DRUG EVALUATION

Drugs 42 (5): 825·876, 19910012·6667/91/0011·0825 /$26 .00/0© Adis International Limited. All rights reserved.

DRE169

OfloxacinA Reappraisal of its Antimicrobial Activity, Pharmacologyand Therapeutic Use

Peter A. Todd and Diana FauldsAdis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: B.I. Davies, Streeklaboratorium voor de Volksgezondheid, DeWever-Ziekenhuis , Heerlen, The Netherlands ; V. Fainstein, Infectious Disease Associates of Houston, Houston ,Texas, USA; R. Janknegt, K1inische Farmacie, Maasland Hospital, Sittard, The Netherlands; R.N. Jones, Anti­infectives Research Center, University of Iowa College of Medicine, Iowa City, Iowa, USA; S. Kawamura, De­partment of Otorhinolaryngology, Juntendo University School of Medicine, Tokyo, Japan; H.C. Neu, DivisionofInfectious Diseases, Department of Medicine, College of Physicians and Surgeons of Columbia University, NewYork, New York, USA; S.R. Norrby, Department of Infectious Diseases, University Hospital of Lund, Lund,Sweden; H.W. Van Landuyt, Department of Microbiology, A.Z, St Jan, Ruddershove, Brugge, Belgium; R. Wise,Department of Medical Microbiology, Dudley Road Hospital, Birmingham, England.

Contents

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SummaryI. Chemistry and Mechanism of Action2. Antimicrobial Activity

2.1 In Vitro Inhibitory Activity2.1.1 Activity Against Resistant Bacteria2.1.2 Comparisons with Other FIuoroquinolones2.I.3 Factors Affecting In Vitro Activity

2.2 Bactericidal Activity2.3 Postantibiotic Effect2.4 Antibacterial Synergy and Antagonism2.5 Emergence of Resistance2.6 Efficacy in Animal Models of Infection

3. Other Pharmacological Properties3.1 Effects on Immune Function3.2 Effects on Intestinal Flora3,3 Toxicity

4. Pharmacokinetic Properties4.1 Absorption and Plasma Concentrations4.2 Distribution4.3 Metabolism and Excretion4.4 Effects of Gender , Age and Various Disease States on Pharmacokinetics

4.4.1 Gender and Age4.4.2 Renal Impairment4.4.3 Hepatic Impairment4.4.4 Other Conditions

5. Clinical Use

826

843843846846849851851853854854855855856856857857857858858861861862862863863

SummarySynopsis

Drugs 42 (5) 1991

5:1 Genitourinary Infections5.1.1 Urinary Tract Infections5.1.2 Prostatitis5.1.3 Sexually Transmitted Diseases

5.2 Lower Respiratory Tract Infections5.2.1 Pulmonary Tuberculosis5.2.2 In Patients with Cystic Fibrosis

5.3 Otorhinolaryngological Infections5.3.1 Topical Treatment

5.4 Skin and Soft Tissue Infections5.5 Bone and Joint Infections5.6 Enteric Infections5.7 Peritonitis in CAPD Patients5.8 Septicaemia5.9 Immunocompromised and Cancer Patients

5.9.1 Treatment5.9.2 Prophylaxis

5.10 Other Infections6. Clinical Tolerability7. Drug Interactions

7.1 Theophylline and Caffeine7.2 Other Drugs

8. Overdosage9. Dosage and Administration10. Place of Ofloxacin in Therapy

Ofloxacin is a fluoroquinolone whose primary mechanism of action is inhibition ofbacterialDNAgyrase. In vitro it hasa broadspectrum ofactivityagainst aerobic Gram-negative and Gram­positive bacteria. although it is poorly activeagainst anaerobes. Ofloxacin, unlike most otherbroadspectrum antibacterial drugs. can be administered orallyas wellas intravenously. Penetration intobodytissues andfluids is highlyefficient. Clinical trialswithorallyand intravenously administeredofloxacin have confirmed its potentialfor use in a widerange ofinfections. where it has generallyproved as effective as standard treatments. Ofloxacin is well tolerated. and in comparison withotheravailable fluoroquinolones is less likely to causeclinically relevant drug interactions.

Ofloxacin thus offers a valuable oraltreatment(with an optionfor intravenous administrationifnecessary) for use in a wide rangeofclinical infections. but witha particular advantage in moresevere or chronic infections when recourse to parenteral broadspectrum agents wouldnormallyberequired. thereby providing costsavings and additionally allowing outpatient treatment.

Antimicrobial Activity

Ofloxacin is a fluoroquinolone, whose mechanism of action involves inhibition of bacterialDNA gyrase. It has a broad range of in vitro activity against aerobic Gram-negative and Gram­positive bacteria. Gram-negative bacteria are almost invariably susceptible, and usually highlysusceptible, to ofloxacin, although a few such bacteria may show only moderate susceptibility,e.g, Pseudomonas stuartii, Providencia species and Gardnerella vaginalis. MIC90 values are some­what higher against Gram-positive bacteria, but these organisms are usually susceptible. However,Nocardia asteroides is resistant and some streptococcal and enterococcal species may show onlymoderate susceptibility and, occasionally, resistance. Many mycobacterial species are susceptibleto ofloxacin, in particular Mycobacterium tuberculosis, with the exception of some rare species

Otloxacin: An Update 827

which may be resistant. Otloxacin in common with other tluoroquinolones is not considered tobe an effective agent against anaerobic bacteria, although some species are susceptible or mod­erately susceptible (e.g. Bacteroides melanogenicus, Peptostreptococcus species, Clostridium per­fringens, Veillonella species, Mobiluncus species). Chlamydia trachomatis is susceptible, and My­coplasma species and Ureaplasma urealyticum show moderate susceptibility. Otloxacin andciprotloxacin show similar antimicrobial activit ies, provided MIC90 values are related to suscep­tibility/resistance breakpoints, and both tluoroquinolones tend to exhibit better activity than nor­tloxacin, enoxacin and petloxacin against some pseudomonal, streptococcal and staphylococcalstrains .

The antibacterial activity of ofloxacin is influenced little, if at all, by inoculum size, growthmedium or the presence of serum. Acidic pH, or the addition of urine or magnesium may reducethe in vitro antibacterial activity of otloxacin. Bacteriostatic and bactericidal activities are usuallyachieved at similar otloxacin concentrations.

Resistance to tluoroquinolones occurs at a low rate in vitro and is chromosomally mediated .High level resistance results from DNA gyrase mutation, requires multiple passage at high drugconcentrations, and occurs infrequently in vivo. Low level resistance results from cell-membranechanges and may occur during single-step exposure at low drug concentrations, generally onlydecreasing susceptibility. It may, however, produce clinical resistance in bacteria which werepreviously only moderately susceptible. There is usually cross-resistance for all tluoroquinolones.Plasmid-mediated resistance has not been noted.

Ofloxacin usually has additive or indifferent effects when combined with other antibacterialagents in vitro but, may occasionally demonstrate synergy and only rarely antagonism .

Pharmacological Properties

At therapeutic concentrations ofloxacin does not exert detrimental effects on the immunesystem in vitro or in vivo. Otloxacin rapidly eliminates aerobic Gram-negative microtlora fromthe gastrointestinal tract and significantly reduces enterococci. However, obligate anaerobic Gram­negative and anaerobic Gram-positive flora are not substantially modified by otloxacin, althoughyeast overgrowth is a rare occurrence. Toxicological studies indicate that ofloxacin has a low toxicpotential, although ofloxacin (at high concentrations) and other fluoroquinolones can cause ar­ticular damage in juvenile animals .

Pharmacokinetic Properties

Ofloxacin is efficiently absorbed with an absolute bioavailability of tablet formulations ap­proaching 100%. Maximum plasma concentrations are reached about I to 2 hours after oraladministration and are linearly related to dose. Food may delay the rate of absorption but doesnot affect its extent. Steady state is reached after 2 to 4 doses at 12-hourly intervals. Followingintravenous administration maximum plasma concentration can be up to 50% higher than afterthe same dose of ofloxacin administered orally. However, after the rapid initial distribution phasefollowing intravenous administration, plasma concentrations are comparable with both routes .As distribution and elimination constants are also unaffected by the route of administration,systemic and parenteral administration can be considered bioequivalent and used interchange­ably.

