ished expression of ompF protein which inhibits antimicro-
bial drug penetration into the bacterial cell; or the decreased
diffusion of quinolone may result from alterations of the struc-
ture of phospholipid bi-layer of the outer membrane
[16,79,98,100]. This latter mechanism may prevent cellular
33
penetration of other antimicrobial agents besides the quino-
lones and some strains of K. pneumoniae, P. aeruginosa, S.
marcescens which resist quinolones exhibit increased resis-
tance to non quinolone classes of drugs indicating decreased
drug penetration [16,98,99]. Gram-positive bacteria which
lack an outer membrane with its associated porins are able to
mutate to 4-quinolone resistance at higher frequencies than
Gram-negative bacteria in vitro and in vivo [79]. The emer-
gence of resistance following treatment with pefloxacin has
been observed in experimental conditions in treating P. aeru-
ginosa peritonitis in an animal model [59] as well as in clinical
settings: resistance development was reported in P. aerugi-
nosa, S. aureus, S. epidermidis and Enterobacter spp. [1]; in
most cases, resistant P. aeruginosa developed late in the
course of a prolonged treatment, especially in treating skeletal
infections or respiratory superinfections in cystic fibrosis pa-
tients; in urinary tract infections (UTI), short course therapy
does not seem to result in emergence of resistance whereas in
complicated UTI with anatomical abnormalities of the urinary
tract the frequency of development of resistance can be high
[9].
Inoculum effect and other factors influencing the antibac-
terial activities of pefloxacin
Generally no significant differences in MIC of pefloxacin
were found when inocula of 103 or 106 cfu were used; but the
use of inocula higher than 106 cfu has been reported to increase
significantly the MICs for Enterobacteriaceae and P. aerugi-
nosa [2,99]; overall effects of inoculum size on MICs of qui-
nolones tended to be small; variation among strains and spe-
cies occurred and the inoculum effect was most marked (up to
32 times the MIC) with Enterobacter cloacae and Serratia
marcescens [2] which had otherwise the highest frequency of
mutants. The influence of pH, cations and various media has
been mentioned in various studies: the pH of the growth me-
dium was found to influence dramatically pefloxacin MIC val-
ues; at pH 5.5 an 8-fold increase in MIC values for 67% of
Gram-negative isolates was obtained compared with pH 7.4
[65]; similarly the effect of pH was demonstrated when sterile
urine at pH 5.5 was added in the medium and MIC values rose
from < 0.1 to 25 mg/1 for the bacteria tested. It has been sug-
gested that acidic pH may reduce quinolone antibacterial ac-
tivity because the 7-piperazine moiety becomes positively
charged and may interfere with cell penetration [80]. This may
result in a decreased pefloxacin activity in urine but high con-
centrations achieved in urine (see Pharmacokinetics section)
exceed by far the MICs for virtually all bacterial urinary patho-
gens [99]. Supplementation of the medium with zinc ions did
not alter the in vitro activity of pefloxacin whereas addition of
magnesium and calcium ions was associated with decreased
susceptibility to pefloxacin [2,99] as evaluated by reduced in-
34
hihition zone diameters: thus presence of magnesium ions at 8
to 16 mM concentrations, similar to those in urine may inter-
fere with in vivo pefloxacin activity in UT1 as well as dimin-
ished pH.
Drug interactions
Numerous studies have evaluated the effects of combina-
tions of pefloxacin with other antibacterial agents: in most
studies the effects were quantitated by measurement of frac-
tional inhibitory concentration values [4,55,88,99] or effects
on killing in time-killing curve studies [28]. Overall against
Gram-negative bacteria, pefloxacin combinations with most
[3-1actams and aminoglycosides were indifferent or additive,
or occasionally synergistic, sometimes up to 50% [88] espe-
cially with P. aeruginosa; they were rarely antagonistic
[23,55,66,88]. Pefloxacin combined with aminoglycosides or
13-1actams showed indifference against 70% of Enterobacteri-
aceae and P. aeruginosa [55]. Killing ofS. aureus with combi-
nation of pefloxacin and rifampin was limited but pefloxacin
suppressed emergence of rifampin-resistant organisms
[29,99]. For pefloxacin in combination with amikacin, imi-
penem or trimethoprim-sulfamethoxazole against various my-
cobacterial species, indifferent or additive effects were ob-
served, rarely synergistic effect and never antagonism [99]. In
animal models, combination therapy has resulted in enhanced
efficacy and diminution or suppression of emergence of resis-
tance in some studies [68,86,99]. But the proper use of combi-
nation therapy and its benefit to prevent resistance have still to
be evaluated in controlled studies in man [1 ].
Pharmacology
The general pharmacological properties of pefloxacin have
been evaluated by using standard tests in several animal spe-
cies (data-on-file, Rh6ne-Poulenc Sant6, unpublished).
Central nervous system (CNS) effects
Intravenous (i.v.) or oral administration of pefloxacin in
doses up to 286 mg/kg was not associated with any excitatory,
anticholinergic, analgesic or antidepressant effects in rodents.
A moderate reduction in spontaneous locomotor activity was
observed but this was not dose- related. Pefloxacin produced
some protection against strychnine-induced convulsions.
There were no effects on core temperature, muscle tone, sleep-
ing times and leptazol-induced seizures. It was concluded that
pefloxacin does not exhibit any neuroleptic or sedative proper-
ties.
Cardiovascular and peripheral nervous system effects
In anaesthetized dogs and cats pefloxacin administered i.v.
at 10 and 20 mg/kg doses and intraduodenally at 25, 50 and
100 mg/kg doses, produced a moderate decrease in the pressor
response to adrenaline, noradrenaline and carotid artery occlu-
sion, but not to isoprenaline, acetylcholine, histamine and
vagal stimulation. Pefloxacin did not prevent contractions of
the cat nictitating membrane induced by adrenaline or electri-
cal stimulation indicating that pefloxacin has no ganglionic
blocking properties. In other studies in anaesthetized dogs,
rapid i.v. injection of 4.6 and 9.2 mg/kg dose of pefloxacin
produced an immediate dose-related systolic and diastolic hy-
potensive effect which was less marked when the drug infu-
sion was slow; after intraduodenal administration of 50 mg/kg,
no changes in blood pressure were observed whereas at 100
and 200 mg/kg some dogs developed hypotension, hypo-
ventilation and some electrocardiographic changes. These
effects are produced by high doses unrelated to therapeutic
doses of pefloxacin. Otherwise in animal gastrointestinal tract,
pefloxacin produced a slight reduction in gastric secretion, in-
creased bile secretion and a minimal increase in intestinal tran-
sit time.
Hormonal effects
Standard tests for hormonal activity using mice, rats and
rabbits and 125 to 500 mg/1 kg dose of pefloxacin did not show
any oestrogen, progesterone or antiandrogenqike effects.
In sum, the potential for pefloxacin to produce adverse ef-
fects at normal therapeutic doses in patients appeared very
limited.
Effects on the immune system
Effects on the immune system have been particularly ana-
lyzed. It is established that antimicrobial agents can modify
some immunological processes, especially phagocytosis and
killing by polymorphonuclear phagocytes (PMN); on gran-
ulocyte function, in vitro studies have shown that pefloxacin
increases the phagocytic and microbicidal activity of PMN
against S. aureus [10]; in rodent PMN and alveolar macro-
phages, pefloxacin (1 to 100 rag/1) increased by 35 to 40%
their phagocytic capacity which was not dose-dependent [21 ];
pefloxacin was also shown to increase the uptake of 3H- thy-
midine into DNA in phytohaemagglutinin-stimulated human
lymphocytes which was suggestive of a stimulation of DNA
synthesis [35]; pefloxacin accumulates in macrophages and
several other types of nucleated cells, and a study of cellular
pharmacokinetics and intracellular distribution of the drug has
shown that macrophages infected with Legionella pneumo-
phila (in guinea pig model) retained approximately 20-30% of
 35

