00003495-19873304000003.

Author:
Institution:
Title:

Monk, Jon P.; Campoli-Richards, Deborah M.

ADIS Drug Information Services, Auckland
Ofloxacin: A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic
Use.[Miscellaneous]

Source:
Abstract:

Drugs. 33(4):346-391, April 1987.

Synopsis: Ofloxacin 1 is one of a new generation of fluorinated quinolones structurally related to nalidixic
acid. It is an orally administered broad spectrum antibacterial drug active against most Gram-negative
bacteria, many Gram-positive bacteria and some anaerobes. Ciprofloxacin is the only other quinolone with
superior in vitro antibacterial activity. However, the pharmacokinetic profile of ofloxacin is superior to that of
ciprofloxacin, with more rapid absorption and a peak serum concentration several times higher. Moreover,
ofloxacin achieves high concentrations in most tissues and body fluids.

The results of clinical trials with ofloxacin have confirmed the potential for use in a wide range of infections,

which was indicated by its in vitro antibacterial and pharmacokinetic profiles. It has proven effective against a
high percentage of infections caused by Gram-negative organisms, slightly less effective against Gram-

positive infections, and effective against some anaerobic infections. Clinical efficacy has also been confirmed
in a variety of systemic infections as well as in acute and chronic urinary tract infections, and ofloxacin has
generally appeared to be at least as effective as alternative orally administered antibacterial drugs. Ofloxacin
is well tolerated and, although experience with the drug in clinical practice to date is limited, bacterial

resistance does not appear to develop readily. Thus, ofloxacin is an orally active drug which offers a valuable
alternative to other broad spectrum antibacterial drugs.

Antibacterial Activity: Ofloxacin is a fluorinated quinolone. In vitro it has been shown to be active against
most Gram-negative bacteria, including Citrobacter, Enterobacter, Klebsiella, Proteus, Salmonella and
Shigella species, Yersinia enterocolitica, Escherichia coli, Neisseriaceae and Haemophilus influenzae, with
MIC90 values of <= 1 mg/L. Against such organisms ofloxacin was as active as other quinolones, except
ciprofloxacin. Compared with non-quinolone antibacterial drugs it was a more potent inhibitor than
gentamicin of Enter-obacteriaceae, and equivalent in potency to aztreonam or cefotaxime against
Enterobacteriaceae and H. influenzae. Among 38 antibacterial drugs only cefotaxime was more potent than
ofloxacin against penicillinase-producing Neisseria gonorrhoea.

Ofloxacin was slightly less potent an inhibitor of Providencia, Serratia and Pseudomonas species, although
against Pseudomonas aeruginosa it had similar activity to enoxacin or norfloxacin, was at least as potent as
gentamicin and was several times more potent than aztreonam or cefotaxime. Other Gram-negative
organisms which were highly susceptible to ofloxacin included Aeromonas hydrophila, Plesiomonas
shigelloides and Vibrio cholerae. It had an MIC90 of 0.0625 mg/L against Legionella pneumophila, and had
equivalent activity to ciprofloxacin against Campylobacter jejuni (MIC range 0.03 to 2 mg/L). Gardnerella
vaginalis was moderately susceptible to ofloxacin (MIC range 1 to 2 mg/L).

Among Gram-positive bacteria, ofloxacin was the most potent quinolone (among the 6 reviewed) against
staphylococci (including S. aureus; MIC90 0.2 to 1 mg/L), and only ciprofloxacin had equivalent activity
against streptococci (including S. pneumoniae and S. faecalis; MIC90 1 to 4 mg/L). Against S. aureus it was
considerably more potent than cefotaxime, gentamicin or co-trimoxazole, while against streptococci it was
more potent than latamoxef (moxalactam) but less so than cefotaxime, ceftriaxone or ceftazidime. Ofloxacin
was active against Listeria monocytogenes, with an MIC90 value of 2 mg/L. Some anaerobic organisms,
including Bacteroides melaninogenicus, Bacteroides fragilis and Clostridium welchii were moderately
susceptible to ofloxacin (MIC90 1 to 8 mg/L). Ofloxacin was active against Chlamydia trachomatis and
Mycoplasma pneumoniae with MIC90 values of 4 and 1.56 mg/L, respectively; and the limited data available
with Mycobacterium tuberculosis indicate an MIC90 of <= 1.5 mg/L.