Otloxacin is 20 to 25% protein bound , with the mean volume of distribution ranging from1.3 to 1.7 L/kg. The drug penetrates rapidly and efficiently into body tissues and fluids (includingbreast milk and the placenta), and achieves effective antimicrobial concentrations in all tissuesevaluated.

The mean elimination half-life of otloxacin is 5 to 8 hours. Mean body clearance ranges fromII to 16 L/h and mean renal clearance is only slightly lower (9 to II Lzh). Ofloxacin is almostexclusively excreted unchanged in urine, with negligible metabolism.

The disposition of ofloxacin is unaffected by gender, and age-related changes in ofloxacindisposition appear highly correlated with creatinine clearance. Indeed, renal impairment can havea profound effect, decreasing renal clearance of ofloxacin and increasing elimination half-life.These changes become clinically significant when creatinine clearance is less than 3 Llh (50 ml/

828

Clinical Use

Drugs 42 (5) 1991

min), and dosage adjustment is required in such patients. Ofloxacin is not efficiently removedby haemodialysis or peritoneal dialysis. Renal clearance of ofloxacin was reduced in patients withalcoholic cirrhosis ; this was not always related to hepatic or renal function test values, althoughit was correlated with a decrease in tubular secretion.

The broad spectrum of in vitroactivity of ofloxacin against aerobic Gram-negative and Gram­positive bacteria combined with its efficient penetration into body tissues and fluids would suggestits clinical use in a wide range of infections . It would not , however, be expected to have anysignificant application, at least as monotherapy, for the treatment of infections where anaerobicbacteria might be frequently encountered.

Ofloxacin was administered orally in most clinical trials. However, the availability of theintravenous formulation and its interchangeability with the oral formulation allows improvedversatility during ofloxacin treatment. The intravenous route can be used when oral therapy isinappropriate (e.g. critical care patients or conditions affecting absorption) but it is usual to switchto oral administration as soon as practicable , often in a few days once improvement is shown,without any dosage adjustment being necessary. Ofloxacin has been extensively studied in nu­merous clinical trials in a wide range of acute or chronic, and mild to severe infections .

Ofloxacin is at least as effective as other standard treatments (e.g, cotrimoxazole) in the treat­ment of uncomplicated and complicated urinary tract infections. It is also highly effective, moreso than carben icillin, in the treatment of acute or chronic bacterial prostatitis. Ofloxacin as single­dose treatment is bacteriologically 100%effective in eradicating Neisseriagonorrhoeae in uncom­plicated gonorrhoeal cervicitis and urethritis, and also eradicates associated pharyngeal or ano­rectal infection . It is equally effective against {J-Iactamase-producing strains of N. gonorrhoeae.Treatment with ofloxacin for I week is also effective in the treatment of nongonococcal urethritisand cervicitis caused by Chlamydia trachomatis, producing similar results to doxycycline; neithertreatment, however, eradicated infections caused by Mycoplasma hominis, and results againstUreaplasma urealyticum were equivocal. As a short course (I to 3 weeks) ofloxacin was alsohighly effective in the treatment of acute salpingitis caused by N. gonorrhoeae or C. trachomatis.Further study is required to elucidate its role in the treatment of obstetric and gynaecologicalinfections caused by other pathogens .

Ofloxacin has proven effective in the treatment of acute or chronic lower respiratory tractinfection (bronchitis and pneumonia), whether community or hospital acquired . It appeared atleast as effective as other treatments such as erythromycin, doxycycline, cotrimoxazole, amoxi­cillin, amoxicillin/clavulanic acid, pivmecillinam, cefotaxime and other fluoroquinolones, and itwas more effective than cefaclor. Ofloxacin was 80 to 100% effective bacteriologically againstmost common respiratory pathogens [Haemophilus influenzae, Klebsiella pneumoniae, Branha­mellacatarrhalis (Moraxella catarrhalis) and Staphylococcus aureus], while rates were lower againstStreptococcus pneumoniae (70 to 75%) and Pseudomonas aeruginosa (about 50%). The relativelylow eradication rate for S. pneumoniae might limit the use of ofloxacin when such an infectionis clinically expected. However, the eradication rate for P. aeruginosa must be considered inrelation to the recalcitrance of these infections even to other parenteral ant ibacterial agents. Ofnote, ofloxacin also proved effective against unusual or less frequent respiratory pathogens , e.g.Mycoplasma pneumoniae, Chlamydia psittaci, Chlamydia pneumoniae, Mycobacterium fortui­tum, Coxiella burnetii, and Legionella pneumophila. Ofloxacin has also been used successfullyin combination with first- and second-line antitubercular drugs in patients with Mycobacteriumtuberculosis pulmonary infection resistant to standard therapy . Limited experience with oral of­loxacin suggests it has clinical efficacy in adults and children with acute exacerbation of cysticfibrosis caused by P. aeruginosa or S.·aureus, and when used in combination with other drugssuch as fosfomycin, azlocillin or ceftazidime it may eradicate these bacteria . However , devel­opment of resistance was occasionally noted for P. aeruginosa. There have been too few com­parisons of ofloxacin with standard treatments in otorhinolaryngological infections to determineits place in the therapy of conditions such as tonsillitis , pharyngitis or otitis . Of note, oral of­loxacin can be effective in the treatment of otitis media or externa caused by P. aeruginosa. A

Ofloxacin: An Update 829

topical otic formulation of ofloxacin is undergoing investigation for use in adults and childrenwith otitis media.

Oral ofloxacin was of similar efficacy to oral cefaclor or cephalexin in the treatment of mildto moderate skin and soft tissue infections (generally caused by staphylococci and streptococci).However, ora l ofloxacin was more effective than intravenous cefotaxime in serious skin and softtissue infections, when multiple pathogens including Gram-negative bacteria were . more fre­quently encountered. Long term treatment with orally administered ofloxacin has provided prom­ising results in patients with bone and joint infections but comparison with other treatments,usually parenteral, are limited.

Ofloxacin for I to 2 weeks is essentially 100% effective clinically and bacteriologically ineliminating enteric infections caused by Salmonella and Shigella species, including those in patientsunresponsive to standard therapies or with resistant strains. Ofloxacin has been studied in thetreatment of other infections such as peritonitis and septicaemia with encouraging preliminaryresults. Ofloxacin has proven highly effective in the treatment and prophylaxis of immunocom­promised and cancer patients with respect to Gram-negative infections, but further investigationof ofloxacin in combination with other agents is required to extend the activity against Gram­positive bacteria.

Clinical Tolerability

Adverse effects during ofloxacin therapy are infrequent, usually mild to moderate in intensity,and rarely necessitate drug withdrawal. The most frequent effects are gastrointestinal (pain/dis­comfort, nausea/vomiting, diarrhoea, anorexia) followed by CNS effects (headache, dizziness,insomnia) and cutaneous reactions (rash, pruritus). Postmarketing surveillance of ofloxacin hasgenerally confirmed its favourable clinical tolerability. The most clinically significant adverseeffects are neurological (psychosis, hallucinations and epilepsy) , although these occur infrequently;The possible pharmacological mechanism appears to be common to all fluoroquinolones, andmay involve GABA receptor antagonism and promotion of CNS excitation. Pseudomembranouscolitis has also been rarely encountered.

Because of the articular damage which has been noted in juvenile animals during toxicologicalstudies, the use of fluoroquinolones is generally not permitted in children. However, ofloxacinhas been used successfully in a few paediatric patients with cystic fibrosis without any evidenceof joint toxicity.

Drug Interactions

Studies indicate that ofloxacin has little or no propensity to interact with theophylline, caffeineor fenbufen . Other fluoroquinolones, however, and most notably enoxacin, may undergo a markedinteraction with these drugs . Quinolones chelate with alkaline earth and transition metal cations,and should not be administered with antacids containing calcium, magnes ium or aluminium,with sucralfate, with divalent or trivalent cations such as iron , or with multivitamins containingzinc, as these may reduce absorption and plasma concentrations of ofloxacin. If required, antacidsshould be administered 2 hours before or after ofloxacin. Ofloxacin does not appear to interactwith ranitidine, pirenzipine, cyclosporin, cefotaxime, c1indamycin or metronidazole. .