the accumulated pefloxacin upon washout whereas from unin-
fected cells pefloxacin was quickly released [ 13].
Gastrointestinal and ecological impact of pefloxacin
Another pharmacological effect of pefloxacin is its poten-
tial impact on microbial ecology in humans: only minor altera-
tions in salivary and faecal microflora result from pefloxacin
therapy [71,91 ]; aerobic enteric bacteria are rapidly eliminated
from stool with a small or no reduction in most anaerobic
species; enterococci and yeasts are unaffected; the flora returns
to normal within a few weeks.
Human pharmacokinetics
Pefloxacin is a fluoroquinolone which is mainly cleared by
the liver; hepatic extraction and biotransformation dominate
the clearance process. The profile of major metabolites of pe-
floxacin has been examined in plasma, urine and bile after
administration to normal volunteers [36,37,60,61,95] (the
main metabolites, their structure and their pharmacokinetics
are described in the section Metabolism).
Analytical methods for pefloxacin
Pefloxacin assays were carried out by means of three main
methods.
1. Microbiological assay. The agar plate diffusion method
used Bacillus subtilis ATCC 6633, or E. coli Kp 1976-712 as
reference organisms, and Difco Antibiotic medium No. 5 ad-
justed at pH 8. The assay was sensitive to 0.06 Bg of pefloxacin
per ml [61]. It expresses total antibacterial activity of the par-
ent compound and of metabolites potentially present in sam-
pies.
2. Fluorometric assay. This assay was used for determina-
tion of drug tissue and plasma levels in rats and dogs and was
compared to specific high-pressure liquid chromatography
(HPLC) assay of pefloxacin; the agreement between both met-
hods was good; the sensitivity was 0.1 Bg of pefloxacin per ml
of plasma or bile and of 0.1 Bg per g of tissue [61].
3. HPLC. Pefloxacin and metabolites were separated by
ion-pair chromatography as described in Montay et al. [60];
quantitative determination of pefloxacin and of its metabolites
in serum and in other body fluids were measured by HPLC
with a detection limit around 0.05 rag/1 for unchanged drug
and for metabolites. HPLC assay was the preferred method
mostly used in pharmacokinetic studies of pefloxacin
[36,37,39,61].
Pharmacokinetic parameters of pefloxacin
Pharmacokinetic parameters following oral and intrave-
nous administration of pefloxacin are summarized in Table 3.
Absorption; plasma half-life After oral administration,
peak concentrations increased proportionally with the dose:
they reached 2.5 mg/1 after 200 mg, 4.2 mg/1 after 400 mg, 5.5
mg/l after 600 mg and slightly less than 7 mg/1 after 800 mg
dose. Absorption was rapid at all doses with peak level reached
at 1.2-1.5 h. The terminal elimination half-life ranged from
6.7 h after a 200 mg dose, to 12.3 h after a 400 mg dose, and to
12.6 + 2.5 h after a 800 mg dose. In a study of multiple-dose
pharmacokinetics [37] of pefloxacin in healthy subjects, re-
ceiving 1 h i.v. infusion of 400 mg every 12 h (15 doses) or oral

TABLE 3
The pharmacokineticprofile of oral and intravenous pefloxacinfollowing single or multiple dose ( 15 doses) administrationto healthy volunteers (unpublisheddata
on file, Rh6ne-Poulenc Sant6)

Parameter Oral Intravenous

Single dose Multiple dose Single dose Multiple dose
200 mg (n=12) 400 mg (n=30) 400 mg (n=18) 400 mg (n=24) 400 mg (n=12)
Cmax (mg/1) 2.5 4.2-4.3 10 5.8 10.1
tmax (b) 1.2 1.3-1.5 1.4 1 1
tz 13(h) 6.7 7.2-12.3 14.8-15.4 8.7-11.3 13.9
AUC (mg/l.h)
0-48 22.6 46.5-68.1 182-230 46.3-54.3 147.4
0-~o ND ND 208 50.8 153.5
Vd (L) 85 94-117 ND 92-134 134
CIp (L/h) 9.42 7.8-9.54 ND 8.7-8.64 8.94
CLr (L/h) 0.51 0.4-0.76 ND 0.69 ND
Cmax= maximum plasma concentration; tma~= time to maximum plasma concentration; t~ B= elimination half-life; AUC = area under the plasma concentration-time
curve; Vd = volume of distribution; CIp = plasma clearance; CLr = renal
clearance; ND = not determined.
36