Growth medium, inoculum size and serum had little influence on the activity of ofloxacin, but reduction of pH
or the presence of urine markedly reduced it. Bacterial resistance to non-quinolone antibacterial drugs did
not influence the activity of ofloxacin, but some reduction in activity has been reported against nalidixic acid-

resistant strains. The antibacterial activity of the quinolones has been attributed to inhibition of the A subunits
of the enzyme DNA gyrase, a type II topoisomerase, which controls supercoiling of DNA in bacteria;
ofloxacin may have an additional mechanism of action possibly involving inhibition of the B subunits of this
enzyme. Inhibition of eukaryotic topoisomerases could confer mutagenic properties on the quinolones.
However, studies in vitro and in vivo have shown ofloxacin to have no mutagenic potential, except at very
high concentrations, and to have less influence than ciprofloxacin or norfloxacin on eukaryotic
topoisomerases.

Pharmacokinetic Properties: After oral administration of a single 300mg dose of ofloxacin a peak serum
concentration of about 3 mg/L is reached within 2 hours. Multiple dose administration for up to 14 days in
healthy subjects did not produce accumulation at a dosage of 300mg twice daily, with peak concentrations
ranging from 3 to 6 mg/L on the final day. Food had no significant effect on the pharmacokinetics of ofloxacin
except to delay absorption, but concurrent antacid consumption may markedly reduce absorption. In

comparison with norfloxacin and ciprofloxacin, at the same dose, ofloxacin was more rapidly absorbed, and
produced a higher serum concentration and area under the plasma concentration-time curve (AUC; 4 times
that of norfloxacin or ciprofloxacin).

The volume of distribution of ofloxacin has been calculated to be > 1 L/kg. The tissue concentrations
achieved were at least as high as the serum concentration for most tissues. In pregnant women, umbilical
cord serum concentrations have been recorded at up to 90% of maternal serum concentrations, with drug
detected in amniotic fluid in over 50% of cases.

After single doses of 100 to 600mg in healthy subjects 70% to 98% of the drug was excreted unchanged in
the urine within 48 hours, and the urinary concentration remained well above the MIC90 for most bacterial
species at 48 hours after administration. Small amounts of desmethyl ofloxacin and ofloxacin N-oxide have
been detected in the urine in some subjects. The elimination half-life of ofloxacin after doses of >= 200mg
has generally been reported at about 6 hours or greater (up to 7.5 hours). The pharmacokinetics of ofloxacin
are altered in patients with renal impairment: after single doses peak serum concentrations are delayed, and
the elimination half-life and AUC are substantially increased depending on the degree of renal impairment.
Thus, dosage adjustments may be required in such subjects.

Therapeutic Trials: With its broad spectrum of antibacterial activity and widespread distribution to most
tissues and body fluids at relatively high concentrations, ofloxacin could be of potential therapeutic
application in many types of infection. In controlled and uncontrolled clinical trials ofloxacin (at dosages of
300 to 800mg daily for 5 to 14 days in most cases) was usually clinically effective in a high percentage of
patients (about 70 to 98%) with respiratory tract infections (including bronchitis, pneumonia and
otorhinolaryngological in-fections), upper or lower urinary tract infections, gonococcal or non-gonococcal
urethritis, skin and soft tissue infections, obstetric and gynaecological infections and biliary tract infections.
Bacteriological response rates were equally good, although in biliary tract infections there was some
discrepancy between clinical and bacteriological response. Few patients with non-gonococcal urethritis have

been treated with ofloxacin, but available results are encouraging. In patients with urinary or lower respiratory
tract infections there tended to be a higher response rate among patients with acute than chronic infections,
as might be expected. Moreover, ofloxacin proved effective in many patients previously resistant to other
antibacterial drugs. Preliminary studies have shown some encouraging results with ofloxacin in patients with
cystic fibrosis and pulmonary tuberculosis.