Dosage and Administration

The usual dosage for ofloxacin is 200 to 400mg orally every 12 hours for 7 to 14 days . Dosagerecommendations can vary between different countries. The lower dosage of 200mg twice dailyis sufficient for urinary tract infection, with only 3 days' administration required for simple cys­titis. A single 400mg dose may be used for uncomplicated gonorrhoea. Other infections usuallyrequire 200 or 300mg twice daily , and for severe infections at least 2 weeks' treatment with 300to 400mg twice daily may be required. A once daily regimen (400mg daily) has been used suc­cessfully in some clinical trials . Ofloxacin can also be administered intravenously using the samedosage recommendations as for oral regimens, as the formulations show bioequivalence. Theintravenous route is only used when necessary , and a change to the oral route should be made

830 Drugs 42 (5) 1991

as soon as practicabl e. An eye drop formulation is also available. Dose reduction and/or pro­longat ion of the dose interval is necessary in patients with renal impairment.

Ofloxacin has been previously reviewed in theJournal (Monk & Campoli-Richards 1987). How­ever, considerable information has been publishedsince then which allows better definition of its placein therapy, and a reappraisal of ofloxacin is there­fore timely. Coverage of this update is generallyrestricted to data published since the review byMonk and Campoli-Richards (1987). At that timethe antimicrobial activity of ofloxacin was well es­tablished so only general overview is provided here(section 2). Significant new data concerning thepharmacokinetics of ofloxacin have become avail­able, particularly with respect to its tissue distri­bution and use in special patient groups (section4). However, greatest attention is given to new dataon the clinical efficacy of ofloxacin compared withother antimicrobial agents (section 5) and to its tol­erability (section 6).

1. Chemistry and Mechanism ofAction

Ofloxacin and other newer 4-quinolones (e.g.ciprofloxacin, enoxacin, norfloxacin, pefloxacin) arestructurally related to the prototype compound,nalidixic acid, differing by 6-fluorine and 7-piper­azinyl substituents on the heterocyclic ring (fig. I).The structure-activity relationship of the 4-quino­lones is reviewed in detail by Stein (1988) and Neu(1989a). To separate the newer 4-quinolones as adistinct class compared with nalidixic acid, the termfluoroqu inolone has been often adopted and willbe used throughout this review. Ofloxacin is com­posed of 2 optical isomers: the (-) isomer is 8 to128 times more potent than the (+) isomer and 2to 8 times as potent as the racemic mixture againstGram-positive and Gram-negative bacteria (Hay­akawa et a1. 1986; Inagaki et a1. 1989).

Ofloxacin acts primarily by inhibiting the re­sealing of DNA strand breaks by the A subunits ofbacterial DNA gyrase (the enzyme which intro­duces negative supercoils into prokaryotic DNA),

possibly by binding to DNA, thus presenting a top­ographically altered substrate to the enzyme. Thispermits exonuclease degradation of the DNA, ul­timately leading to cell death. Mammalian DNAgyrase is unaffected by ofloxacin at therapeuticconcentrations. The exact bactericidal mechanismof ofloxacin is unknown but appears to involveother actions directly or indirectly linked to DNAgyrase activity , which may not be common to all4-quinolones (see section 2.2). This, together witha variable ability to penetrate the outer bacterialcell membrane via porin and nonporin pathways,may explain the differences in antimicrobial po­tency between these compounds (Monk & Cam­poli-Richards 1987; Paton & Reeves 1988; Stein1988).

2. Antimicrobial Activity

The accepted breakpoints with broth and agardilution methods for determination of the mini­mum inhibito ry concentrations (MIC) of ofloxacinare: ~ 2 mg/L (susceptible), 4 mg/L (moderatelysusceptible) and ~ 8 mg/L (resistant) [Fuchs 1989].A standard 5-/Lg ofloxacin disc is used for routinesusceptibility testing: inhibition zone diameters ~12mm indicate resistance, 13 to 15mm moderatesusceptibility and ~ 16mm susceptibility (Fuchs eta1. 1989).

2.1 In Vitro Inhibitory Activity

The in vitroantimicrobial spectrum of ofloxacinbased on MIC90 (MIC for 90% of tested strains)values was well established at the time of the pre­vious review in the Journal (Monk & Campoli­Richards 1987) and has also been reviewed else­where (Drew & Gallis 1988; Fuchs 1989; Maple eta1. 1990; Neu 1989b; Paton & Reeves 1988; Wolf­son & Hooper 1989). Table I shows a representa­tive sample of MIC90 values, but it should not be

Ofloxacin: An Update

considered as giving a definitive range of such val­ues. There have been many individual reports ofthe in vitro activity of ofloxacin against clinical iso­lates (partly because ofloxacin is being used as oneof the standard fluoroquinolones for susceptibilitytesting), some of which have shown outlying MIC90values. This may reflect local differences in floraor sampling methods. Furthermore, some 'drift' inMIC90 values may occur, particularly in areaswhere fluoroquinolones have been extensively usedfor some time, because of the possible develop­ment of bacterial resistance (section 2.5).

Ofloxacin has a broad spectrum of activityagainst aerobic Gram-negative and Gram-positivebacteria. In particular, Gram-negative bacteria areusually highly susceptible to ofloxacin, althoughvarious Pseudomonas species and Providenciastuartii show borderline susceptibility. MIC90 val­ues against Gram-positive bacteria are generallyhigher than for Gram-negative bacteria . Staphylo­coccus and Corynebacterium species are suscepti­ble, as are most Streptococcus species (althoughStreptococcus pyogenes and occasional strains ofStreptococcus pneumoniae may show borderlinesusceptibility). Enterococci and Listeria monocy­togenes also show borderline susceptibility , whileNocardia asteroides is resistant. The activity of of­loxacin against the many Mycobacterium species

831

has been reviewed elsewhere (Leysen et al. 1989).Many species of slow-growing mycobacteria weresusceptible (MIC90 0.5 to 2.0 mg/L) [M. tubercu­losis, M. bovis, M. xenopi, M. kansasii, M. gor­danae. M. terrae and M. triviale], while others wereresistant (MIC90 ~ 8 mg/L) [M. avium, M. intra­cellulare, M. scrofulaceum, M. szulgai, M. non­chromogenicum]. Rapid-growing mycobacteria wereusually susceptible (M. phlei, M. thermoresistible,M. aurum and M. fortuitum), with MIC90 valuesof 0.25 to I mg/L, although M. chelonae was re­sistant (MIC90 > 16 mg/L). M. leprae is also sus­ceptible to ofloxacin (Franzblau & White 1990).Most anaerobic bacteria show moderate suscepti­bility or resistance to ofloxacin. Chlamydia andmycoplasma species are usually susceptible to of­loxacin, and Ureaplasma urealyticum is moder­ately susceptible. Ofloxacin has additionally beenshown to have activity against Coxiella burnetii(Raoult et al. 1989), as well as Leishmania dono­vani (Raether et al. 1989), Francisella tubearensis(Syrjala et al. 1991), and Plasmodium falciparum(Divo et al. 1988).

2.1.1 Activity Against Resistant BacteriaAt the time of the previous review in the Jour­

nal, bacterial resistance to nonquinolone antibac­terial drugs was shown to have no influence on

Ofloxacin Enoxacin Pefloxacin

Norfloxacin Ciprofloxacin Nalidixic acid

Fig. 1. Structural formulae of ofloxacin, related fluoroquinolone s and nalidixic acid.