peftoxacin 400 mg every 12 h (15 doses), plasma concentra-
tions, and half-lives were very similar (Table 3): multiple dose
produced Cmax of 7.9 to 10 mgfl and 9.6 to 10.1 mg/1 respec-
tively after oral and i.v. administration of 400 mg for 10 days.
In these studies, steady-state concentrations were achieved
within 48 h. The ranges of AUC values after oral dose of 400
mg were 46.5 to 68.1 and 182 to 230 mg/1.h for single and
repeated doses, respectively [61]. AUC values after i.v. ad-
ministration were quite identical (Table 3). The bioavailability
of oral pefloxacin is considered as 100% indicating that peflo-
xacin absorption is complete and uninfluenced by the dose. In
contrast to the results obtained with some other quinolones the
bioavailability of orally administered pefloxacin does not
seem to be affected by a fat-rich breakfast, no pharmacokinetic
parameters which did not differ from those determined in the
same fasting volunteers [82].
Distribution The pharmacokinetics of pefloxacin have
been described using a 2-compartment open model [36]. After
1 h i.v. infusion of pefloxacin (200 to 800 mg) the mean vol-
umes of distribution were 23.2 to 68.21 for the central compart-
ment and 64.8 to 100.9 1 for the peripheral compartment. The
apparent volumes of distribution from oral or i.v. administra-
tion have been determined as 1.7 to 1.9 1/kg [37] which sug-
gests a good distribution in extravascular compartments, and
high tissue and body fluid concentrations of pefloxacin. In
comparison with plasma concentrations, peftoxacin achieved
equivalent or higher levels in aortic valve, blister fluid, bone,
cardiac muscle, peritoneum, prostate and bronchial secretions
[20,22,32,36,54,61,74]; in cerebrospinal fluid pefloxacin
reached 2.4 to 9 mg/1 after a 7.5 mg/kg i.v. dose, and 6.5 to 13
mg/l after a 15 mg/kg i.v. dose of pefloxacin in patients with
inflamed meninges; these values which were 58 and 52% of
the serum level were high enough to eradicate infecting or-
ganisms [96]. The good tissue and fluid penetration is to be
related to the physicochemical characteristics of the drug as
described above and in addition to its low serum protein bind-
ing of 20 to 30% in man [61 ].
Excretion Urinary recoveries ranged from 11.1 to 17% of
the administered oral dose; renal clearances ranged from 12.9
to 21.9 ml/min and total clearances ranged from 111 to 135
ml/min [36,37,61]. Non-renal clearance accounted for the
major part of total drug clearance. In the multiple dose phar-
macokinetic study the total serum clearance decreased signif-
icantly from 123 ml/min for the first dose to 87 ml/min for the
last dose which suggests that multiple dosing saturated a non-
renal clearance pathway of pefloxacin [30,61 ]. The low contri-
bution of renal clearance to the elimination of pefloxacin was
confirmed by the fact that only ~ 10% of the dose administered
is excreted in the urine as unchanged pefloxacin [37,61 ]. Some
biliary excretion of pefloxacin occurs, but this is not a major
route of elimination (unpublished data on file Rh6ne-Poulenc
Santr).
Metabolism
Since the high value of total body clearance of pefloxacin

TABLE 4
Pefloxacin, N-demethyl and N-oxide metabolites plasma concentrations 1.0 and 12 h after multiple i.v. (400 mg b.i.d.) dosing (meanSD) (after Frydman et al., ref, 37)

Concentration (mg/1)

+ 1.0 h (Cmax) + 12 h (Cmin)

Dose Pefloxacin Norfloxacin Pefloxacin Pefloxacin Norfloxacin Pefloxacin

N-oxide N-oxide

Day 1 5.80+1.59 0.10+0.03 0.090.07 1.490.52 0.070.03 0.14+0.03

Day 3 morning 4.38+2.04 0.11 +0.03 0.090.03 1.330.46 0.08+0.03 0.14+0.03
Day 3 evening 5.44+0.76 0.16+0.07 0.20-1:0.07 1.91 :t:0.59 0.14+0.03 0.23+0.03
Day 4 morning 5.480.23 0.19+0.03 0.260.03 2.420.66 0.150.03 0.260.03
Day 4 evening 6.55+ 1.40 0.22+0.03 0.290.07 2.80:t: 1.28 0.18+0.03 0.30~0.07
Day 5 morning 6.97+ 1.42 0.24+0.01 0.320.07 3.161.18 0.18+0.03 0.30+0.07
Day 5 evening 0.08+1.69 0.260.07 0.340.07 3.40~1.42 0.20+0.07 0.350.10
Day 6 morning 7.351.83 0.260.10 0.370.10 3.311.18 0.190.03 0.350.10
Day 6 evening 7.66 1.66 0.25+0.03 0.350.10 3.36 1.18 0.200.03 0.360.10
Day 7 morning 7.35 1.48 0.280.03 0.370.10 3.55+1.25 0.20+0.03 0.360.10
Day 7 evening 8.21+ 1.80 0.27+0.03 0.38+0.10 3.54:t:1.45 0.230.03 0.370.10
Day 8 morning 7.17 1.59 0.260.03 0.38+0.07 3.64 1.45 0.200.03 0.38+0.10
Day 8 evening 8.12 1.66 0.250.03 0.390.10 4.03 1.70 0.220.03 0.370.07
Day 9 morning 6.992.46 0.270.03 0.360.07 3.78 1.28 0.20-t:0.03 0.360.10
Day 9 evening 7.592.07 0.250.03 0.380.10 4.09+1.49 0.290.03 0.330. l0
Day 10 morning 9.55+ 1.63 0.280.03 0.42+0.07 4.22 1.52 0.220.03 0.390.10

