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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
O
II

/ NF ~ . COOH
CH3-- N
\ / ~ ~N / CH3SO3H,2H20
C17H20N303F I
C2H5 M.M.=465,5

Fig. 1. Mesylatedihydratepefloxacin.

water, the pKa is 6.3, corresponding to carboxylic function; when ranging from 1 to 4 mg/1 are somewhat compatible with
the pKb is 7.6, corresponding to the nitrogen atom of the 4- its in vivo achievable concentrations. Among Pseudomonas
methyl-I- piperazinyl function of the molecule. The above and Acinetobacter, many strains have become resistant to pe-
mentioned physicochemical characteristics indicate that pe- floxacin and other fluoroquinolones [5]. Among other Gram-
floxacin is poorly liposoluble and predominantly hydrosol- negative aerobic bacteria, some gastrointestinal pathogens
uble (all data on physicochemical properties went from Roger- such as Aeromonas sp., Campylobacter spp. [87] and genital
Bellon and Rh6ne-Poulenc data- on-file, and investigator's pathogens such as N. gonorrhoeae or H. ducreyi [93] are very
brochure; unpublished data). 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-
Microbiology raxella) catarrhalis are very susceptible to pefloxacin.

Gram-positive cocci Staphylococci including S. aureus


Spectrum of antibacterial activity and coagulase-negative staphylococci even resistant to other
antibiotics are susceptible or moderately susceptible to peflo-
In terms of structure-activity relationship, the marked xacin, with MICs in the range 0.125-0.5 rag/1. Initially methi-
enhancement of antibacterial activity of pefloxacin as com- cillin-resistant strains (MRSA) were as susceptible to peflo-
pared to the parent compound, nalidixic acid, is to be related to xacin as methicillin-sensitive (MET-S) staphylococci [15];
the presence of the fluorine at position 6 and of the piperazine changes as a function of time have occurred and an overall
moiety at position 7 of the molecule of pefloxacin. The resistance of 41.2% of S. aureus to pefloxacin was evaluated
spectrum of antibacterial activity of pefloxacin is shown in recently (96.8% among MRSA and 10.1% among MET-S
Table 2. strains) (personal communication, 1990). The streptococci of
groups A, B, C and G, enterococci, Streptococcus pneumo-
Enterobacteriaceae Pefloxacin, as other fluoroquinolo- niae, and non haemolytic streptococci (not shown in Table 2)
nes, is highly active against the Enterobacteriaceae (Citro- [45,73] are resistant to pefloxacin with MICs in the range 4 to
bacter, Enterobacter, Klebsiella, Morganella, Proteus); the 16 mg/1.
minimal inhibitory concentrations (MICs) ofpefloxacin for all
genus and species of this family of bacteria ranges usually Miscellaneous The MICs of pefloxacin for Legionella
between 0.03 and 4 or 8 mg/l (15, 45, 49, 99); against Salmo- pneumophilaweremoderatelylow(MIC50/MIC90:1.0/1.0mg/
nella, Shigella and Yersinia (data not shown in Table 2) the 1) [98]; for Eikenella corrodens, Vibrio cholerae, the MICs
MIC50/MIC90 were lower: 0.12/1.0, 0.06/0.06, 0.12/0.25 mg/1, were very low whereas Helicobacter pylori, Listeria monocy-
respectively [56]. As shown in Table 2, for most species of togenes and Nocardia astero'ides were resistant to pefloxacin,
Enterobacteriaceae, pefloxacin was significantly more active with MIC50 of 8 mg/1 or more [56]. Mycobacteria (Table 2)
than nalidixic acid. [33, 48] are moderately or not susceptible to pefloxacin and
most anaerobes including Bacteroi'des, Clostridium and Fuso-
Gram-negative aerobic bacteria Although moderate sus- bacterium spp are resistant to pefloxacin [31]. Mycoplasma
ceptibility to pefloxacin is noted for some Gram- negative aer- spp and Chlamydiae are poorly susceptible to pefloxacin
obic bacilli such as Pseudomonas aeruginosa, Acinetobacter (MIC50/MIC90: 2/8 mg/l) whereas Rickettsia conori and Cox-
spp., Alcaligenes, Pseudomonas spp. including Xanthomonas iella burneti are susceptible at therapeutically achievable con-
maltophilia [89], the MICs of pefloxacin for these bacteria 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


in E. coli [ 17] has been completely identified and DNA gyrases
The primary target of pefloxacin like that of other quino- have been purified from Pseudomonas aeruginosa, Citrobac-
lones is bacterial D N A gyrase (topoisomerase II) which is an terfreundii, Staphylococcus aureus and many other organisms
essential bacterial enzyme with a variety of activities 100. Whether pefloxacin binds directly to DNA gyrase or to
[76,79,98,101] : the DNA gyrase is responsible for the intro- DNA, or to the DNA gyrase-DNA complex is still a matter of
duction of negative superhelical twists into double-stranded debate [76]. Whatever the mechanism, the inhibition of DNA
D N A and for catenation and decatenation of two duplex DNA gyrase by quinolones results in inhibition of bacterial multipli-
circles interlocked like links in a chain; as a result of the quino- cation and the expected effect should be bacteriostatic: in fact
lone activity, most biochemical functions of D N A gyrase on new 4-quinolones and pefloxacin as well are strongly bacteri-
cell physiology are affected as well as DNA replication and cidal but in a complex manner; the bactericidal effect has been
33