832

Table I. In vitro antimicrobial spectrum of ofloxacin (adapted from Fuchs 1989)8

Drugs 42 (5) 1991

Organism

Gram-negative bacteria-EnterobacteriaceaeEscherichia coli

Shigella spp.Klebsiella spp.Enterobacter aerogenes

Enterobacter cloacaeEnterobacter agglomerans

Hafnia alveiSerratia marcescensCitrobacter diversusCitrobacter freundiiSalmonella spp.Proteus mirabifis

Proteus vulgarisMorganella morganiiProvidencia retlgeri

Providencia stuartiiYersinia enterocofitica

Other Gram-negative bacteriaAeromonas spp.Vibrio choleraeVibrio parahaemolyticusPlesiomonas shigelloidesAcinetobacter calcoaceticusPseudomonas aeruginosaPseudomonas maltophi/iaOther Pseudomonas spp.Eikenella corrodensCampylobacter jejuniHelicobacter pyloriHaemophifus influenzaeHaemophifus ducreyiBordetella pertussisCapnocytophaga spp.Branhamella catarrhalisNeisseria meningitidisNeisseria gonorrhoeaeLegionella pneumophifaGardnerella vaginalisFlavobacterium Spp.l,2Pasteurella multocida1

Eikenella corrodens1

Brucella mefitensis3.7

Edwardsiella tarda4

Alcaligenes spp.2Moraxella spp.2

MICgo (mg/L)

0.6-1.0

0.03-0.13

0.06-1.0

0.13-0 .250.13-1.00.13-2.0

0.060.5-1.00.060.25-0.50.06-0.50.13-0.50.13-0 .050.13-0.250.25-1.0

2.0-4.0

0.06-0.13

0,015

0.015

0.130,015

0.25-2 .02.0-8.02.0-4.00.5-8.00.030.25-1.01.00.030.030.030.25-0.50.06-0.130.015-0.030.008-0.060.032.00.25-1.00.060.060.78-2.0

0.03

0.50.5

Organism

Gram-positive bacteriaStaphylococcus aureus (meth-S)Staphylococcus aureus (meth-R)Coagulase-negative staphylococciStreptococcus pneumoniaeStreptococcus pyogenesStreptococcus agalactiae

EnterococciListeria monocytogenesNocardia asteroidesMycobacterium tuberculosisMycobacterium intracellulareCorynebacterium diphtheriaeCorynebacterium jeikeium

Corynebacterium urealyticum

Anaerobic bacteriaBacteroides fragms (group)Bacteroides melaninogenicus

Fusobacterium spp.Peptostreptococcus spp.Clostridium perfringensClostridium difficifeEubacterium spp.Veiffonella spp.Mobifuncus spp.

Various other organismsChlamydia trachomatisMycoplasma hominis5

Mycoplasma pneumoniae6

Ureaplasmaurealyticum

MICgO (mg/L)

0.5

0.25-1.0

0.5

2.02.0-4.01.0-2.02.0-8.0

4.032-641.08.01.01.0

0.5

4.0-8.0

2.04.0-322.0-4.0

1.0168.02.02.0

0.5-1.01.01.564.0

a All data taken from Fuchs (1989) except for additional superscripted references: 1 Goldstein & Citron (1988); 2 Appelbaum etal. (1988); 3 Baykal et al. (1989); 4 Bergan et al. (1988); 5 Ridgway (1986); 6 Osada & Ogawa (1983); 7 Garcia-Rodriguezet al. (1991).

Ofloxacin: An Update

bacterial susceptibility to ofloxacin, but nalidixicacid-resistant strains showed a small (2- to 4-fold)increase in ofloxacin MIC90 values, with moststrains still remaining susceptible to ofloxacin.There was usually cross-resistance between thefluoroquinolones (Monk & Campoli-Richards1987). Subsequent studies have generally con­firmed these findings; in particular, methicillin-re­sistant Staphylococcus aureusand {:1-lactamase-pro­ducing bacteria showed no increased resistance toofloxacin (Appelbaum et al. 1989; Ling et al. 1988;Machka et al. 1988; Nishioka et al. 1988; Verbist1988; Watanabe et al. 1987). Nevertheless, thereare recent reports of methicillin-resistant S. aureus(Shalit et al. 1989)and {:1-lactam-resistant B.fragilis(Kato et al. 1988) with increased resistance to of­loxacin. In the latter case, the acquired resistanceto ofloxacin and {:1-lactams may have involved achange in cell wall permeability rather than DNAgyrase mutation (see section 2.5).

2.1.2 Comparisons with OtherFluoroquinolonesIt is clearly established that the fluoroquino­

lones have significantly improved antimicrobialactivity compared with the older nonfluorinatedquinolones such as nalidixic acid, pipemidic acid,oxolinic acid and cinoxacin (Maple et al. 1990;Neu1989b). Further comparison is unnecessary asclinical use of the latter agents has generally beensuperseded by the fluoroquinolones.

Previous reviews in the Journal have exten­sively compared the antimicrobial activity of of­loxacin (Monk & Campoli-Richards 1987)with thatof other fluoroquinolones including ciprofloxacin(Campoli-Richards et al. 1988), norfloxacin(Holmes et at. 1985), enoxacin (Henwood & Monk1988)and pefloxacin (Gonzalez & Henwood 1989),and there are many other comparative reviews(Fuchs 1989; Neu 1989b; Maple et al. 1990; Paton& Reeves 1988; Wolfson & Hooper 1989). Whiledifferences in potencies exist between these fluor­oquinolones, they generally possess similar anti­microbial activity when MIC90 values are relatedto susceptibility/resistance breakpoints for individ­ual agents. Ofloxacin and ciprofloxacin in partie-

833

ular show remarkably similar antimicrobial activ­ities, with both agents tending to be more activethan norfloxacin, enoxacin and pefloxacin againstsome pseudomonal, streptococcal and staphylo­coccal strains .

Ofloxacin has also been compared with manyother newer and investigational fluoroquinolones(for reviews see Janknegt & Hekster 1989; Neuman& Esanu 1988; Stein 1988; Wolfson & Hooper1989). Attempts have been made with these newerfluoroquinolones to improve pharmacokineticproperties and to extend antimicrobial activity tocover 'gaps' where established fluoroquinolonesencounter resistance or moderate susceptibility, e.g.Pseudomonas and Gardnere//a species, variousstreptococci and enterococci, N. asteroides, U.urealyticum, slow-growing mycobacteria and an­aerobes. In some cases the newer fluoroquinolonesmay exhibit an improved in vitro spectrum, but atthis stage of their development the clinical rele­vance of this is unknown .

The in vitro antimicrobial activity of ofloxacinand other fluoroquinolones has been compared withthat of numerous agents from other antibacterialclasses, and the reader is directed to the previouslymentioned reviews on fluoroquinolones in theJournal for more details.

2.1.3 Factors Affecting In Vitro ActivityIt has been previously shown (Monk & Cam­

poli-Richards 1987) that inoculum size (between105 to 108 colony-forming units [cfuj/rnl) or hu­man serum has little influence on in vitroofloxacinactivity assessed by MIC or minimum bactericidalconcentration (MBC) values; activity was similaron Mueller-Hinton, Columbia, nutrient and brain­heart infusion agars, but was markedly decreasedby pH reduction from 7.4 to 5.5, add ition of urineor high magnesium ion concentration. The effectsof pH, urine and magnesium have been subse­quently confirmed to decrease activity (Fukada1988; Yew et al. 1990c). Other recent studies havesuggested that addition of animal or human serummay lower the MIC of ofloxacin against someorganisms (Berti et at. 1989; Fabbri et al. 1990;Miglioli et al. 1990). Morrissey et al. (1989) noted

834

that ofloxacin was bactericidal against S. aureus at106 cfu/ml but only bacteriostatic at 1010 cfu/ml,A bactericidal effect was restored at the high in­oculum by bubbling with oxygen. Thus, oxygenwould appear necessary for cell kill. This may beof clinical relevance when fluoroquinolones areused to treat infections where bacterial concentra­tions are high or conditions are anaerobic , espe­cially in neutropenic patients where a bactericidaleffect is particularly desirable.

Inhibitory zone diameters of ofloxacin duringstandard disc susceptibility testing may vary be­tween Mueller-Hinton agar batch lots, possibly asa result of significant batch lot variation in cationcontent (Fuchs et al. 1989).

Ofloxacin shows good penetration into culturedtissue cells, macrophages and leucocytes, and in vi­tro activity was maintained against intracellularorganisms (Bonina et al. 1989; Crowle et al. 1988;Fitzgeorgeet al. 1988;Pascual et al. 1989 a, b, 1990;Dne & Osada 1988).