HSN
N--oxide
,3c- N\_.?\--,~.~.~ \
/
H3C - - N / ~ N -
N-demethyl
( norfloxocin ]
Fig. 2.
indicated extra-renal elimination routes, it was likely to as-
sume that the drug was partly metabolized. In fact, after admin-
istration of a single oral dose of ~4C-pefloxacin, 70% and 25%
of radioactivity were detected in urine and faeces, respecti-
vely, within 7 days and there was no hepatic first-pass metab-
olism of pefloxacin (unpublished data on file, Rh6ne-Poulenc
Sant6). It has been shown that an extensive metabolic bio-
transformation (85 to 90%) occurs to pefloxacin in the human
body [37,61 ]. The main pharmacokinetic parameters of peflo-
xacin and its metabolites derived from the data of the multiple
i.v. infusion are summarized in Table 4 [37]. Metabolism of
pefloxacin has been shown to result in two main metabolites,
N-demethyl pefloxacin (norfloxacin), pefloxacin N-oxide, the
latter having little antibacterial activity [61]; the piperazine
ring is the main site of metabolism: the ring is hydroxylated,
N-oxidised, demethylated, formylated and acetylated (Fig. 2);
the major metabolites are found in the serum; in the urine were
recovered the parent compound pefloxacin, pefloxacin N-
oxide, norfloxacin, oxonorfloxacin, oxopefloxacin and traces
of pefloxacin glucuronide. Except for pefloxacin N-oxide and
glucuronide analog, the other metabolites exhibit antibacterial
activity equal to that of pefloxacin. The urinary excretion of
N-demethyl pefloxacin and pefloxacin N-oxide accounted for
20-21% of the dose administered [61 ]. Total urinary recovery
of parent drug and metabolites was estimated at 59% of the
administered dose of pefloxacin. Pefloxacin concentrations in
bile were 10-20 mg/1 2-12 h after administration of 800 mg
of the drug. In sum, the predominant elimination of pefloxacin
occurs by extra-renal route, by means of metabolization into
two main metabolites N-demethyl and N-oxide pefloxacin
which are excreted together with the remaining parent com-
pound by renal and biliary route [36,37,61].
Therapeutic use
Similarly to nalidixic acid and due to its high concentrations
in human urine, pefloxacin was initially restricted to genito-
37
0
II
/ C--O--GLUC
petloxacin g l u c u r o n i d e
~ H --N/--~N--H3C --N ~ N
Oxo- N-dernet hyl Oxo - pefloxocin
(oxonor - f IoxQci n )
urinary tract infections [42] and many therapeutic trials have
demonstrated the efficacy of pefloxacin in these indications
[9]. Simultaneously pefloxacin had proved eventually active
in a wide variety of infectious conditions due to its spectrum
of antibacterial activity and its remarkable pharmacokinetics.
Thus many data are currently available on pefloxacin thera-
py with i.v. infusion or by oral therapy in various infections
ranging from mild to severe in immunocompromised pa-
tients.
Urogenital tract infections
Pefloxacin was administered at doses of 800 or 1200 mg
daily in patients with uncomplicated and complicated lower
and upper urinary tract infections (UTI): the overall clinical
cure rate ranged from 72 to 94% of patients and bacteriological
eradication was obtained in 76 to 93% of the cases
[9,12,42,99]. In a recent single dose trial of treatment of cysti-
tis the bacteriological cure rate was 95.2% at the first follow-
up with a single dose of 800 mg of pefloxacin administered
orally; it was shown to be safe and at least as effective as a
five-day regimen of co-trimoxazole (960 mg) or a five-day
treatment with norfloxacin in uncomplicated cystitis in women
[70]. In a randomised study in patients with upper gynaecol-
ogical tract infections the efficacy of oral pefloxacin (400 mg
twice daily) following i.v. initial infusion for 3 days was com-
pared to oral ampicillin (500 mg 4 times a day) combined with
intramuscular (i.m.) gentamicin (60 or 80 mg 3 times daily):
clinical cure rates were 93.3 and 94.4%, respectively with both
regimens; bacteriological eradication was obtained in 100% of
cases with pefloxacin but only in 61% of cases with the combi-
nation group [69]. In male acute uncomplicated gonococcal
urethritis, a single dose of pefloxacin (800 mg) proved as effi-
cient as 1.0 g of cefotaxime, with cure rates of 100%, but both
drugs bad no effect on post-gonococcal urethritis, which was
found in 9% of the pefloxacin group and in 20% of the cefotax-
ime group: Chlamydia trachomatis, Mycoplasma hominis and
Ureaplasma urealyticum were not eradicated [85]. Inprostati-
tis, pefloxacin at a 400 mg twice daily dose was given as mon-
38
otherapy for a mean duration of 44 days (range 3 to 105 days)
with an overall success rate of 74% (persistence or relapse in
26% of cases) [40]. Due to the high prostatic concentrations of
pefloxacin as measured in the order of 10 mg/kg, it should be
expected that most acute and chronic prostatitis due to Ente-
robacteriaceae should be eradicated, but not those in which
enterococci are involved.
Respiratory tract infections (RTIs)
Since many respiratory pathogens such as H. influenzae, B.
catarrhalis, K. pneumoniae, S. aureus, Legionella spp., M.
pneumoniae were susceptible to pefloxacin, experimental [38]
and clinical [57,63] evaluation of pefloxacin efficacy in the
treatment of lower respiratory infections was carried out.
These studies included intensive-care patients with nosoco-
mialpulmonary infections; the predominant pathogens were S.
aureus, P. aeruginosa and Enterobacteriaceae; i.v. admin-
istration of 400 mg 2 or 3 times daily for 4 to 28 days produced
67% cure, failure and relapse in 26 and 2% of patients respecti-
vely, the latter often in relation to underlying pathology. Open
studies of acute exacerbations of chronic bronchitis have con-
firmed the effectiveness of pefloxacin in eradicating H. influ-
enzae [54]; but since least susceptible of the common respira-
tory pathogens is S. pneumoniae, most studies have noted
slower clinical responses or failure to eradicate this pathogen
from sputum in bronchitis. In 176 patients with community-
acquired RTI, bronchitis, pneumonia and bronchopneumonia,
pefloxacin 800 mg daily was administered for 9-10 days; 86%
of infecting pathogens were eradicated; in 15% of patients
failure was due to non susceptible species, S. pneumoniae and
]3-haemolytic streptococci (unpublished data-on-file, Rh6ne
Poulenc Sant6). In the experimental animal model of legionel-
losis [25] and in patients with severe legionnaires' disease [26]
it has been shown that pefloxacin in combination therapy was
superior to erythromycin used alone, and that pefloxacin alone
may be as active as combination therapy (with erythromycin or
rifampin) at 800 mg i.v. dose. A particularly important sub-
group of patients with acute exacerbations and superinfections
of severe pulmonary pathology is that of cystic' fibrosis
patients: pefloxacin [24] and other fluoroquinolones (cipro-
floxacin, ofloxacin) have been used successfully in this parti-
cular situation; the clinical response as determined by para-
meters such as fever, amount of sputum and pulmonary func-
tion tests, was similar or better than conventional regimen with
antipseudomonal [3-1actam combined with an aminoglycoside
[99]; P. aeruginosa developed resistance but it was noted that
the apparent instability of fluoroquinolone resistance in P. ae-
ruginosa allows repeated use of this class of drugs. However,
it should not be recommended to use extensively pefloxacin in
cystic fibrosis patients due to several limitations such as the
age of patients, the lack of extensive experience with pefloxa-
cin in these patients, and the official indications of pefloxacin
(as stated in High risk patients section).
Bone and joint infections
Therapy of bone and joint infections require prolonged anti-
biotic therapy with a drug which achieves and maintains high
bone tissue and joint fluid concentrations: several studies have
shown a good penetration of pefloxacin into bone tissue
[20,22], reaching concentrations of at least 1 mg/kg; in clinical
trials, prolonged treatment with oral pefloxacin administered
at a 400 mg twice daily dose resulted in 86 to 100% of clinical
cure [6,20,22,51] in chronic osteomyelitis, mostly due to S.
aureus or P. aeruginosa, as well as in superinfections of total
joint arthroplasty or in septic arthritis. Combination therapy of
pefloxacin with amoxycillin or with aminoglycosides was
used in order to avoid the development of pefloxacin resist-
ance and in some cases in which an enterococcal infection was
observed [6]. The duration of treatment ranged from 1 to 16
months and the oral daily dose of pefloxacin was 800 mg or
1200 rag; in these indications, it is recommended to initiate the
treatment with i.v. infusion, for a few days, followed by oral
route for a prolonged period of time. Pefloxacin has also been
recommended as a drug for peri-operative prophylaxis in pa-
tients undergoing prosthetic hip and knee surgery [53] in rela-
tion to its early and high rate of penetration into bone tissue.
Gastrointestinal tract infections and intra-abdominal in-
fections
Pefloxacin achieves high concentrations in stools (as stated
in the Pharmacokinetics section) and is active against all of the
major bacterial pathogens of the gastro- intestinal tract such as
Salmonella spp., Shigella spp., Campylobacter spp. and ente-
rotoxigenic E. coil (see Microbiology section) [67,99]. Peflo-
xacin should be used in the treatment of acute bacterial gast-
roenteritis and traveller's diarrhea: there are several reports
with other fluoroquinolones (ciprofloxacin, norfloxacin)
given for the control of infections due to Salmonella spp.,
Shigella spp. or Campylobacterjejuni [99], with rapid eradi-
cation of the pathogens by the quinolone relative to placebo;
Salmonella typhi in the stools has been eradicated and the
symptoms of typhoid fever regressed within 10 days by using
pefloxacin [41 ] given orally at 400 mg twice daily dose. These
data suggest that short periods of treatment with pefloxacin
may be effective in the management of typhoid fever and non-
typhoid salmonellosis. The use of fluoroquinolones in the tre-
atment of biliary tract or intra-abdominal infections has been
limited to date: however, high biliary concentrations of these
agents would suggest their potential efficacy in the treatment
of biliary tract infections: in patients with biliary infections,
the efficacy and safety of 800 mg daily dose of pefloxacin was