described as 'biphasic' [100] with a single rapidly killing ef- penetration of other antimicrobial agents besides the quino-
fect followed by a paradoxical reduced killing phase in the lones and some strains of K. pneumoniae, P. aeruginosa, S.
presence of increased quinolone concentration; in bacterial marcescens which resist quinolones exhibit increased resis-
cells incubated with pefloxacin, non-replicative DNA synthe- tance to non quinolone classes of drugs indicating decreased
sis (DNA repair), termed SOS response, is induced and SOS drug penetration [16,98,99]. Gram-positive bacteria which
response which is thought to protect bacteria from further da- lack an outer membrane with its associated porins are able to
mage to DNA, prevents replication, blocking cell division and mutate to 4-quinolone resistance at higher frequencies than
producing filarnentation [50,100]. Thus the end result of the Gram-negative bacteria in vitro and in vivo [79]. The emer-
SOS response is harmful for the bacteria with morphological gence of resistance following treatment with pefloxacin has
and biochemical disturbances. The expression of such a bacte- been observed in experimental conditions in treating P. aeru-
ricidal effect of pefloxacin has been evaluated on the basis of ginosa peritonitis in an animal model [59] as well as in clinical
minimum bactericidal concentration (MBC): the MBC values settings: resistance development was reported in P. aerugi-
have been generally reported as the same as, or within 2 dilu- nosa, S. aureus, S. epidermidis and Enterobacter spp. [1]; in
tions of the MIC values [2,84,90]; the killing rate of pefloxacin most cases, resistant P. aeruginosa developed late in the
as measured by time-kill curves was rapid at concentrations course of a prolonged treatment, especially in treating skeletal
attainable at therapeutic doses and was reported as more rapid infections or respiratory superinfections in cystic fibrosis pa-
than that of cephalosporins of third generation against Entero- tients; in urinary tract infections (UTI), short course therapy
bacteriaceae and P. aeruginosa; against S. aureus including does not seem to result in emergence of resistance whereas in
methicillin-resistant strains the killing rate of pefloxacin was complicated UTI with anatomical abnormalities of the urinary
at least equivalent to that of pristinamycin ] 11 ]. tract the frequency of development of resistance can be high
[9].
Resistance mechanisms
Inoculum effect and other factors influencing the antibac-
Very unusually among antibacterial agents, plasmid-medi- terial activities of pefloxacin
ated resistance to the 4-quinolones does not occur and enzy-
matic inactivation of pefloxacin by bacteria has not been de- Generally no significant differences in MIC of pefloxacin
scribed: resistance to pefloxacin and other quinolones has were found when inocula of 103 or 106 cfu were used; but the
been described as developing by bacterial chromosomal mu- use of inocula higher than 106 cfu has been reported to increase
tation [79,98,100]: spontaneous mutations to high-level resis- significantly the MICs for Enterobacteriaceae and P. aerugi-
tance to nalidixic acid map in the gyr-A locus (which codes for nosa [2,99]; overall effects of inoculum size on MICs of qui-
the two subunits A of the DNA gyrase) in E. coli chromosome; nolones tended to be small; variation among strains and spe-
these mutations can produce cross-resistance but to a lesser cies occurred and the inoculum effect was most marked (up to
degree to the new fluoroquinolones [17,64,98]; the B subunit 32 times the MIC) with Enterobacter cloacae and Serratia
ofDNA gyrase may also interact with the fluoroquinolones but marcescens [2] which had otherwise the highest frequency of
mutation confers hyper susceptibility to 4-quinolones which mutants. The influence of pH, cations and various media has
possess a 7-piperazine ring like pefloxacin [79]. The mutations been mentioned in various studies: the pH of the growth me-
which affect DNA gyrase, subunit A, occur at a frequency of dium was found to influence dramatically pefloxacin MIC val-
10-6 to 10-8; spontaneous single-step mutations conferring re- ues; at pH 5.5 an 8-fold increase in MIC values for 67% of
sistance to high concentrations of ofloxacin, ciprofloxacin or Gram-negative isolates was obtained compared with pH 7.4
pefloxacin have been occasionally reported at a frequency of [65]; similarly the effect of pH was demonstrated when sterile
about 10-7 [98]. Mutations which may occur in a variety of loci urine at pH 5.5 was added in the medium and MIC values rose
(nal B, gyr B, pur B, etc...) of the chromosome in E. coli have from < 0.1 to 25 mg/1 for the bacteria tested. It has been sug-
been recognized as conferring low levels of resistance to nali- gested that acidic pH may reduce quinolone antibacterial ac-
dixic acid but the effects of these mutations on susceptibility to tivity because the 7-piperazine moiety becomes positively
fluoroquinolones are unknown. The biochemical mechanism charged and may interfere with cell penetration [80]. This may
of resistance in mutants is categorized by reduced permeability result in a decreased pefloxacin activity in urine but high con-
of the porins of Gram-negative bacilli associated with dimin- centrations achieved in urine (see Pharmacokinetics section)
ished expression of ompF protein which inhibits antimicro- exceed by far the MICs for virtually all bacterial urinary patho-
bial drug penetration into the bacterial cell; or the decreased gens [99]. Supplementation of the medium with zinc ions did
diffusion of quinolone may result from alterations of the struc- not alter the in vitro activity of pefloxacin whereas addition of
ture of phospholipid bi-layer of the outer membrane magnesium and calcium ions was associated with decreased
[16,79,98,100]. This latter mechanism may prevent cellular susceptibility to pefloxacin [2,99] as evaluated by reduced in-
34

hihition zone diameters: thus presence of magnesium ions at 8 Cardiovascular and peripheral nervous system effects
to 16 mM concentrations, similar to those in urine may inter-
fere with in vivo pefloxacin activity in UT1 as well as dimin- In anaesthetized dogs and cats pefloxacin administered i.v.
ished pH. at 10 and 20 mg/kg doses and intraduodenally at 25, 50 and
100 mg/kg doses, produced a moderate decrease in the pressor
Drug interactions response to adrenaline, noradrenaline and carotid artery occlu-
sion, but not to isoprenaline, acetylcholine, histamine and
Numerous studies have evaluated the effects of combina- vagal stimulation. Pefloxacin did not prevent contractions of
tions of pefloxacin with other antibacterial agents: in most the cat nictitating membrane induced by adrenaline or electri-
studies the effects were quantitated by measurement of frac- cal stimulation indicating that pefloxacin has no ganglionic
tional inhibitory concentration values [4,55,88,99] or effects blocking properties. In other studies in anaesthetized dogs,
on killing in time-killing curve studies [28]. Overall against rapid i.v. injection of 4.6 and 9.2 mg/kg dose of pefloxacin
Gram-negative bacteria, pefloxacin combinations with most produced an immediate dose-related systolic and diastolic hy-
[3-1actams and aminoglycosides were indifferent or additive, potensive effect which was less marked when the drug infu-
or occasionally synergistic, sometimes up to 50% [88] espe- sion was slow; after intraduodenal administration of 50 mg/kg,
cially with P. aeruginosa; they were rarely antagonistic no changes in blood pressure were observed whereas at 100
[23,55,66,88]. Pefloxacin combined with aminoglycosides or and 200 mg/kg some dogs developed hypotension, hypo-
13-1actams showed indifference against 70% of Enterobacteri- ventilation and some electrocardiographic changes. These
aceae and P. aeruginosa [55]. Killing ofS. aureus with combi- effects are produced by high doses unrelated to therapeutic
nation of pefloxacin and rifampin was limited but pefloxacin doses of pefloxacin. Otherwise in animal gastrointestinal tract,
suppressed emergence of rifampin-resistant organisms pefloxacin produced a slight reduction in gastric secretion, in-
[29,99]. For pefloxacin in combination with amikacin, imi- creased bile secretion and a minimal increase in intestinal tran-
penem or trimethoprim-sulfamethoxazole against various my- sit time.
cobacterial species, indifferent or additive effects were ob-
served, rarely synergistic effect and never antagonism [99]. In Hormonal effects
animal models, combination therapy has resulted in enhanced
efficacy and diminution or suppression of emergence of resis- Standard tests for hormonal activity using mice, rats and
tance in some studies [68,86,99]. But the proper use of combi- rabbits and 125 to 500 mg/1 kg dose of pefloxacin did not show
nation therapy and its benefit to prevent resistance have still to any oestrogen, progesterone or antiandrogenqike effects.
be evaluated in controlled studies in man [1 ]. In sum, the potential for pefloxacin to produce adverse ef-
fects at normal therapeutic doses in patients appeared very
limited.
Pharmacology
Effects on the immune system