2.2 Bactericidal Activity

It had previously been shown that there was littledifference (i.e. ~ 4-fold) between MBC values andMIC values of ofloxacin against Gram-negative andGram-positive organisms. Additionally, time-kill­curves indicated a very rapid bactericidal effect,which was similar for all fluoroquinolones andsomewhat faster than for l3-lactam antimicrobialagents (Monk & Campoli-Richards 1987). Subse­quent studies have confirmed these findings (Verb­ist 1987). MIC and MBC values of ofloxacin weresimilar against fast-growing M. fortuitum (Yew etal. I990c). Against slow-growing mycobacterialonger contact with ofloxacin is required for a bac­tericidal effect: up to 1 and 3 days for M. tuber­culosis and M. kansasii, respectively (Tsukamura1990).

Lewin and Smith (1988) have described 3mechanisms of killing for the 4-quinolones. Mech­anism A is exhibited by all fluoroquinolones (butnot nonfluorinated quinolones), requires compe­tent RNA and protein synthesis, and is thereforeblocked by subinhibitory concentrations of chlor-

Drugs 42 (5) 1991

amphenicol or rifampicin . A second bactericidalmechanism not requiring RNA or protein synthe­sis (mechanism B) operates against nongrowingbacteria made bacteriostatic by either chloram­phenicol or rifampicin. Ofloxacin displays thismechanism against E. coli and Staphylococcus spe­cies, whereas the B mechanism is absent for cip­rofloxacin against staphylococci. A third bacteri­cidal mechanism is exhibited by norfloxacin(mechanism C). This mechanism requires proteinand RNA synthesis but is most active in nondi­viding bacteria.

Several studies have reported the ex vivo bac­tericidal activity of ofloxacin in biological fluidsafter oral or intravenous administration of the drugto healthy volunteers . Significant serum and/or ur­inary bactericidal activity was exhibited againstEnterobacteriaceae and Pseudomonas aeruginosa:at similar doses ofloxacin was more potent thanpipemidic acid, equivalent to norfloxacin but lesspotent than ciprofloxacin (Cruciani et al. 1988;Zeiler et al. 1988). No significant increase in serumbactericidal activity was noted when ofloxacin wascombined with cefotaxime against Enterobacteri­aceae (Weber et al. 1989), with metronidazole orclindamycin against Gram-negative and Bacter­oides species, or with metronidazole against Gram­positive isolates, although there was a distinct in­crease in activity against Gram-positive isolateswhen ofloxacin and clindamycin were combined(Boeckh et al. 1988).

2.3 Postantibiotic Effect

Persistent suppression of bacterial growth afterwithdrawal of exposure to an antimicrobial agentis termed the postantibiotic effect. Rajagopalan­Levasseur et al. (1990) found that neither ofloxa­cin, ciprofloxacin nor pefloxacin exhibited any sig­nificant postantibiotic effect against Legionellapneumophila in macrophage-free growth condi­tions in vitro. However, pefloxacin showed a pos­tantibiotic effect against L. pneumophila in humanmacrophages for up to 72 hours after withdrawalof drug exposure, while with the same concentra­tion of ofloxacin or ciprofloxacin the postantibioticeffect was lost within 24 hours. The reasons for or

Ofloxacin: An Update

significance of these differences between fluoro­quinolones have not been established.

2.4 Antibacterial Synergy and Antagonism

There was little published information concern­ing the activity of ofloxacin in combination withother antibacterial drugs at the time of the pre­vious review in the Journal (Monk & Campoli­Richards 1987). Neither synergy nor antagonismwas seen when ofloxacin was combined with chlor­amphenicol, ceftazidime, cotrimoxazole, trimetho­prim, rifampicin, carbenicillin, tetracycline ortobramycin against Pseudomonas cepacia when us­ing the standard MIC checkboard technique.Chloramphenicol and rifampicin were serious ant­agonists of the bactericidal activity of ofloxacinagainst E. coli as a result of their inhibition of pro­tein and RNA synthesis , respectively, both of whichare necessary requirements for full bactericidal ac­tivity (section 2.2). General reviews of fluoroquin­olones have usually indicated indifferent or addi­tive effects with other antibacterial drugs, occasionalsynergy and rarely antagonism (Drew & Gallis1988; Fuchs 1989; Gonzalez & Henwood 1989; Neu1991; Paton & Reeves 1988; Stein 1988).

Studies with otloxacin specifically have shownsimilar results. Ofloxacin showed no synergy withpristinamycin against S. aureus (Avril et al. 1989),with cefotaxime against Enterobacteriaceae (Weberet al. 1989), with metronidazole against Gram-ne­gative or Gram-positive bacteria and with clinda­mycin against Gram-negative bacteria, althoughactivity against a few isolates of S. aureus and S.pneumoniae indicated synergy between ofloxacinand clindamycin (Deppermann et al. 1989). How­ever, relatively few strains were anal ysed in thesestudies.

Other studies have examined larger numbers ofclinical isolates using the checkboard technique.Ofloxacin showed some degree of synergy withgentamicin, piperacillin and ceftazidime againstPseudomonas species (25 to 39% of isolates) butlittle synergy with these agents against Gram-posi­tive bacteria (I to 18%) or Enterobacteriaceae (13to 20%) [Foleno et al. 1989]. Ofloxacin showed little

835

synergy (~ 20% of isolates) with cefpirome againstEnterobacteriaceae, P. aeruginosa, Acinetobactercalcoaceticus, enterococci and S. aureus (Le Noc etal. 1988). Some degree of synergy (~ 25% of iso­lates) was noted for ofloxacin with: piperacillinagainst Enterobactercloacae, Serratia marcescens,P. stuartii and P. aeruginosa; gentamicin againstE. coli and P. stuartii; and metronidazole againstBacteroides fragilis (Chin & Neu 1990). Theseauthors showed little (~ 20% of isolates) or no syn­ergy for ofloxacin with: piperacillin against E. coli.Klebsiella pneumoniae, and P. aeruginosa; genta­micin against K. pneumoniae, E. cloacae. S. mar­cescens, A. calcoaceticus, var. anitratus and P. aeru­ginosa; vancomycin, gentamicin or rifampicinagainst methicillin-susceptible or -resistant S. au­reus and Streptococcus faecalis; clindamycin againstB. fragilis; and clindamycin or metronidazoleagainst Clostridium species and Peptostreptococcusspecies. Importantly, no antagonism was noted inthe above mentioned studies . However, Madhavanet al. (1989) demonstrated antagonism between of­loxacin and amikacin or gentamicin against about60% of Gram-negative isolates. The in vitro de­velopment of decreased susceptibility to ofloxacinin P. aeruginosa during serial passage at subinhi­bitory ofloxacin concentrations was significantlyreduced by combination with silver sulphadiazine(Modak et al. 1988).

2.5 Emergence of Resistance

The mechanisms involved in resistance to of­loxacin and other fluoroquinolones have been dis­cussed in detail elsewhere (Earnshaw 1989; Lewinet al. 1990; Stein 1988). Chromosomal mutationconfers resistance by 2 mechanisms. The firstmechanism involves high-level resistance causedby changes to the A subunits of DNA gyrase, in­variably leading to clinical resistance and cross-re­sistance between all quinolones. High-level fluoro­quinolone resistance does not occur during in vitrosingle-step exposure to lowdrug concentrations butrequires repeated passage at high drug concentra­tions, where it occurs at a low rate (10-7 to 10-10

depending on the species, and at a considerably

836

lower rate than for nalidixic acid). The secondmechanism is low-level resistance caused bychanges to cell membrane porin channels. This mayconfer cross-resistance between quinolones andother antibacterial agents, as porin channels are in­volved in the cellular penetration of many anti­bacterial drug classes. Low-level resistance may de­velop during single-step in vitro drug exposure andis clinically significant for bacteria with MIC val­ues close to resistance breakpoints (Campoli-Rich­ards et al. 1988; Felmingham et al. 1988; Fuchs1989; Monk & Campoli-Richards 1987; Piddock &Wise 1988;Stein 1988),where it may impart clinicalresistance to fluoroquinolones upon moderatelysusceptible bacteria (such as some Pseudomonasand Staphylococcus species). Kato et al. (1988) havedemonstrated that clinical isolates of B.fragiliswereless frequently susceptible over time and that quin­olone-resistant strains were also less susceptible tol3-lactam antibiotics than quinolone-susceptiblestrains, implying low-level resistance acquisitioncaused by membrane permeability changes.