compared to that of a combination of ampicillin with gentami-
cin [14]: the pathogens isolated in operated patients were pre-
dominantly E. coli and Klebsiella spp.; they were eradicated
and 100% of patients were cured in the pefloxacin group ver-
sus 94% in the ampicillin-gentamicin group. Since intra-abdo-
minal abscesses include frequently anaerobes which are
poorly susceptible to fluoroquinolones, metronidazole (500
mg i.v.) has been combined with pefloxacin (400 mg i.v. twice
daily) in the treatment of severe intra-abdominal infections;
the efficacy and safety of this combination was compared to
that of gentamicin (1.5 mg/kg every 8 h) plus metronidazole in
an open randomized comparative study [72]: 86.7% of patients
in the pefloxacin group were cured or improved versus 84.5%
in the gentamicin group; bacterial eradication was obtained in
95.5% with pefloxacin+metronidazole versus 82.3% with
gentamicin+metronidazole. Pefloxacin has proved at least as
efficient as gentamicin when combined with metronidazole in
the treatment of severe post-operative abdominal infections.
Severe infections: immunocompromised patients
Pefloxacin has proved effective in the treatment of most
severe bacterial infections as was seen above in nosocomial
pneumonia.
In the treatment of septicaemia due to Gram-negative bac-
teria, pefloxacin was given at 400 mg twice a day (i.v.) or trice
a day (1200 mg) as first line treatment, or second line treatment
after failure of the first treatment in 60 patients with various
entry sites of Gram-negative septicaemia (cutaneous, diges-
tive, i.v. catheter): a satisfactory outcome was achieved in 87%
of cases; failures or relapses in this series were associated with
local or systemic underlying conditions [7,58]. In experimen-
tal [83,86] and human endocarditis [97], especially when
methicillin-resistant staphylococci were involved, pefloxacin
was used as single agent and in combination therapy (with
fosfomycin in the rat endocarditis model; with rifampin or an
aminoglycoside in patients). In these studies it has been con-
cluded that combination therapy has proved more effective
than pefloxacin alone, possible benefits of the combination
resulting from suppression of in vivo emergence of resistance
to pefloxacin even if in vitro data showed only indifferent or
additive action of combined agents. The indication of peflo-
xacin in difficult-to- treat endocarditis requires further investi-
gation since published data are too sparse and inconclusive.
In febrile neutropenic patients, pefloxacin has been used as
a single agent (in 400 mg 8-hourly i.v. dose) in the treatment of
32 various episodes of fever of which six were clinically and
seven microbiologically documented; as expected on the basis
of previous experimental studies in a neutropenic animal
model [38], the clinical response was favorable in 23 patients
(72%), with a sustained fall in temperature to less than 38C
and decreasing signs of infection [8]. It was suggested there-
39
fore that pefloxacin should be used as 'first-line' empirical
treatment for the neutropenic febrile patient.
In Gram-negative bacillary meningitis associated with
neuro-surgical procedures, pefloxacin was used [75] on the
basis of previous experimental evaluation in a rabbit model
[77] and of good penetration of pefloxacin in human inflamed
meninges as described above [96]; moreover, it has been
shown that pefloxacin remained in therapeutic concentrations
in the brain tissue even three days after discontinuation of the
drug [46]. The bacterial eradication of Gram-negative bacteria
was obtained in 80% of patients with an i.v. dose of 800 mg
twice daily; 87% of the bacteria (P. aeruginosa, A. calcoace-
ticus, K. pneumoniae, Enterobacter cloacae, Salmonella and
C. diversus) were eradicated in this particular study [75]. Since
of all previously available antibiotics, only 3d generation ce-
phalosporins and chloramphenicol cross the blood- brain-bar-
rier in adequate concentrations, many failures were reported
due to rapid emergence of resistance to the former and to only
bacteriostatic activity of the latter; among fluoroquinolones,
the advantage of pefloxacin is that it penetrates in high con-
centrations into CSF; high dosages up to 1600 mg daily dose
did not result in clinical or laboratory significant side effects in
these patients. Thus pefloxacin seems to be a potentially effi-
cacious treatment for neurosurgical associated bacterial men-
ingitis.
Miscellaneous The efficacy of pefloxacin in the treatment
of soft tissue injuries was evaluated in 28 patients including
renal transplant patients receiving azathioprine, patients with
mediastinitis or serious post-operative wound infections. With
pefloxacin used at doses of 400 mg three times daily for 4 days
followed by 400 mg twice daily, the clinical results were excel-
lent: 82% of patients were cured and 90% of bacterial isolates
(Enterobacteriaceae, P. aeruginosa, S. aureus) were eradi-
cated; two patients failed to respond to treatment due to Strep-
tococcus viridans as the infecting organism (data-on-file,
Rh6ne-Poulenc Sant6). The efficacy of pefloxacin was asses-
sed as well in exacerbations of chronic otitis media, tonsillitis,
acute or severe otitis media: oral pefloxacin 400 mg for 7 to 18
days resulted in a cure in 68% of patients and improvement in
26%; bacteriological eradication was obtained in over 90% of
cases (staphylococci, P. aeruginosa, and Enterobacteriaceae)
(data-on-file, Rh6ne-Poulenc Sant6, unpublished).
Approved therapeutic indications Based on clinical tri-
als and on therapeutic use as described above, the approved
therapeutic indications have taken also into account the anti-
bacterial activity and pharmacokinetic characteristics of peflo-
xacin. The indications are limited to the adult patients and to
severe infections due to staphylococci and Gram-negative ba-
cilli, involved especially in septicaemia and endocarditis; me-
ningitis; lower respiratory tract infections; upper respiratory
40
tract infections; renal and urinary tract infections; gynaecolo-
gical infections; abdominal and hepato-biliary infections;
bone and joint infections; skin and soft tissue infections [92].
Pefioxacin is indicated in a limited range of mild infections
(see the following section Pharmacy).
Contraindications Pefloxacin should not be used in
patients known as having a history of allergy to quinolones and
azaquinolones. Since studies in beagle pups have shown 4-
quinolones to be deposited in immature cartilage with evi-
dence of degeneration, the use of pefloxacin in children is
contraindicated (in patients of less than 15 years of age). Peflo-
xacin is contraindicated in patients with deficit in dehydroge-
nase-glucose-6-phosphate; in pregnant women or nursing
women. In common with other quinolones, pefloxacin may
induce photosensitisation: it is therefore necessary that pa-
tients avoid exposure to UV light or to sun during therapy and
5 days after pefloxacin treatment is discontinued [92]. Peflox-
acin should not be used as first line therapy in infections
suspected or bacteriologically documented as due to S.
pneumoniae, streptococci and enterococci, especially in non-
nosocomial respiratory tract infections.
Clinical pharmacology: pharmacy
Recommended range of doses
Pefloxacin has been administered orally and parenterally at
doses ranging from 800 mg up to 1200 mg daily for a variety
of mild to severe infections encountered in general practice as
well as in hospital situations.
The recommended oral dose is 400 mg taken twice daily,
morning and evening together with a meal in order to avoid
gastrointestinal disturbances (see Side Effects section).
Parenteralpefloxacin should be administered as a slow 1 h
intravenous infusion twice daily. The drug which is in the form
of a 400 mg dose (ampule) should be mixed with 250 mg of a
5% glucose solution; a saline solution should be avoided due
to a possible precipitation of pefloxacin. On starting the treat-
ment, by using a loading dose of 800 mg (oral or i.v.), the drug
achieves immediate high blood concentrations.
Available dosage forms
Two presentations of the drug are available.
Tablets. White tablets in 50 or 100 tablet boxes, each tablet
containing 400 mg of pefloxacin mesylate dihydrate plus
starch, gelatine, talc, magnesium stearate, sodium carboxy-
methyl starch (excipient); the tablet is coated with hydroxy-
propylmethylcellulose, ethylcellulose, dibutyl sebacate, titane
oxide, talc, polyoxyethylene glycol 6000. Each tablet is 18
mm long, 9 mm wide, 4.7 mm thick and has an oblong shape
of 11 mm curve radius; its weight is 780 rag.
Parenteralfi~rm. Pefloxacin mesylate dihydrate, 400 mg is
in suspension with: sodium ascorbate, methanesulfonic acid,
for parenteral preparation, final volume: 5 ml per ampule, l0
ampules per box. According to French Ministry of Health reg-
ulations, both formulations are registered in Table A (requires
a prescription by a physician). Pefloxacin in both formulations
has been marketed in France in 1985 for hospital use only (see
approved therapeutic indications in Therapeutic use section);
it has been marketed in general practice in 1988 for single dose
prescription only for acute uncomplicated cystitis in women
and for gonococcal urethritis in man; in 1990, the indications
of pefloxacin in general practice have been extended to acute
and chronic prostatitis and to bone and joint infections to be
treated with the oral form (following initial i.v. treatment in
hospital) (28 tablets per box) [92].
Other countries where pefloxacin is available: in several
European countries, pefloxacin is available in both formula-
tions for oral and parenteral use: Belgium, The Netherlands,
Italy, Greece, Bulgaria, Hungary, Turkey; in several other
countries namely Indonesia, Thailand, South-Korea, Singa-
pore, The Philippines, Israel, Argentina, Mexico, Uruguay,
Colombia, both formulations are available as well. In Egypt
and Madagascar the oral formulation only has been marketed.
In all the countries mentioned above, pefloxacin is used in
grossly the same indications as those in France. In Russia and
in Poland pefloxacin is not available yet but registration is in
process. Pefloxacin is not available in the U.S.A.
Toxicology
Preclinical toxicology of pefloxacin has been examined in
the Swiss mouse, Wistar rat, New Zealand rabbit and beagle
dog (data-on-file, Rh6ne-Poulenc Sant6).
Acute toxicity studies in mice, rats and rabbits after i.v.,
intraperitoneal, oral and subcutaneous administration have
shown that pefloxacin has minimal acute toxicity. The LDs0
values for pefloxacin were: mice, oral 1000 mg/kg, i.v. 255
mg/kg; rats, oral 2400 mg/kg, i.v. 300 mg/kg. In other studies,
the minimum lethal oral dose in rabbits was approximately
1750 mg/kg. Studies in the dog could not be completed, as the
emetic effects of pefloxacin at doses in excess of 500 mg/kg
appeared before any toxic effect.
Short and medium term toxicity: in a 4-week study, in rats,
a 100 mg/kg dose was well tolerated, and at 300 mg/kg there
were reductions in bodyweight gain, sedation, anaemia, gast-
rointestinal inflammation, slight increases in liver, spleen and