Effects on the immune system have been particularly ana-


The general pharmacological properties of pefloxacin have lyzed. It is established that antimicrobial agents can modify
been evaluated by using standard tests in several animal spe- some immunological processes, especially phagocytosis and
cies (data-on-file, Rh6ne-Poulenc Sant6, unpublished). killing by polymorphonuclear phagocytes (PMN); on gran-
ulocyte function, in vitro studies have shown that pefloxacin
Central nervous system (CNS) effects increases the phagocytic and microbicidal activity of PMN
against S. aureus [10]; in rodent PMN and alveolar macro-
Intravenous (i.v.) or oral administration of pefloxacin in phages, pefloxacin (1 to 100 rag/1) increased by 35 to 40%
doses up to 286 mg/kg was not associated with any excitatory, their phagocytic capacity which was not dose-dependent [21 ];
anticholinergic, analgesic or antidepressant effects in rodents. pefloxacin was also shown to increase the uptake of 3H- thy-
A moderate reduction in spontaneous locomotor activity was midine into DNA in phytohaemagglutinin-stimulated human
observed but this was not dose- related. Pefloxacin produced lymphocytes which was suggestive of a stimulation of DNA
some protection against strychnine-induced convulsions. synthesis [35]; pefloxacin accumulates in macrophages and
There were no effects on core temperature, muscle tone, sleep- several other types of nucleated cells, and a study of cellular
ing times and leptazol-induced seizures. It was concluded that pharmacokinetics and intracellular distribution of the drug has
pefloxacin does not exhibit any neuroleptic or sedative proper- shown that macrophages infected with Legionella pneumo-
ties. phila (in guinea pig model) retained approximately 20-30% of
35

the accumulated pefloxacin upon washout whereas from unin- per ml [61]. It expresses total antibacterial activity of the par-
fected cells pefloxacin was quickly released [ 13]. ent compound and of metabolites potentially present in sam-
pies.
Gastrointestinal and ecological impact of pefloxacin 2. Fluorometric assay. This assay was used for determina-
tion of drug tissue and plasma levels in rats and dogs and was
Another pharmacological effect of pefloxacin is its poten- compared to specific high-pressure liquid chromatography
tial impact on microbial ecology in humans: only minor altera- (HPLC) assay of pefloxacin; the agreement between both met-
tions in salivary and faecal microflora result from pefloxacin hods was good; the sensitivity was 0.1 Bg of pefloxacin per ml
therapy [71,91 ]; aerobic enteric bacteria are rapidly eliminated of plasma or bile and of 0.1 Bg per g of tissue [61].
from stool with a small or no reduction in most anaerobic 3. HPLC. Pefloxacin and metabolites were separated by
species; enterococci and yeasts are unaffected; the flora returns ion-pair chromatography as described in Montay et al. [60];
to normal within a few weeks. 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
Human pharmacokinetics and for metabolites. HPLC assay was the preferred method
mostly used in pharmacokinetic studies of pefloxacin
[36,37,39,61].
Pefloxacin is a fluoroquinolone which is mainly cleared by
the liver; hepatic extraction and biotransformation dominate Pharmacokinetic parameters of pefloxacin
the clearance process. The profile of major metabolites of pe-
floxacin has been examined in plasma, urine and bile after Pharmacokinetic parameters following oral and intrave-
administration to normal volunteers [36,37,60,61,95] (the nous administration of pefloxacin are summarized in Table 3.
main metabolites, their structure and their pharmacokinetics
are described in the section Metabolism). Absorption; plasma half-life After oral administration,
peak concentrations increased proportionally with the dose:
Analytical methods for pefloxacin 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
Pefloxacin assays were carried out by means of three main dose. Absorption was rapid at all doses with peak level reached
methods. at 1.2-1.5 h. The terminal elimination half-life ranged from
1. Microbiological assay. The agar plate diffusion method 6.7 h after a 200 mg dose, to 12.3 h after a 400 mg dose, and to
used Bacillus subtilis ATCC 6633, or E. coli Kp 1976-712 as 12.6 + 2.5 h after a 800 mg dose. In a study of multiple-dose
reference organisms, and Difco Antibiotic medium No. 5 ad- pharmacokinetics [37] of pefloxacin in healthy subjects, re-
justed at pH 8. The assay was sensitive to 0.06 Bg of pefloxacin 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- reached 2.4 to 9 mg/1 after a 7.5 mg/kg i.v. dose, and 6.5 to 13
tions, and half-lives were very similar (Table 3): multiple dose mg/l after a 15 mg/kg i.v. dose of pefloxacin in patients with
produced Cmax of 7.9 to 10 mgfl and 9.6 to 10.1 mg/1 respec- inflamed meninges; these values which were 58 and 52% of
tively after oral and i.v. administration of 400 mg for 10 days. the serum level were high enough to eradicate infecting or-
In these studies, steady-state concentrations were achieved ganisms [96]. The good tissue and fluid penetration is to be
within 48 h. The ranges of AUC values after oral dose of 400 related to the physicochemical characteristics of the drug as
mg were 46.5 to 68.1 and 182 to 230 mg/1.h for single and described above and in addition to its low serum protein bind-
repeated doses, respectively [61]. AUC values after i.v. ad- ing of 20 to 30% in man [61 ].
ministration were quite identical (Table 3). The bioavailability
of oral pefloxacin is considered as 100% indicating that peflo- Excretion Urinary recoveries ranged from 11.1 to 17% of
xacin absorption is complete and uninfluenced by the dose. In the administered oral dose; renal clearances ranged from 12.9
contrast to the results obtained with some other quinolones the to 21.9 ml/min and total clearances ranged from 111 to 135
bioavailability of orally administered pefloxacin does not ml/min [36,37,61]. Non-renal clearance accounted for the
seem to be affected by a fat-rich breakfast, no pharmacokinetic major part of total drug clearance. In the multiple dose phar-
parameters which did not differ from those determined in the macokinetic study the total serum clearance decreased signif-
same fasting volunteers [82]. 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-
Distribution The pharmacokinetics of pefloxacin have renal clearance pathway of pefloxacin [30,61 ]. The low contri-
been described using a 2-compartment open model [36]. After bution of renal clearance to the elimination of pefloxacin was
1 h i.v. infusion of pefloxacin (200 to 800 mg) the mean vol- confirmed by the fact that only ~ 10% of the dose administered
umes of distribution were 23.2 to 68.21 for the central compart- is excreted in the urine as unchanged pefloxacin [37,61 ]. Some
ment and 64.8 to 100.9 1 for the peripheral compartment. The biliary excretion of pefloxacin occurs, but this is not a major
apparent volumes of distribution from oral or i.v. administra- route of elimination (unpublished data on file Rh6ne-Poulenc
tion have been determined as 1.7 to 1.9 1/kg [37] which sug- Santr).
gests a good distribution in extravascular compartments, and
high tissue and body fluid concentrations of pefloxacin. In
comparison with plasma concentrations, peftoxacin achieved Metabolism
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 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
37
0
II

HSN / C--O--GLUC
petloxacin g l u c u r o n i d e

N--oxide

,3c- N\_.?\--,~.~.~ \

/
H3C - - N / ~ N - ~ H --N/--~N--H3C --N ~ N

N-demethyl Oxo- N-dernet hyl Oxo - pefloxocin


( norfloxocin ] (oxonor - f IoxQci n )