There is no evidence for enzymatic inactivationof the fluoroquinolones or plasmid-mediatedtransfer offluoroquinolone resistance. However, invitro studies have shown that low levels of oflox­acin can inhibit conjugal plasmid transfer (Scaz­zocchio et al. 1988) and increase plasmid elimin­at ion from bacteria (Fu et al. 1988). It remainsspeculative as to whether this has any clinical rel­evance with respect to limiting or eliminating plas­mid-mediated resistance to other antimicrobialagents; a gain in aminoglycoside and l3-lactam sus­ceptibility with concomitant plasmid loss has beenreported in a patient receiving ciprofloxacin (Lewinet al. 1988).

Of particular relevance is the possible devel­opment of fluoroquinolone resistance duringclinical use of these drugs. At the time of the pre­vious review of ofloxacin (Monk & Campoli-Rich­ards 1987), the fluoroquinolones had not been usedsufficiently to determine whether resistance emerg­ence would prove a problem in clinical practice.Analyses of clinical isolates over time in areas wherefluoroquinolones have been used for several yearshave often indicated an increase in ofloxacin re-

Drugs 42 (5) 1991

sistance, particularly for moderately susceptibleisolates such as P. aeruginosa, S. aureus and En­terococcus faecalis, implying acquisition of low-levelresistance (Aoki & Kashiwagi 1991; Fujiwara et al.1991; Garvez et al. 1991 ; Kresken & Wiedemann1988; Lode 1990; Nagatake et al. 1990; Nishiokaet al. 1988; Shalit et al. 1989), although occasion­ally no change in bacterial susceptibility was dem­onstrated (Nosner et al. 1989). Clinical reports andtrials have indicated acquisition of fluoroquino­lone cross-resistance during treatment with oflox­acin or other fluoroquinolones in various bacteria,e.g, Neisseria gonorrhoeae (section 5.1.3), M. tu­berculosis (section 5.2.1), P. aeruginosa (section5.2.2), Salmonella typhimurium (section 5.6), Bru­cella melitesis(section 5.10). Recently, Scully et al.(1991) reported that resistance of P. aeruginosa toofloxacin developed in 15%of isolates during longterm treatment with ofloxacin 800 mg/day inpatients with severe infection. Clearly, some reser­vation must be expressed concerning indiscrimi­nate use of fluoroquinolones, which might lead toresistance emergence and therefore limit the ther­apeutic value of fluoroquinolones, as has occurredso often in the past with other antibacterial drugclasses. In addition, it might be more appropriateto combine ofloxacin with other antimicrobialagents in clinical situations where resistanceemergence might be expected to be a clinical prob­lem, such as with P. aeruginosa (Scully et al. 1991).

2.6 Efficacy in Animal Models of Infection

The in vivo activity of ofloxacin has been ex­tensively studied and compared with that of otherantimicrobial agents in numerous animal modelsof infection. Ofloxacin was active against generalchallenge or specific infection (meningitis , pneu­monia, pyelonephritis and subcutaneous abscess)with a broad range of Gram-negative and Gram­positive .bacteria. It was also active against Chla­mydia psittaci pneumonia and general challengewith B. fragilis, M. fortuitum and M. tuberculosis(Monk & Campoli-Richards 1987).

There have been numerous more recent reportsevaluating ofloxacin in rodent models of infection .

Ofloxacin: An Update

Ofloxacin was active against general challenge withE. coli(Obana & Nishino 1989), P. aeruginosa fol­lowing whole-body irradiation (Brook & Ledney1990), intracellular pathogens (s. typhimurium andL. pneumophila) [Fernandes et al. 1988; Fu et al.1990] and various mycobacteria (M. kansasii, M.leprae and M. tuberculosis) [Grosset et al. 1988;Tomioka et al. 1990; Truffot-Pernot et al. 1990].In models of more specific infection ofloxacin wasactive against pneumonia caused by Streptococcuspneumonia (Azoulay-Dupuis et al. 1991) and K.pneumoniae in normal and alloxan-induced dia­betic animals (Obana & Nishino 1988), and vari­ous models of pyelonephritis caused by E. coli,Klebsiella oxytoca, P. aeruginosa, methicillin-re­sistant S. aureus, E. faecalis, S. marcescens or mixedfaecal pathogens (Aricioglu et al. 1990; Kawabataet al. 1988; Miglioli et al. 1989; Obana & Nishino1988, 1989; Ritzerfeld 1988), as well as that causedby S. faecalis or S. marcescens in animals withchemically-induced diabetes (Kawabata et al. 1988;Obana & Nishino 1988). Ofloxacin has little pro­phylactic efficacy in preventing Pneumocystis car­inii pneumonia in immunosuppressed mice (Brun­Pascaud et al. 1991). In addition, ofloxacin has noeffect on Treponema pal/Mum in experimental sy­philis (Veller-Fornasa et al. 1987), and is thereforeunlikely to mask this infection when ofloxacin isused to treat urogenital infections .

3. Other Pharmacological Properties3.1 Effects on Immune Function

In vitro and animal studies of the effects of of­loxacin on immune function (Aquilini et al. 1989;Chung & Chung 1988; Corrales et al. 1990; Ezz EIDin et al. 1988; Fantoni et al. 1988; Riesbeck etal. 1989; Tawfik et al. 1990;Zehavi-Willner & Shalit1989; see also Monk & Campoli-Richards 1987)have frequently yielded conflicting results. It gen­erally appeared that 'therapeutic' drug concentra­tions « 5 mg/L) had little significant effect on cell­ular immune function, while higher concentrationscould have some suppressant effect in some in­stances. The relevance of these experimental stud­ies to any potential effect on human immune func-

837

tion during therapeutic treatment with ofloxacincan only be speculative.

Of more importance is the study of human im­mune function during treatment with ofloxacin.Munno et al. (1990) found no change in T or Bcell counts, plasma interferon gamma or serum im­munoglobulin levels in 20 elderly patients treatedwith ofloxacin 600 rug/day orally for 10 days. Big­lino et al. (1990) studied ex vivo leucocyte functionin cells removed from patients who had receivedofloxacin 600 rug/day orally for 5 days. Cells werestimulated with a wide range of mitogens, tetanustoxoid and Newcastle Disease virus to assess mi­togen- and antigen-induced leucocyte proliferation,and production of interferon gamma, interferon al­pha and interleukin-2. There were significant in­creases in the proliferative response to pokeweedmitogen (but not to phytohaemagglutinin, concan­avalin-A or tetanus toxoid) and in interferon alphaproduction. As expected during any antimicrobialtreatment there is a reduction (normalisation) ofleucocyte counts in ofloxacin-treated patients whichis related to resolution of the infectious process (DeSimone et al. 1991; Yamaoka et al. 1991).

3.2 Effects on Intestinal Flora

Oral treatment with usual therapeutic doses ofofloxacin for up to 1 week in healthy volunteerscaused a rapid elimination of Enterobacteriaceaefrom the gastrointestinal tract while having littleor no effect on anaerobic flora (reviewed in Monk& Campoli-Richards 1987). Subsequent studies inhealthy subjects and patients have confirmed thesefindings (Bartoloni et al. 1989; Edlund & Nord1988; Edlund et al. 1988; Kern et al. 1987; Leighet al. 1988; Pecquet et al. 1987; Shah et al. 1987;van Saene etal. 1988). Aerobic Gram-negative florawere rapidly suppressed . Enterococci were signifi­cantly reduced. Obligate anaerobic Gram-negativeand anaerobic Gram-positive flora were not sub­stantially modified, although yeast overgrowth wasa rare occurrence.