In bronchitis the efficacy of ofloxacin was significantly greater than that of cefaclor and similar to that of cotrimoxazole, while in pneumonia it was similar to that of cotrimoxazole and doxycycline. The efficacy of

ofloxacin in urinary tract infections was significantly greater than that of pipemidic acid, and at least as good
as that of nalidixic acid, amoxycillin plus clavulanic acid, nitrofurantoin and co-trimoxazole. Other
comparative studies showed ofloxacin to be at least as effective as amoxycillin and doxycycline in obstetric
and gynaecological infections, pipemidic acid in otitis media, cefaclor, co-trimoxazole and doxycycline in skin
and soft tissue infections, and amoxycillin in tonsillitis.

The response rate to ofloxacin in patients with otitis media was lower than for other types of infection (50 to
70% cure clinically and/or bacteriologically). Patients with tonsillitis showed an excellent bacteriological
response rate (98%) but a lower clinical response (71%), and a similar relationship was seen in patients with
enteritis (82% vs 45% response rates). Bacteriological results from clinical trials have confirmed the findings
of in vitro studies, with ofloxacin eradicating 75 to 95% of Gram-negative aerobic bacteria, except

Pseudomonas aeruginosa which was slightly less sensitive (60% of strains eradicated), and also being active
against a high percentage of Gram-positive aerobic bacteria and some anaerobic bacteria. Superinfections
were reported following ofloxacin therapy in 2 to 17% of trial populations, although the terminology was not
defined in most studies; the rate tended to be lower than with most comparative treatments.

Side Effects: Ofloxacin has been administered to nearly 16,000 patients in clinical trials, and side effects
have been reported in 3.3% of this population. The incidence of drug-related adverse clinical reactions in
individual studies has ranged from 2.5 to 8.5%. Gastrointestinal symptoms, mainly nausea/vomiting,
pain/discomfort, diarrhoea and anorexia, were reported most frequently, followed by central nervous system
events and dermatological or hypersensitivity reactions. The incidence of side effects did not appear to be

dose related, and serious reactions were rare. Minor changes in mean laboratory values were not considered
clinically significant and were usually attributable to the disease process, but some cases of eosinophilia
were considered possibly drug related. About 1.5 million patients have been treated with ofloxacin
subsequent to its first launch, and post-marketing surveillance in this time has revealed 806 spontaneously
reported adverse reactions in 338 patients. A number of previously unidentified reactions were reported,
including some cases of hallucinations and psychotic reactions, but most symptoms were mild and
reversible.

Dosage and Administration: The recommended oral dosage of ofloxacin in respiratory tract infections is 400
to 600mg daily, and in urinary tract infections it is 200 to 600mg daily, in divided doses (usually twice daily)
for 3 to 10 days. Higher dosages (up to 800mg daily) may be required in patients with severe or complicated
infections. A dosage of 400mg daily has been used most frequently in patients with skin and soft-tissue
infections, obstetric and gynaeco-logical infections and biliary tract infections, while 600mg daily has been
used most frequently in patients with otitis media or enteritis. Single-dose therapy has been used

successfully for the treatment of uncomplicated gonococcal urethritis. Treatment has been continued for up
to 3 months in some studies in patients with chronic infections, but too few patients have been included to
date in such studies to fully establish the long term tolerability of ofloxacin. In a preliminary study of
pulmonary tuberculosis a dosage of 300mg once daily was administered for 8 months.

Despite reports of a pharmacokinetic interaction between enoxacin and theophylline, this does not seem to
occur with ofloxacin and dosage adjustments for either theophylline or ofloxacin are probably not necessary.
Patients receiving antacids may respond poorly to ofloxacin because of reduced absorption. It is important
that the dosage of ofloxacin be adjusted in patients with renal insufficiency.

Ofloxacin is contraindicated in children or adolescents during the growth phase, and the drug should not be
administered during pregnancy or in breast-feeding mothers.

Copyright 1987 Adis International

Language:

English.

Document Type:

Drug Evaluation: PDF Only.

Journal Subset:

Clinical Medicine.

ISSN:
NLM Journal Code:

0012-6667
ec2, 7600076