Fig. 2.

indicated extra-renal elimination routes, it was likely to as- urinary tract infections [42] and many therapeutic trials have
sume that the drug was partly metabolized. In fact, after admin- demonstrated the efficacy of pefloxacin in these indications
istration of a single oral dose of ~4C-pefloxacin, 70% and 25% [9]. Simultaneously pefloxacin had proved eventually active
of radioactivity were detected in urine and faeces, respecti- in a wide variety of infectious conditions due to its spectrum
vely, within 7 days and there was no hepatic first-pass metab- of antibacterial activity and its remarkable pharmacokinetics.
olism of pefloxacin (unpublished data on file, Rh6ne-Poulenc Thus many data are currently available on pefloxacin thera-
Sant6). It has been shown that an extensive metabolic bio- py with i.v. infusion or by oral therapy in various infections
transformation (85 to 90%) occurs to pefloxacin in the human ranging from mild to severe in immunocompromised pa-
body [37,61 ]. The main pharmacokinetic parameters of peflo- tients.
xacin and its metabolites derived from the data of the multiple
i.v. infusion are summarized in Table 4 [37]. Metabolism of Urogenital tract infections
pefloxacin has been shown to result in two main metabolites,
N-demethyl pefloxacin (norfloxacin), pefloxacin N-oxide, the Pefloxacin was administered at doses of 800 or 1200 mg
latter having little antibacterial activity [61]; the piperazine daily in patients with uncomplicated and complicated lower
ring is the main site of metabolism: the ring is hydroxylated, and upper urinary tract infections (UTI): the overall clinical
N-oxidised, demethylated, formylated and acetylated (Fig. 2); cure rate ranged from 72 to 94% of patients and bacteriological
the major metabolites are found in the serum; in the urine were eradication was obtained in 76 to 93% of the cases
recovered the parent compound pefloxacin, pefloxacin N- [9,12,42,99]. In a recent single dose trial of treatment of cysti-
oxide, norfloxacin, oxonorfloxacin, oxopefloxacin and traces tis the bacteriological cure rate was 95.2% at the first follow-
of pefloxacin glucuronide. Except for pefloxacin N-oxide and up with a single dose of 800 mg of pefloxacin administered
glucuronide analog, the other metabolites exhibit antibacterial orally; it was shown to be safe and at least as effective as a
activity equal to that of pefloxacin. The urinary excretion of five-day regimen of co-trimoxazole (960 mg) or a five-day
N-demethyl pefloxacin and pefloxacin N-oxide accounted for treatment with norfloxacin in uncomplicated cystitis in women
20-21% of the dose administered [61 ]. Total urinary recovery [70]. In a randomised study in patients with upper gynaecol-
of parent drug and metabolites was estimated at 59% of the ogical tract infections the efficacy of oral pefloxacin (400 mg
administered dose of pefloxacin. Pefloxacin concentrations in twice daily) following i.v. initial infusion for 3 days was com-
bile were 10-20 mg/1 2-12 h after administration of 800 mg pared to oral ampicillin (500 mg 4 times a day) combined with
of the drug. In sum, the predominant elimination of pefloxacin intramuscular (i.m.) gentamicin (60 or 80 mg 3 times daily):
occurs by extra-renal route, by means of metabolization into clinical cure rates were 93.3 and 94.4%, respectively with both
two main metabolites N-demethyl and N-oxide pefloxacin regimens; bacteriological eradication was obtained in 100% of
which are excreted together with the remaining parent com- cases with pefloxacin but only in 61% of cases with the combi-
pound by renal and biliary route [36,37,61]. 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
Therapeutic use 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
Similarly to nalidixic acid and due to its high concentrations Ureaplasma urealyticum were not eradicated [85]. Inprostati-
in human urine, pefloxacin was initially restricted to genito- 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) cin in these patients, and the official indications of pefloxacin
with an overall success rate of 74% (persistence or relapse in (as stated in High risk patients section).
26% of cases) [40]. Due to the high prostatic concentrations of
pefloxacin as measured in the order of 10 mg/kg, it should be Bone and joint infections
expected that most acute and chronic prostatitis due to Ente-
robacteriaceae should be eradicated, but not those in which Therapy of bone and joint infections require prolonged anti-
enterococci are involved. biotic therapy with a drug which achieves and maintains high
bone tissue and joint fluid concentrations: several studies have
Respiratory tract infections (RTIs) shown a good penetration of pefloxacin into bone tissue
[20,22], reaching concentrations of at least 1 mg/kg; in clinical
Since many respiratory pathogens such as H. influenzae, B. trials, prolonged treatment with oral pefloxacin administered
catarrhalis, K. pneumoniae, S. aureus, Legionella spp., M. at a 400 mg twice daily dose resulted in 86 to 100% of clinical
pneumoniae were susceptible to pefloxacin, experimental [38] cure [6,20,22,51] in chronic osteomyelitis, mostly due to S.
and clinical [57,63] evaluation of pefloxacin efficacy in the aureus or P. aeruginosa, as well as in superinfections of total
treatment of lower respiratory infections was carried out. joint arthroplasty or in septic arthritis. Combination therapy of
These studies included intensive-care patients with nosoco- pefloxacin with amoxycillin or with aminoglycosides was
mialpulmonary infections; the predominant pathogens were S. used in order to avoid the development of pefloxacin resist-
aureus, P. aeruginosa and Enterobacteriaceae; i.v. admin- ance and in some cases in which an enterococcal infection was
istration of 400 mg 2 or 3 times daily for 4 to 28 days produced observed [6]. The duration of treatment ranged from 1 to 16
67% cure, failure and relapse in 26 and 2% of patients respecti- months and the oral daily dose of pefloxacin was 800 mg or
vely, the latter often in relation to underlying pathology. Open 1200 rag; in these indications, it is recommended to initiate the
studies of acute exacerbations of chronic bronchitis have con- treatment with i.v. infusion, for a few days, followed by oral
firmed the effectiveness of pefloxacin in eradicating H. influ- route for a prolonged period of time. Pefloxacin has also been
enzae [54]; but since least susceptible of the common respira- recommended as a drug for peri-operative prophylaxis in pa-
tory pathogens is S. pneumoniae, most studies have noted tients undergoing prosthetic hip and knee surgery [53] in rela-
slower clinical responses or failure to eradicate this pathogen tion to its early and high rate of penetration into bone tissue.
from sputum in bronchitis. In 176 patients with community-
acquired RTI, bronchitis, pneumonia and bronchopneumonia, Gastrointestinal tract infections and intra-abdominal in-
pefloxacin 800 mg daily was administered for 9-10 days; 86% fections
of infecting pathogens were eradicated; in 15% of patients
failure was due to non susceptible species, S. pneumoniae and Pefloxacin achieves high concentrations in stools (as stated
]3-haemolytic streptococci (unpublished data-on-file, Rh6ne in the Pharmacokinetics section) and is active against all of the
Poulenc Sant6). In the experimental animal model of legionel- major bacterial pathogens of the gastro- intestinal tract such as
losis [25] and in patients with severe legionnaires' disease [26] Salmonella spp., Shigella spp., Campylobacter spp. and ente-
it has been shown that pefloxacin in combination therapy was rotoxigenic E. coil (see Microbiology section) [67,99]. Peflo-
superior to erythromycin used alone, and that pefloxacin alone xacin should be used in the treatment of acute bacterial gast-
may be as active as combination therapy (with erythromycin or roenteritis and traveller's diarrhea: there are several reports
rifampin) at 800 mg i.v. dose. A particularly important sub- with other fluoroquinolones (ciprofloxacin, norfloxacin)
group of patients with acute exacerbations and superinfections given for the control of infections due to Salmonella spp.,
of severe pulmonary pathology is that of cystic' fibrosis Shigella spp. or Campylobacterjejuni [99], with rapid eradi-
patients: pefloxacin [24] and other fluoroquinolones (cipro- cation of the pathogens by the quinolone relative to placebo;
floxacin, ofloxacin) have been used successfully in this parti- Salmonella typhi in the stools has been eradicated and the
cular situation; the clinical response as determined by para- symptoms of typhoid fever regressed within 10 days by using
meters such as fever, amount of sputum and pulmonary func- pefloxacin [41 ] given orally at 400 mg twice daily dose. These
tion tests, was similar or better than conventional regimen with data suggest that short periods of treatment with pefloxacin
antipseudomonal [3-1actam combined with an aminoglycoside may be effective in the management of typhoid fever and non-
[99]; P. aeruginosa developed resistance but it was noted that typhoid salmonellosis. The use of fluoroquinolones in the tre-
the apparent instability of fluoroquinolone resistance in P. ae- atment of biliary tract or intra-abdominal infections has been
ruginosa allows repeated use of this class of drugs. However, limited to date: however, high biliary concentrations of these
it should not be recommended to use extensively pefloxacin in agents would suggest their potential efficacy in the treatment
cystic fibrosis patients due to several limitations such as the of biliary tract infections: in patients with biliary infections,
age of patients, the lack of extensive experience with pefloxa- the efficacy and safety of 800 mg daily dose of pefloxacin was
39