838 Drugs 42 (5) 1991

Table II. Summary of some of the main pharmacokinetic char­

acteristics of ofloxacin (see text for details). Unless indicated .

mean values or a range of typical mean values are given for

human volunteers

Abbreviations: C = plasma concentration; Cmax = maximum

plasma concentration; Cssmin = minimum plasma concentrationat steady state; Cssmax = maximum plasma concentration atsteady state ; CL = clearance; Foral = bioavailability after oraladministration; tmax = time to maximum plasma concentration;tv~ = elimination half-life; Vd = volume of distribution.

maximum plasma concentrations (Cmax) arereached (tmax) on average I to 2 hours after tabletadministration (Borner et al. 1988; Flor 1989; Flor& Beals 1991; Leigh et al. 1988; Okhamafe & Ak­erele 1989; Wise & Lockley 1988; Yuk et al. 1991).Absorption is faster when ofloxacin is admini­stered as an oral solution compared with tablets(tmax is approximately halved), while bioavailabil­ity is the same (Flor & Beals 1991). Bioavailabilityof oral ofloxacin is unaffected by food, but tmax

may be delayed (Ichihara et al. 1984; Kalager et al.1986;Okhamafe & Akerele 1989; Verho et al. 1986).With intravenous infusion tmax is reached at theend of a 30-minute infusion (Farinotti et al. 1988;Flor 1989; Lode et al. 1988; Yuk et al. 1991).

Cmax and area under the plasma concentration-

3.3 Toxicity

Toxicological studies in in vitro and animalmodels indicate ofloxacin has a low toxic potential(for review see Davis & McKenzie 1989). How­ever, ofloxacin (at high concentrations) and otherfluoroquinolones may cause cartilage damage injuvenile animals, and their use is therefore usuallyrestricted in humans aged less than 18 years, dur­ing pregnancy, and in nursing mothers. Ofloxacinhas been used in some children with little evidenceof articular intolerance (see section 6).

4. Pharmacokinetic Properties

The basic pharmacokinetic profile of orally ad­ministered ofloxacin is well established (Monk &Campoli-Richards 1987) and an overview is pro­vided here based on newer references and selectedolder references. Significant new pharmacokineticinformation has recently become available for of­loxacin after intravenous administration (section4.1) and during use in special patient groups (sec­tion 4.4).

Significant differences exist between the phar­macokinetic profiles of the different fluoroquino­lone agents (for reviews see Bergeron 1989; Sorge!et al. 1989; Wolfson & Hooper 1989). Ofloxacin isdistinguished by its near complete absorption afteroral administration, low protein binding, negligiblemetabolic inactivation, extensive body distributionand virtually exclusive renal elimination (table II).

Concentrations of ofloxacin in biological fluidsand tissues can be measured by microbiological as­say or high performance liquid chromatography(HPLC), which show good correlation (Verho et al.1985). Numerous HPLC techniques for determin­ation of ofloxacin and its metabolites have beensubsequently described (Chan et al. 1989b; Fadiran& Ojakoya 1990; Katagiri et al. 1988; Le Coguic etal. 1988; Matsubayashi et al. 1989; Mignot et al.1988; Notarianni & Jones 1988; Ochiai et al. 1988).

4.1 Absorption and Plasma Concentrations

Ofloxacin is efficiently absorbed : the absolutebioavailability of tablet formulations approaches100% (Lode et al. 1987; Yuk et al. 1991). Mean

Pharmacokinetic variable

tmax after oral administration

Cmax after single 300mg dose orallyCssmax after 300mg twice daily orally

Cssmin after 300mg twice daily orally

C-dose relationship

Time to steady-state after twice daily

administration

ForalIn vitro protein binding

Apparent Vd

Transfer across placenta and into milk

Tissue and body fluid penetration

CLplasma

CLrenal

tV2~

Metabolism and excretion

Value

1-2h

2.8-4.6 mg/L

3.3-5.9 mg/L

1.0-1.4 mg/L

linear

2-4 doses

"' 100%20-25%

1.3-1.7 L/kgEfficient (~ 100%)

Efficient (usually ~

100%)

11-16 L/h

9-11 L/h

5-8h

Excreted almost

exclusively as

unchanged ofloxacin

in urine

Ofloxacin: An Update 839

Fig. 2. Mean plasma ofloxacin concentrations in 24 healthyvolunteers after a last dose of oral (e) or intravenous (8)ofloxacin 400mg following repeated l2-hourly administra ­tion for 1 week (after Flor 1989).

time curve (AUC) values for ofloxacin are linearlyrelated to dose (100 to 600mg) after oral or intra­venous administration (Flor 1989; Lode et al. 1988;Verho et al. 1985). With either route of adminis­tration steady state is reached after 2 to 4 dosesgiven at 12-hourly intervals (De Bernardis et al.1988; Farinotti et al. 1988; Flor 1989). Plasma of­loxacin concentrations have been reported for awide range of dose schedules and routes of admin­istration (for review see Flor 1989). For example,mean Cmax was 2.8 to 4.6 mg/L after a single oraldose of ofloxacin 300mg, increasing to 3.3 to 5.9mg/L with a mean trough concentration of 1.0 to1.4 mg/L at steady-state with the same dose re­peated 12-hourly (Monk & Campoli-Richards1987).

Cmax values can be up to 50% higher after intra­venous infusion compared with oral administra­tion , but concentrations decline rapidly from thispeak. After the initial distribution phase, plasmaconcentrations are comparable and decrease simi­larly for both administration routes (fig. 2). Dis­tribution and elimination pharmacokinetic con­stants were also unaffected by the route ofadministration (Flor 1989; Yuk et al. 1991). Thissimilar plasma concentration profile for systemicand parenteral ofloxacin administration indicates

4 8 12 16Time (hours)

20 24

bioequivalence and supports the interchangeabilityof both formulations. Route of administration willnot be distinguished in subsequent sections of thispharmacokinetic overview.

4.2 Distribution

Ofloxacin is 20 to 25% protein bound (Lode etal. 1987;Nomura et al. 1985),with a reported meanvolume of distribution ranging from 1.3 to 1.7 L/kg (Farinotti et al. 1988;Flor 1989;Yuk et al. 1991),suggesting extensive extravascular penetration. In­deed, ofloxacin shows rapid and efficient penetra­tion into most body tissues and fluids, reaching ef­fective antimicrobial concentrations with nonotable exceptions ; this represents one of the ad­vantages of the fluoroquinolones as a group com­pared with some other antimicrobial drug classessuch as the ~-Iactams (Sorgel et al. 1989). Further­more, compared with other fluoroquinolones andciprofloxacin in particular, ofloxacin usually showsmore efficient tissue penetration and reaches higherconcentrations (Bergeron 1989; Sorgel et al. 1989;Wolfson & Hooper 1989). The following overviewis based primarily on newer references and pref­erentially those which used AUC ratio determin­ations, which provide a better assessment of pen­etration than isolated time point concentrationcomparisons.

Penet ration of ofloxacin into experimentally in­duced blister fluid is close to 100%, suggesting highextravascular space penetration (Dominguez-GilHurle et al. 1989; Kalager et al. 1986; Lockley etal. 1984; Warlich et al. 1990; Wise & Lockley 1988).This is confirmed with approximately 100% pen­etration of ofloxacin into a wide range of tissuesand fluids with even higher penetration (200 to500%) occurring in some instances (table III). Of­loxacin shows active penetration within some cells,in particular leucocytes and macrophages, which issignificant for activity against intracellular patho­gens (Perea 1990). High concentrations of ofloxa­cin are found in faecal material: greater than 50mg/g on average after 7 oral doses of ofloxacin200mg 12 hourly in healthy volunteers (Leigh etal. 1988). While eliminating Gram-negative bac-

840

Table III. Penetration of ofloxacin into tissues and fluids in humans

Drugs 42 (5) 1991

<100%

Aqueous humor 25% (6)Cerebrospinal fluid

inflamed meninges 50-75% (11,22,

27)uninflamed meninges 30-50% (3, 4)

Fat (12)Sweat 30% (26)

100%

Bone and cartilage (16)Female genitourinary tract (8, 14, 38)

Gallbladder tissue (7)

Gingival tissue and alveolar bone (20)

Liver and muscle (12)Lymph (27)Middle ear mucosa and mucous membrane

(31)Otorhinolaryngological tissues (18, 23, 37)Pancreatic juice (5, 21)Prostate tissue and secretions (1, 13, 17, 19,29,38)Saliva (20, 25, 33)Skin (34)Sputum (10, 33)Tears (26)

Tonsils (32)

200-500%

Bile (7, 21)

Bronchoalveolar lavage fluid (15)

Kidney (1)Lung (9, 24, 36)

Vaginal fluid (30)

1 Aubert et al. (1988); 2 Berger et al. (1990); 3 Bitar et al. (1988); 4 Bouquet et al. (1989); 5 Brattst rorn et al. (1988); 6 Bron

et al. (1989); 7 Chin et al. (1990); 8 Cho et al, (1984); 9 Couraud et al, (1987); 10 Davies et al. (1987); 11 Drancourt et al.