adrenal weight, a small rise in ALT, a fall in alkaline phospha-
tase and hyperleucocytosis; at 3000 mg/kg, animals died wit-
hin 3 to 9 days after starting pefloxacin administration. The
maximum tolerated dose lay between 100 and 300 mg/kg,
some 7 to 20 times greater than the recommended therapeutic
dosage in humans. In the rabbit, oral pefloxacin 400 mg/kg for
14 days was found to be toxic, but not at 100 mg/kg. In young
dogs, pefloxacin 25 to 100 mg/kg was administered daily for 6
weeks: tolerance to 25 and 50 mg/kg doses was good; after
administration of 100 mg/kg, vomiting was observed, with
mild and transient changes in alkaline phosphatase and ALT;
there was also moderate to severe joint disturbances, mild in-
terstitial nephritis and fundal mucosa fibrosis in some animals.
In a 3-month study in young dogs doses of 50 and 100 mg/kg
produced transient falls in alkaline phosphatase, vomiting and
joint disturbances resulting in hind limb stiffness; a 200 mg/kg
dose produced vomiting, anorexia, weight loss, listlessness
and azoospermia; there were joint cartilage lesions, patches of
erosion and superficial detachment on limb joint cartilage sur-
face; no ophthalmological aberrations occurred in any animal
studied; ophthalmological examinations revealed no treat-
ment-related effects on the conjunctiva, cornea, iris, lens or
retina, and no changes in optic nerve histopathology. There
was some evidence of poor local tolerance (haemorrhage and
oedema) at the site of injection and hence caution should be
exerted when injecting concentrated solutions of pefloxacin in
humans.
Long-term toxicity studies of up to 12 months' duration
were performed in rats and dogs. In a 6-month study in rats,
there was excellent tolerance to the dose of 50 mg/kg; at 150
mg/kg only reduced weight gain and mild anaemia were ob-
served; there was also a small reduction in the weight of the
prostate gland; after 6 weeks' treatment with 500 mg/kg there
was increased salivation, diuresis, reduced weight gain and
25% mortality. Autopsy revealed a yellow coloration of mus-
cle, caecal dilatation, testicular atrophy and changes in seminal
vesicle, prostate and ovarian weight; in a 12-month study in
rats there was no significant clinical, ophthalmological or bio-
chemical abnormalities following daily administration of oral
pefloxacin 12 to 96 mg/kg. In male and female beagle dogs 25
and 50 mg/kg were generally well tolerated in 12 months dura-
tion study; pefloxacin 100 mg/kg produced lens opacities in 5
of 14 dogs, detected at post-trial ophthalmoscopy; 2 of 14
control animals also showed lens opacities. There was also
testicular damage and joint cartilage erosion in young animals
treated with pefloxacin 100 mg/kg.
Reproduction studies: administration of oral pefloxacin 100
and 400 mg/kg from the 6th and 17th days of gestation in
Sprague-Dawley rats produced no teratogenic effects; doses
of 600 and 1000 mg/kg reduced maternal food intake and the
rate of bodyweight gain, with a reduction in the number of live
fetuses and mean litter weight. In the New Zealand white rab-
41
bit, administration of pefloxacin 25, 50 and 100 mg/kg from
the 7th to 19th days of gestation had no significant effects on
reproduction, except for a small slowing of maternal body
weight gain following treatment with 100 mg/kg. Pefloxacin
passes the placental barrier and diffuses into the fetus, but no
significant fetal malformations have been attributed to the ad-
ministration of pefloxacin in rabbits and rats.
Mutagenicity: in vitro and in vivo tests have shown that
pefloxacin has no mutagenic potential. In vitro, pefloxacin
was inactive in the Ames' test and in vivo in the CD1 mouse
chromosomal mutation test at doses up to 750 mg/kg. More-
over, in an in vitro DNA repair test on rat hepatocytes, peflo-
xacin was not genotoxic. At the end of a 2-year carcinogenicity
study there was an increase in the number of benign tumours
and hyperplasia in the kidney but no increase in the number of
malignant tumours: this was observed at the highest dose level
(96 and 384 mg/kg) and mostly found when the animals were
killed at the end of experiment. Pefloxacin has no mutagenic
and genotoxic properties: the tumorigenic potential of peflo-
xacin in man can be regarded as negligible.
Effect on spermatogenesis: in the rat, pefloxacin at doses of
150 mg/kg produced testicular lesions of comparable severity
to other antibiotics. However, when compared with the thera-
peutic dosage in humans, the doses required to induce such
lesions were much higher for pefloxacin than those used in
man: this suggests a safety margin for pefloxacin. In addition,
dosages of pefloxacin 25 to 100 mg/kg did not modify fertility
in male rats.
Pefloxacin concentrations in human, dog and rat eyes: ste-
ady-state pefloxacin concentrations in human, beagle dog and
rat lens, plasma and humor were measured after repeated daily
administration of pefloxacin. Pefloxacin lens concentrations
in humans [74] were more than 7 times lower than those obser-
ved in the lenses of beagle dogs receiving the minimal daily
cataractogenic dose (100 rag/kg). The human lens concentra-
tions of pefloxacin were close to those observed in rats, in
which no cataractogenic potential has been reported for this
drug. These data suggest that the potential for cataract induc-
tion by pefloxacin in man is extremely low.
Human toxicity
Since the launch of pefloxacin in 1985 in France, hundreds
of thousands of patients have been treated with this drug: the
French clinical experience and the results of international trials
have shown that pefloxacin is generally well tolerated, with
adverse effects in the known range of side effects of the fluoro-
quinolones, usually transient and mild to moderate in severity
[3,9,24,42,78].
Gastrointestinal disorders, such as nausea, epigastric pain
42
and vomiting were the most frequent adverse events observed