compared to that of a combination of ampicillin with gentami- fore that pefloxacin should be used as 'first-line' empirical
cin [14]: the pathogens isolated in operated patients were pre- treatment for the neutropenic febrile patient.
dominantly E. coli and Klebsiella spp.; they were eradicated In Gram-negative bacillary meningitis associated with
and 100% of patients were cured in the pefloxacin group ver- neuro-surgical procedures, pefloxacin was used [75] on the
sus 94% in the ampicillin-gentamicin group. Since intra-abdo- basis of previous experimental evaluation in a rabbit model
minal abscesses include frequently anaerobes which are [77] and of good penetration of pefloxacin in human inflamed
poorly susceptible to fluoroquinolones, metronidazole (500 meninges as described above [96]; moreover, it has been
mg i.v.) has been combined with pefloxacin (400 mg i.v. twice shown that pefloxacin remained in therapeutic concentrations
daily) in the treatment of severe intra-abdominal infections; in the brain tissue even three days after discontinuation of the
the efficacy and safety of this combination was compared to drug [46]. The bacterial eradication of Gram-negative bacteria
that of gentamicin (1.5 mg/kg every 8 h) plus metronidazole in was obtained in 80% of patients with an i.v. dose of 800 mg
an open randomized comparative study [72]: 86.7% of patients twice daily; 87% of the bacteria (P. aeruginosa, A. calcoace-
in the pefloxacin group were cured or improved versus 84.5% ticus, K. pneumoniae, Enterobacter cloacae, Salmonella and
in the gentamicin group; bacterial eradication was obtained in C. diversus) were eradicated in this particular study [75]. Since
95.5% with pefloxacin+metronidazole versus 82.3% with of all previously available antibiotics, only 3d generation ce-
gentamicin+metronidazole. Pefloxacin has proved at least as phalosporins and chloramphenicol cross the blood- brain-bar-
efficient as gentamicin when combined with metronidazole in rier in adequate concentrations, many failures were reported
the treatment of severe post-operative abdominal infections. due to rapid emergence of resistance to the former and to only
bacteriostatic activity of the latter; among fluoroquinolones,
Severe infections: immunocompromised patients the advantage of pefloxacin is that it penetrates in high con-
centrations into CSF; high dosages up to 1600 mg daily dose
Pefloxacin has proved effective in the treatment of most did not result in clinical or laboratory significant side effects in
severe bacterial infections as was seen above in nosocomial these patients. Thus pefloxacin seems to be a potentially effi-
pneumonia. cacious treatment for neurosurgical associated bacterial men-
In the treatment of septicaemia due to Gram-negative bac- ingitis.
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 Miscellaneous The efficacy of pefloxacin in the treatment
after failure of the first treatment in 60 patients with various of soft tissue injuries was evaluated in 28 patients including
entry sites of Gram-negative septicaemia (cutaneous, diges- renal transplant patients receiving azathioprine, patients with
tive, i.v. catheter): a satisfactory outcome was achieved in 87% mediastinitis or serious post-operative wound infections. With
of cases; failures or relapses in this series were associated with pefloxacin used at doses of 400 mg three times daily for 4 days
local or systemic underlying conditions [7,58]. In experimen- followed by 400 mg twice daily, the clinical results were excel-
tal [83,86] and human endocarditis [97], especially when lent: 82% of patients were cured and 90% of bacterial isolates
methicillin-resistant staphylococci were involved, pefloxacin (Enterobacteriaceae, P. aeruginosa, S. aureus) were eradi-
was used as single agent and in combination therapy (with cated; two patients failed to respond to treatment due to Strep-
fosfomycin in the rat endocarditis model; with rifampin or an tococcus viridans as the infecting organism (data-on-file,
aminoglycoside in patients). In these studies it has been con- Rh6ne-Poulenc Sant6). The efficacy of pefloxacin was asses-
cluded that combination therapy has proved more effective sed as well in exacerbations of chronic otitis media, tonsillitis,
than pefloxacin alone, possible benefits of the combination acute or severe otitis media: oral pefloxacin 400 mg for 7 to 18
resulting from suppression of in vivo emergence of resistance days resulted in a cure in 68% of patients and improvement in
to pefloxacin even if in vitro data showed only indifferent or 26%; bacteriological eradication was obtained in over 90% of
additive action of combined agents. The indication of peflo- cases (staphylococci, P. aeruginosa, and Enterobacteriaceae)
xacin in difficult-to- treat endocarditis requires further investi- (data-on-file, Rh6ne-Poulenc Sant6, unpublished).
gation since published data are too sparse and inconclusive.
In febrile neutropenic patients, pefloxacin has been used as Approved therapeutic indications Based on clinical tri-
a single agent (in 400 mg 8-hourly i.v. dose) in the treatment of als and on therapeutic use as described above, the approved
32 various episodes of fever of which six were clinically and therapeutic indications have taken also into account the anti-
seven microbiologically documented; as expected on the basis bacterial activity and pharmacokinetic characteristics of peflo-
of previous experimental studies in a neutropenic animal xacin. The indications are limited to the adult patients and to
model [38], the clinical response was favorable in 23 patients severe infections due to staphylococci and Gram-negative ba-
(72%), with a sustained fall in temperature to less than 38C cilli, involved especially in septicaemia and endocarditis; me-
and decreasing signs of infection [8]. It was suggested there- ningitis; lower respiratory tract infections; upper respiratory
40

tract infections; renal and urinary tract infections; gynaecolo- propylmethylcellulose, ethylcellulose, dibutyl sebacate, titane
gical infections; abdominal and hepato-biliary infections; oxide, talc, polyoxyethylene glycol 6000. Each tablet is 18
bone and joint infections; skin and soft tissue infections [92]. mm long, 9 mm wide, 4.7 mm thick and has an oblong shape
Pefioxacin is indicated in a limited range of mild infections of 11 mm curve radius; its weight is 780 rag.
(see the following section Pharmacy). Parenteralfi~rm. Pefloxacin mesylate dihydrate, 400 mg is
in suspension with: sodium ascorbate, methanesulfonic acid,
Contraindications Pefloxacin should not be used in for parenteral preparation, final volume: 5 ml per ampule, l0
patients known as having a history of allergy to quinolones and ampules per box. According to French Ministry of Health reg-
azaquinolones. Since studies in beagle pups have shown 4- ulations, both formulations are registered in Table A (requires
quinolones to be deposited in immature cartilage with evi- a prescription by a physician). Pefloxacin in both formulations
dence of degeneration, the use of pefloxacin in children is has been marketed in France in 1985 for hospital use only (see
contraindicated (in patients of less than 15 years of age). Peflo- approved therapeutic indications in Therapeutic use section);
xacin is contraindicated in patients with deficit in dehydroge- it has been marketed in general practice in 1988 for single dose
nase-glucose-6-phosphate; in pregnant women or nursing prescription only for acute uncomplicated cystitis in women
women. In common with other quinolones, pefloxacin may and for gonococcal urethritis in man; in 1990, the indications
induce photosensitisation: it is therefore necessary that pa- of pefloxacin in general practice have been extended to acute
tients avoid exposure to UV light or to sun during therapy and and chronic prostatitis and to bone and joint infections to be
5 days after pefloxacin treatment is discontinued [92]. Peflox- treated with the oral form (following initial i.v. treatment in
acin should not be used as first line therapy in infections hospital) (28 tablets per box) [92].
suspected or bacteriologically documented as due to S. Other countries where pefloxacin is available: in several
pneumoniae, streptococci and enterococci, especially in non- European countries, pefloxacin is available in both formula-
nosocomial respiratory tract infections. tions for oral and parenteral use: Belgium, The Netherlands,
Italy, Greece, Bulgaria, Hungary, Turkey; in several other
countries namely Indonesia, Thailand, South-Korea, Singa-
Clinical pharmacology: pharmacy 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
Recommended range of doses
grossly the same indications as those in France. In Russia and
in Poland pefloxacin is not available yet but registration is in
Pefloxacin has been administered orally and parenterally at process. Pefloxacin is not available in the U.S.A.
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. Toxicology
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). Preclinical toxicology of pefloxacin has been examined in
Parenteralpefloxacin should be administered as a slow 1 h the Swiss mouse, Wistar rat, New Zealand rabbit and beagle
intravenous infusion twice daily. The drug which is in the form dog (data-on-file, Rh6ne-Poulenc Sant6).
of a 400 mg dose (ampule) should be mixed with 250 mg of a Acute toxicity studies in mice, rats and rabbits after i.v.,
5% glucose solution; a saline solution should be avoided due intraperitoneal, oral and subcutaneous administration have
to a possible precipitation of pefloxacin. On starting the treat- shown that pefloxacin has minimal acute toxicity. The LDs0
ment, by using a loading dose of 800 mg (oral or i.v.), the drug values for pefloxacin were: mice, oral 1000 mg/kg, i.v. 255
achieves immediate high blood concentrations. mg/kg; rats, oral 2400 mg/kg, i.v. 300 mg/kg. In other studies,
the minimum lethal oral dose in rabbits was approximately
Available dosage forms 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
Two presentations of the drug are available. appeared before any toxic effect.
Tablets. White tablets in 50 or 100 tablet boxes, each tablet Short and medium term toxicity: in a 4-week study, in rats,
containing 400 mg of pefloxacin mesylate dihydrate plus a 100 mg/kg dose was well tolerated, and at 300 mg/kg there
starch, gelatine, talc, magnesium stearate, sodium carboxy- were reductions in bodyweight gain, sedation, anaemia, gast-
methyl starch (excipient); the tablet is coated with hydroxy- rointestinal inflammation, slight increases in liver, spleen and
41