during clinical trials and were reported in 7% of the patients;
they represented -50% of all reported effects. The relatively
high number in outpatients with these side effects is explained
by the less severe diseases treated and the relative importance
given to such a minor adverse event. Cases of pseudomembra-
nous colitis have been reported occasionally in patients who
were simultaneously receiving another antibiotic [78].
Skin disorders: as with every fluoroquinolone in use, photo-
sensitivity has been observed with pefloxacin. The frequency
of this event during clinical trials was 0.6%; this effect is re-
lated to the dose and duration of treatment, but depends mainly
on the amount of sun exposure. Cases of pruriginous and ery-
thematous eruptions predominant on the face and forearms
after exposure to sunlight have been cited in 11 subjects and
pefloxacin was discontinued in 7 patients [51 ]; these adverse
effects appeared on average after 39 days of pefloxacin ther-
apy. In outpatients other skin disorders have been cited such as
cases of angio-oedema sometimes associated with other symp-
toms of anaphylactoid reaction such as dyspnoea [78]. In fact
these are rare events due to the fact that patients receiving i.v.
treatment are not exposed to the sun and that most outpatients
receive only a single dose of pefloxacin; it is likely to recom-
mend to outpatients expected to receive more than a single
dose to avoid sun exposure.
Central nervous system (CNS) and psychiatric reactions:
CNS and psychiatric reactions have been observed in 1-2% of
the patients during clinical trials. Such CNS and psychiatric
reactions with pefloxacin are of great concern as is the case
with all fluoroquinolones. Convulsions, confusion, disorienta-
tion and abnormal movements have been reported in 11 inpa-
tients, receiving pefloxacin either orally or i.v. An epileptic
history or other pre-existing brain lesions were noted in several
of these patients. Neurological toxicity has been reported in 2
elderly women who received pefloxacin 400 mg twice daily:
CNS symptoms were cleared 3 to 5 days following withdrawal
of pefloxacin. This confirms that adjustment of the doses
should be made in the elderly. In outpatients pefloxacin ap-
pears to be very well tolerated with regard to CNS and psy-
chiatric reactions. There were few reports of CNS effects, all of
them benign; vertigo, insomnia, headaches, dizziness, were
the main side effects noted. No cases of convulsions were
reported in outpatients receiving pefloxacin [52 ].
Musculoskeletal lesions." the most frequently reported mus-
culoskeletal side effect was arthralgia which occurred in 0.9%
of patients during clinical trials. Of 25 cases of arthralgia re-
ported in an inpatient population receiving oral pefloxacin, 4
occurred in children under 16 years of age [78]; the possibility
of human arthritis following 4-quinolone-induced damage to
articular cartilage appears only a remote possibility [3] and
reported cases of arthralgia were transient. No description of
blistering or erosion of cartilage is found in the medical litera-
ture as occurring in man (adults or children) as was described
in juvenile animals (beagle pups) after administration of peflo-
xacin.
Biological abnormalities: biological tolerance of pefloxa-
cin has been evaluated [78]. Laboratory abnormalities repor-
ted with pefloxacin concern mainly thrombocytopenia and
neutropenia, reported in 37 inpatients. The thrombocytopenia
was usually mild, rarely below 20,000 ml, and returned to
normal when the drug was discontinued. In 9 patients, heparin
had been co-administered. Neutropenia was exceptionally
below 1000/ml, and associated in most of the cases with differ-
ent concurrent treatments. In several patients (4.8% of 1,437
patients) biological findings were probably related to peflo-
xacin administration, including eosinophilia (3 cases), eleva-
ted AST, ALT and/or alkaline phosphatase, moderately in-
creased serum creatinine, elevated transaminase levels: 5
patients discontinued therapy (unpublished data-on-file,
Rh6ne-Poulenc Sant6). Pefloxacin, as other fluoroquinolones,
did not cause clinically significant changes in laboratory in-
dices. Kidney and liver function tests did not generally dem-
onstrate any changes. When such changes did occur, they
could usually be explained by other causes.
Long-term use ofpefloxacin: pefloxacin is effective in long-
term therapy of many severe chronic infections: its indications
in treating osteomyelitis, prostatitis, respiratory superinfec-
tions in cystic fibrosis and Gram-negative meningitis impose
prolonged administration of pefloxacin. Published data indi-
cate a relative lack of acquisition of resistance, and not more
adverse reactions after prolonged courses of pefloxacin than
after short course treatment [3,99].
High risk patients groups
The indications of pefloxacin in children, pregnant women.
and nursing women, have been discussed above (Therapeutic
Use and Pharmacy sections). However in children with cystic
fibrosis, due to the high risk respiratory infections in these
patients, fluoroquinolones have been used successfully [24];
other rare indications of pefloxacin in children were: menin-
gitis with resistant bacteria (Gram-negative bacilli): methi-
cillin-resistant S. aureus infections; osteomyelitis with P. ae-
ru,~inosa and chronic suppurative otitis media with P. aeru-
,~inosa and other Gram-negatives. In these particular situa-
tions, the recommended dose was up to 15 mg/kg in the most
severe infections [3,24].
In elderly patients, single and multiple dose pharmacoki-
netic studies of pefloxacin [27,47] have shown differences in
kinetics of the drug and in pharmacokinetic parameters, espe-
cially a lower volume of distribution, a lower plasma clearance
in relation to a lower metabolic clearance and prolonged elimi-