adrenal weight, a small rise in ALT, a fall in alkaline phospha- bit, administration of pefloxacin 25, 50 and 100 mg/kg from
tase and hyperleucocytosis; at 3000 mg/kg, animals died wit- the 7th to 19th days of gestation had no significant effects on
hin 3 to 9 days after starting pefloxacin administration. The reproduction, except for a small slowing of maternal body
maximum tolerated dose lay between 100 and 300 mg/kg, weight gain following treatment with 100 mg/kg. Pefloxacin
some 7 to 20 times greater than the recommended therapeutic passes the placental barrier and diffuses into the fetus, but no
dosage in humans. In the rabbit, oral pefloxacin 400 mg/kg for significant fetal malformations have been attributed to the ad-
14 days was found to be toxic, but not at 100 mg/kg. In young ministration of pefloxacin in rabbits and rats.
dogs, pefloxacin 25 to 100 mg/kg was administered daily for 6 Mutagenicity: in vitro and in vivo tests have shown that
weeks: tolerance to 25 and 50 mg/kg doses was good; after pefloxacin has no mutagenic potential. In vitro, pefloxacin
administration of 100 mg/kg, vomiting was observed, with was inactive in the Ames' test and in vivo in the CD1 mouse
mild and transient changes in alkaline phosphatase and ALT; chromosomal mutation test at doses up to 750 mg/kg. More-
there was also moderate to severe joint disturbances, mild in- over, in an in vitro DNA repair test on rat hepatocytes, peflo-
terstitial nephritis and fundal mucosa fibrosis in some animals. xacin was not genotoxic. At the end of a 2-year carcinogenicity
In a 3-month study in young dogs doses of 50 and 100 mg/kg study there was an increase in the number of benign tumours
produced transient falls in alkaline phosphatase, vomiting and and hyperplasia in the kidney but no increase in the number of
joint disturbances resulting in hind limb stiffness; a 200 mg/kg malignant tumours: this was observed at the highest dose level
dose produced vomiting, anorexia, weight loss, listlessness (96 and 384 mg/kg) and mostly found when the animals were
and azoospermia; there were joint cartilage lesions, patches of killed at the end of experiment. Pefloxacin has no mutagenic
erosion and superficial detachment on limb joint cartilage sur- and genotoxic properties: the tumorigenic potential of peflo-
face; no ophthalmological aberrations occurred in any animal xacin in man can be regarded as negligible.
studied; ophthalmological examinations revealed no treat- Effect on spermatogenesis: in the rat, pefloxacin at doses of
ment-related effects on the conjunctiva, cornea, iris, lens or 150 mg/kg produced testicular lesions of comparable severity
retina, and no changes in optic nerve histopathology. There to other antibiotics. However, when compared with the thera-
was some evidence of poor local tolerance (haemorrhage and peutic dosage in humans, the doses required to induce such
oedema) at the site of injection and hence caution should be lesions were much higher for pefloxacin than those used in
exerted when injecting concentrated solutions of pefloxacin in man: this suggests a safety margin for pefloxacin. In addition,
humans. dosages of pefloxacin 25 to 100 mg/kg did not modify fertility
Long-term toxicity studies of up to 12 months' duration in male rats.
were performed in rats and dogs. In a 6-month study in rats, Pefloxacin concentrations in human, dog and rat eyes: ste-
there was excellent tolerance to the dose of 50 mg/kg; at 150 ady-state pefloxacin concentrations in human, beagle dog and
mg/kg only reduced weight gain and mild anaemia were ob- rat lens, plasma and humor were measured after repeated daily
served; there was also a small reduction in the weight of the administration of pefloxacin. Pefloxacin lens concentrations
prostate gland; after 6 weeks' treatment with 500 mg/kg there in humans [74] were more than 7 times lower than those obser-
was increased salivation, diuresis, reduced weight gain and ved in the lenses of beagle dogs receiving the minimal daily
25% mortality. Autopsy revealed a yellow coloration of mus- cataractogenic dose (100 rag/kg). The human lens concentra-
cle, caecal dilatation, testicular atrophy and changes in seminal tions of pefloxacin were close to those observed in rats, in
vesicle, prostate and ovarian weight; in a 12-month study in which no cataractogenic potential has been reported for this
rats there was no significant clinical, ophthalmological or bio- drug. These data suggest that the potential for cataract induc-
chemical abnormalities following daily administration of oral tion by pefloxacin in man is extremely low.
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 Human toxicity
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 Since the launch of pefloxacin in 1985 in France, hundreds
treated with pefloxacin 100 mg/kg. of thousands of patients have been treated with this drug: the
Reproduction studies: administration of oral pefloxacin 100 French clinical experience and the results of international trials
and 400 mg/kg from the 6th and 17th days of gestation in have shown that pefloxacin is generally well tolerated, with
Sprague-Dawley rats produced no teratogenic effects; doses adverse effects in the known range of side effects of the fluoro-
of 600 and 1000 mg/kg reduced maternal food intake and the quinolones, usually transient and mild to moderate in severity
rate of bodyweight gain, with a reduction in the number of live [3,9,24,42,78].
fetuses and mean litter weight. In the New Zealand white rab- Gastrointestinal disorders, such as nausea, epigastric pain
42

and vomiting were the most frequent adverse events observed ture as occurring in man (adults or children) as was described
during clinical trials and were reported in 7% of the patients; in juvenile animals (beagle pups) after administration of peflo-
they represented -50% of all reported effects. The relatively xacin.
high number in outpatients with these side effects is explained Biological abnormalities: biological tolerance of pefloxa-
by the less severe diseases treated and the relative importance cin has been evaluated [78]. Laboratory abnormalities repor-
given to such a minor adverse event. Cases of pseudomembra- ted with pefloxacin concern mainly thrombocytopenia and
nous colitis have been reported occasionally in patients who neutropenia, reported in 37 inpatients. The thrombocytopenia
were simultaneously receiving another antibiotic [78]. was usually mild, rarely below 20,000 ml, and returned to
Skin disorders: as with every fluoroquinolone in use, photo- normal when the drug was discontinued. In 9 patients, heparin
sensitivity has been observed with pefloxacin. The frequency had been co-administered. Neutropenia was exceptionally
of this event during clinical trials was 0.6%; this effect is re- below 1000/ml, and associated in most of the cases with differ-
lated to the dose and duration of treatment, but depends mainly ent concurrent treatments. In several patients (4.8% of 1,437
on the amount of sun exposure. Cases of pruriginous and ery- patients) biological findings were probably related to peflo-
thematous eruptions predominant on the face and forearms xacin administration, including eosinophilia (3 cases), eleva-
after exposure to sunlight have been cited in 11 subjects and ted AST, ALT and/or alkaline phosphatase, moderately in-
pefloxacin was discontinued in 7 patients [51 ]; these adverse creased serum creatinine, elevated transaminase levels: 5
effects appeared on average after 39 days of pefloxacin ther- patients discontinued therapy (unpublished data-on-file,
apy. In outpatients other skin disorders have been cited such as Rh6ne-Poulenc Sant6). Pefloxacin, as other fluoroquinolones,
cases of angio-oedema sometimes associated with other symp- did not cause clinically significant changes in laboratory in-
toms of anaphylactoid reaction such as dyspnoea [78]. In fact dices. Kidney and liver function tests did not generally dem-
these are rare events due to the fact that patients receiving i.v. onstrate any changes. When such changes did occur, they
treatment are not exposed to the sun and that most outpatients could usually be explained by other causes.
receive only a single dose of pefloxacin; it is likely to recom- Long-term use ofpefloxacin: pefloxacin is effective in long-
mend to outpatients expected to receive more than a single term therapy of many severe chronic infections: its indications
dose to avoid sun exposure. in treating osteomyelitis, prostatitis, respiratory superinfec-
Central nervous system (CNS) and psychiatric reactions: tions in cystic fibrosis and Gram-negative meningitis impose
CNS and psychiatric reactions have been observed in 1-2% of prolonged administration of pefloxacin. Published data indi-
the patients during clinical trials. Such CNS and psychiatric cate a relative lack of acquisition of resistance, and not more
reactions with pefloxacin are of great concern as is the case adverse reactions after prolonged courses of pefloxacin than
with all fluoroquinolones. Convulsions, confusion, disorienta- after short course treatment [3,99].
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 High risk patients groups
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 The indications of pefloxacin in children, pregnant women.
of pefloxacin. This confirms that adjustment of the doses and nursing women, have been discussed above (Therapeutic
should be made in the elderly. In outpatients pefloxacin ap- Use and Pharmacy sections). However in children with cystic
pears to be very well tolerated with regard to CNS and psy- fibrosis, due to the high risk respiratory infections in these
chiatric reactions. There were few reports of CNS effects, all of patients, fluoroquinolones have been used successfully [24];
them benign; vertigo, insomnia, headaches, dizziness, were other rare indications of pefloxacin in children were: menin-
the main side effects noted. No cases of convulsions were gitis with resistant bacteria (Gram-negative bacilli): methi-
reported in outpatients receiving pefloxacin [52 ]. cillin-resistant S. aureus infections; osteomyelitis with P. ae-
Musculoskeletal lesions." the most frequently reported mus- ru,~inosa and chronic suppurative otitis media with P. aeru-
culoskeletal side effect was arthralgia which occurred in 0.9% ,~inosa and other Gram-negatives. In these particular situa-
of patients during clinical trials. Of 25 cases of arthralgia re- tions, the recommended dose was up to 15 mg/kg in the most
ported in an inpatient population receiving oral pefloxacin, 4 severe infections [3,24].
occurred in children under 16 years of age [78]; the possibility In elderly patients, single and multiple dose pharmacoki-
of human arthritis following 4-quinolone-induced damage to netic studies of pefloxacin [27,47] have shown differences in
articular cartilage appears only a remote possibility [3] and kinetics of the drug and in pharmacokinetic parameters, espe-
reported cases of arthralgia were transient. No description of cially a lower volume of distribution, a lower plasma clearance
blistering or erosion of cartilage is found in the medical litera- in relation to a lower metabolic clearance and prolonged elimi-
43