nation half-life in relation to physiologically reduced kidney
function; however, by the third day of treatment Cmax values
were superimposable on those obtained in young adults given
400 mg twice daily. It has been concluded that although a
dosage of 400 mg of pefloxacin twice daily is well tolerated in
elderly subjects, it is recommended to decrease the doses after
the third day of treatment [92].
The pharmacokinetics of pefloxacin have been extensively
studied in patients with various degrees of chronic renal insuf-
ficiency [34,36,62]: the absence of effect of renal failure on
pefloxacin kinetics is explained by the high degree of its meta-
bolism (see Pharmacokinetics section); no modification in the
distribution and elimination parameters was found in mild and
in severe renal impairment as compared to the normal subjects
[62]; there was no accumulation of the active N-desmethyl me-
tabolite in severe renal failure; its apparent elimination half-life
was about twice that of the parent compound (23-31 h) [62]:
total and renal clearances and urinary recovery of pefloxacin
decreased in relation to the degree of renal impairment. From
these data it was concluded that modification of the dosage
regimen of pefloxacin unlike other new quinolones is not re-
quired in patients with renal insufficiency. Pefloxacin has been
found to be poorly removed by haemodialysis: thus supple-
mentary doses at the end of dialysis are not required [34].
The pharmacokinetics of pefloxacin in patients with liver
cirrhosis were shown significantly altered as compared to that
in healthy volunteers [18]: the elimination half-life was much
longer: 35.1 + 19 h ( 11 +2.6 h in normal subjects); the volume of
distribution was decreased by 18%; the total plasma clearance
was substantially decreased: 2.66 l/h/1.73 m 2 vs 8.19 l/h/1.73
m 2 in normal subjects. Otherwise a significant accumulation of
pefloxacin in ascites was observed after repeated administra-
tion as well as a notable increase of urinary excretion of uncha-
nged pefloxacin (3 or 4 times increase). It was concluded that
reduced plasma clearance of pefloxacin in patients with cirrho-
sis was related to decreased hepatic metabolism of the drug.
Consequently dosage adjustments are necessary in treating
liver failure patients with pefloxacin; recommended adjust-
ments include the following scheme: pefloxacin i.v. should be
administered at 8 mg/kg dose (1 h infusion) twice daily if there
is neither ascites nor jaundice; once daily in the presence of
jaundice; every 36 h in the presence of ascites; once every 2
days in the presence of both symptoms [92].
Drug interactions
Coadministration of pefloxacin and other drugs may have a
significant effect in patients and in metabolism and pharmaco-
kinetics of either drug.
43
Interactions with theophylline
Studies on the effects of fluoroquinolones on the clearance
of theophylline [94] showed a significant increase of plasma
concentrations of theophylline, up to 19.6% and total body
clearance of theophylline decreased by 29.4% with pefloxacin
coadministration. It has been suggested that the interaction
was not produced by the parent compound but by its oxo-
metabolites; the interaction was interpreted as an effect on
cytochrome P450-related isoenzymes with reduction of the
N-demethylation of theophylline [19,94]. Thus it is recom-
mended to measure plasma theophylline concentrations in pa-
tients receiving pefloxacin and theophylline therapy for proper
dosage adjustments. Similar interactions may occur with caf-
feine which is structurally related [19]: caffeine metabolism
may be delayed resulting in CNS effects in coffee consumers
receiving pefloxacin.
Interactions with antacids
Concomitant administration of pefloxacin with cimetidine
has been shown to produce an increase in the pefloxacin half-
life, a reduction in total clearance but no change in volume of
distribution and renal clearance [81 ]; coadministration of pe-
floxacin with antacids containing hydroxides of aluminium
and magnesium may delay or reduce the absorption of peflo-
xacin [ 19]. It is therefore recommended to make proper dosage
adjustments according to the kind of antacid used.
Other drug interactions
Pefloxacin may significantly prolong the prothrombin time
following administration of coumarin and it is recommended
to closely monitor both drugs in patients receiving coadmini-
stration of both treatments (unpublished data-on-file, Rh6ne
Poulenc Sant6). Recent studies suggest that CNS effects may
occur with concomitant administration of quinolones and non
steroidal antiinflammatory drugs (NSAIDS) via interactions
with y-aminobutyric acid (GABA) receptors: in vitro studies
have shown that quinolones inhibit binding of radio-labelled
GABA to mouse synaptic cell membranes; in the presence of
various NSAIDS, the dose of quinolones required to reduce
GABA binding by 50% was reduced by up to 10,000 fold,
suggesting that GABA inhibition may occur at clinically
achievable quinolone concentrations when coadministered
with NSAIDS [19]; whether this experimental observation is
clinically relevant is not confirmed yet. No evidence of a phar-
macokinetic interaction was found between cyclosporin and
pefloxacin in renal transplant patients [ 19].
In conclusion, most drug interactions involving coadmini-
stration of pefloxacin and other drugs are suspected but are
44
poorly documented. Further investigations are required. How-
ever the available information suggests that in the elderly and
in patients with liver disease, particularly vulnerable to kinetic
interactions with pefloxacin, a careful surveillance and proper
dosage adjustments should be made.
Acknowledgements
We are very grateful to Doctor Yvan Brumpt (Roger- Bellon
Laboratories) for his help in providing all necessary docu-
ments and available information on pefloxacin, and to Marie-
Jeanne Julliard for her careful and efficient secretarial assis-
tance.
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