nation half-life in relation to physiologically reduced kidney Interactions with theophylline


function; however, by the third day of treatment Cmax values
were superimposable on those obtained in young adults given Studies on the effects of fluoroquinolones on the clearance
400 mg twice daily. It has been concluded that although a of theophylline [94] showed a significant increase of plasma
dosage of 400 mg of pefloxacin twice daily is well tolerated in concentrations of theophylline, up to 19.6% and total body
elderly subjects, it is recommended to decrease the doses after clearance of theophylline decreased by 29.4% with pefloxacin
the third day of treatment [92]. coadministration. It has been suggested that the interaction
The pharmacokinetics of pefloxacin have been extensively was not produced by the parent compound but by its oxo-
studied in patients with various degrees of chronic renal insuf- metabolites; the interaction was interpreted as an effect on
ficiency [34,36,62]: the absence of effect of renal failure on cytochrome P450-related isoenzymes with reduction of the
pefloxacin kinetics is explained by the high degree of its meta- N-demethylation of theophylline [19,94]. Thus it is recom-
bolism (see Pharmacokinetics section); no modification in the mended to measure plasma theophylline concentrations in pa-
distribution and elimination parameters was found in mild and tients receiving pefloxacin and theophylline therapy for proper
in severe renal impairment as compared to the normal subjects dosage adjustments. Similar interactions may occur with caf-
[62]; there was no accumulation of the active N-desmethyl me- feine which is structurally related [19]: caffeine metabolism
tabolite in severe renal failure; its apparent elimination half-life may be delayed resulting in CNS effects in coffee consumers
was about twice that of the parent compound (23-31 h) [62]: receiving pefloxacin.
total and renal clearances and urinary recovery of pefloxacin
decreased in relation to the degree of renal impairment. From Interactions with antacids
these data it was concluded that modification of the dosage
regimen of pefloxacin unlike other new quinolones is not re-
Concomitant administration of pefloxacin with cimetidine
quired in patients with renal insufficiency. Pefloxacin has been
has been shown to produce an increase in the pefloxacin half-
found to be poorly removed by haemodialysis: thus supple-
life, a reduction in total clearance but no change in volume of
mentary doses at the end of dialysis are not required [34].
distribution and renal clearance [81 ]; coadministration of pe-
The pharmacokinetics of pefloxacin in patients with liver
floxacin with antacids containing hydroxides of aluminium
cirrhosis were shown significantly altered as compared to that
and magnesium may delay or reduce the absorption of peflo-
in healthy volunteers [18]: the elimination half-life was much
xacin [ 19]. It is therefore recommended to make proper dosage
longer: 35.1 + 19 h ( 11 +2.6 h in normal subjects); the volume of
adjustments according to the kind of antacid used.
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 Other drug interactions
pefloxacin in ascites was observed after repeated administra-
tion as well as a notable increase of urinary excretion of uncha- Pefloxacin may significantly prolong the prothrombin time
nged pefloxacin (3 or 4 times increase). It was concluded that following administration of coumarin and it is recommended
reduced plasma clearance of pefloxacin in patients with cirrho- to closely monitor both drugs in patients receiving coadmini-
sis was related to decreased hepatic metabolism of the drug. stration of both treatments (unpublished data-on-file, Rh6ne
Consequently dosage adjustments are necessary in treating Poulenc Sant6). Recent studies suggest that CNS effects may
liver failure patients with pefloxacin; recommended adjust- occur with concomitant administration of quinolones and non
ments include the following scheme: pefloxacin i.v. should be steroidal antiinflammatory drugs (NSAIDS) via interactions
administered at 8 mg/kg dose (1 h infusion) twice daily if there with y-aminobutyric acid (GABA) receptors: in vitro studies
is neither ascites nor jaundice; once daily in the presence of have shown that quinolones inhibit binding of radio-labelled
jaundice; every 36 h in the presence of ascites; once every 2 GABA to mouse synaptic cell membranes; in the presence of
days in the presence of both symptoms [92]. 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
Drug interactions
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
Coadministration of pefloxacin and other drugs may have a pefloxacin in renal transplant patients [ 19].
significant effect in patients and in metabolism and pharmaco- In conclusion, most drug interactions involving coadmini-
kinetics of either drug. stration of pefloxacin and other drugs are suspected but are
44

poorly documented. Further investigations are required. How- Prospective randomized comparison of pefloxacin and ampicillin plus
gentamicin in the treatment of bacteriologically proven biliary tract infec-
ever the available information suggests that in the elderly and
tions. J Antimicrob Chemother 1990; 26 (suppl B): 167.
in patients with liver disease, particularly vulnerable to kinetic 15 Clarke AM, Zemcov SJV, Campbell ME. In vitro activity of pefloxacin
interactions with pefloxacin, a careful surveillance and proper compared to enoxacin, norfloxacin, gentamicin and new ]3-lactams. J
dosage adjustments should be made. Antimicrob Chemother 1985; 15: 39.
16 Cohen SP, Murry M, Hooper LM, Wolfson JS, Levy SB. Cross-
resistance to fluoroquinolones in multiple antibiotic resistant (Mar). Es-
cherichia coil selected by tetracycline or chloramphenicol: decreased
Acknowledgements drug accumulation associated with membrane changes in addition to
OmpF reduction. Antimicrob Agents Chemother 1989; 33:1318-1325.
17 Cmmplin GC, Smith JT. Nalidixic acid and bacterial chromosome repli-
We are very grateful to Doctor Yvan Brumpt (Roger- Bellon cation. Nature (London) 1976; 260: 643.
18 Danan G, Montay G, Cunci R, Erlinger S. Pefloxacin kinetics in cirrhosis.
Laboratories) for his help in providing all necessary docu-
Clin Pharmacol Ther 1985; 38: 439.
ments and available information on pefloxacin, and to Marie- 19 Davey GC. Overview of drug interactions with the quinolones. J Antimi-
Jeanne Julliard for her careful and efficient secretarial assis- crob Chemother 1988; 22 (suppl C): 97.
tance. 20 Dellamonica E Bernard E, Etesse H, Gerraffo R. The diffusion of peflo-
xacin into bone and the treatment of osteomyelitis. J Antimicrob Chemo-
ther 1986:17 (suppl B): 93.
21 Desnottes JF, Jacoto F, Bruel J, Bassoullet MT, Niel G. Effects of peflo-
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