(1988); 12 Diiben et al. (1986); 13 Fujita & Munakata (1988); 14 Hayasaki et al. (1984); 15 Loos et al. (1987); 16 Meissner etal. (1990); 17 Morita & Hasuda (1989); 18 Murai et al. (1984); 19 Naber et al. (1987); 20 Pappalardo et al. (1989); 21 Pederzoli

et al. (1989); 22 Pioget et al. (1989); 23 Sanbe et al. (1984); 24 Serour et al. (1991); 25 Shiiki (1989); 26 Sorgel et al. (1987);27 Stahl et al. (1986a); 28 Symonds et al. (1988); 29 Tallarigo et al. (1989); 30 Tartaglione et al. (1988); 31 Thorn (1987);32 Van Landuyt et al. (1988); 33 Warlich et al. (1990); 34 Watanabe et al. (1984); 35 Weissenbacher et al. (1984); 36 Wijnandset al. (1988); 37 Yamamoto et al. (1984); 38 Yasumoto & Asakawa (1988).

teria completely, ofloxacin had little effect onGram-positive and anaerobic flora (see section 3.2).This would appear to be explained by the highbinding of the drug to faecal material, leaving onlya low free concentration (Edlund et al. 1988). Asofloxacin is excreted primarily in urine as un­changed drug, high concentrations are found inurine (section 4.3). Following maternal adminis­tration of ofloxacin, the drug efficiently penetratesinto breast milk and across the placenta (~ 100%)[Giamarellou et al. 1989].

Distribution of a number of novel ofloxacinformulations has been reported. A controlled-re­lease periodontal insert (PT-Ol) maintained a hu­man gingival crevicular fluid concentration greaterthan 2 mg/L for up to 7 days after insertion (Hi­gashi et al. 1990). A topical ophthalmic ointmenthas been investigated in animals , showing signifi­cant penetration into the cul-de-sac and some pen-

etration into the aqueous humor (Jing-Sheng et al.1989). Topical application of a 0.3% ofloxacin so­lution in children with purulent otit is media or ex­terna led to negligible systemic absorpt ion (serumofloxacin concentration remained below 0.013mg/L) [Baba et al. 1990b].

4.3 Metabolism and Excretion

Ofloxacin undergoes only limited metabolismand is mainly excreted unchanged in urine. Meanbody clearance values for ofloxacin have usuallyranged from 11 to 16 Llh while mean renal clear­ance was slightly less at 9 to 11 Llh, indicating lim­ited extrarenal clearance of the drug (Borner et al.1988; Farinotti et al. 1988; Lode et al. 1987, 1988;Yuk et al. 1991). About 70 to 80% of an admini­stered dose is recovered in urine within 24 hoursand this recovery can increase with longer collec-

Ofloxacin: An Update

tions. Thus, very high urinary concentrations areachieved: with usual therapeutic doses, peak ur­inary ofloxacin concentrations are several orders ofmagnitude above MIC90 values for usual patho­gens, and MIC90 values are exceeded in urine forat least 2 days after single dose administration andfor at .least 4 days after repeated 12-hourly admin­istration for several days (Dagrosa et al. 1986; Ichi­hara et al. 1984; Leigh et al. 1988; Verho et al.1986).

Wong and Flor (1990) recently performed a de­tailed metabolic study of ofloxacin after oraladministration ofa single radiolabelled 400mg dose.79% of the radiolabel was recovered in urine and8% in faeces in the 7 days after administration. 90to 95% and 80% of the radiolabel in urine andfaeces, respectively, was intact ofloxacin. Desme­thyl ofloxacin and ofloxacin N-oxide each ac­counted for about 1% and 7% of the radiolabel inurine and faeces, respectively. The balance of theradiolabel in urine and faeces was identified as theglucuronide conjugate ofofloxacin . Other previousstudies have indicated low recovery of metabolitesin urine (Lode et al. 1987, 1988) and low recoveryof ofloxacin in faeces (Ichihara et al. 1984). Themean plasma elimination half-life of ofloxacin hasbeen variously reported as ranging from about 5 to8 hours (Farinotti et al. 1988; Leigh et al. 1988;Wise & Lockley 1988; Wong & Flor 1990), prob­ably being somewhat dependent on the methodsused for calculation.

4.4 Effects of Gender, Age and VariousDisease States on Pharmacokinetics

4.4.1 Gender and AgeThe dispos ition of ofloxacin is unaffected by

gender (Okhamafe & Akerele 1989).Compared withyoung subjects, the elderly show greater interin­dividual variability, and mean values for Cmax,

AUC and elimination half-life are increased, whilerenal clearance is decreased (Flor 1989; Freymannet al. 1989; Graber et al. 1988; Rademaker et al.1989; Veyssier et al. 1986). Some authors recom­mended reducing ofloxacin dosage by half in theelderly (Freymann et al. 1989; Norrby & Ljungberg

841

1989), while others did not routinely recommendsuch a reduction (Flor 1989; Rademaker et al.1989). The age-related changes in ofloxacin phar­macokinetics appeared highly correlated with cre­atinine clearance (Freymann et al. 1989; Norrby &Ljungberg 1989; Rademaker et al. 1989), which isnot unexpected considering the drug is primarilyexcreted unchanged in urine. Rather than routinedosage reduction in the elderly, it may be moreappropriate to adopt the dosage recommendationsfor renal impairment.

4.4.2 Renal ImpairmentThere have been numerous, almost exclusively

single dose, studies of ofloxacin disposition inpatients with various degrees of renal impairment,including those undergoing haemodialysis andcontinuous ambulatory peritoneal dialysis (CAPD)(Chan et al. 1987; Dominguez-Gil Hurle et al. 1989;Fillastre et al. 1990; Flor 1989; Kampf et al. 1990;Passlick et al. 1989; Sanchez Navarro et al. 1990;Tsubakihara et al. 1989; White et al. 1988; see alsoMonk & Campoli-Richards 1987). As would be ex­pected for a drug primarily excreted unchanged inurine, increasing renal impairment has a progres­sive effect on the disposition of ofloxacin. Whilevolume of distribution and Cmax are not signifi­cantly affected, there is a progressive decrease inrenal clearance of ofloxacin with no significantchange in nonrenal clearance. As a consequence,AUC values and elimination half-life increase.These changes only become clinically significantwhen creatinine clearance is less than 50 ml/minand become extremely marked below 10 ml/min(see fig. 3). Prolongation of the normal dose inter­val and/or dose reduction is therefore required insuch patients (see section 9). Interindividual vari­ability may be considerable in patients with severerenal failure, and therapeutic drug monitoring hasbeen recommended by some authors (Kampf et al.1990; White et al. 1988).

It is generally accepted that ofloxacin is not ef­ficiently removed by haemodialysis (Flor 1989;Kampf et al. 1990; Lameire et al. 1991) or CAPD(Chan et al. 1989a; Flor 1989; Lameire et al. 1991;Passlick et al. 1989), although one group (Tsuba-

842

Time (hours)

Fig. 3. Mean plasma ofloxacin concentrations after a singleoral dose of ofloxacin in 20 healthy subjects with renal im­pairment: • creatinine clearance > 50 ml/min (n = 7); • 10­50 ml/min (n =6);" < 10 ml/min (n =7) [after Flor 1989].

kihara et al. 1989) reported ofloxacin was highlyremoved by haemodialysis. It is nevertheless rec­ommended that ofloxacin be administered at theend of haemodialysis sessions. Ofloxacin effi­ciently penetrates into peritoneal fluid in CAPDpatients, with a mean peritoneal effluent concen­tration of2 mg/L (Janknegt 1991) but CAPD doesnot provide an effective means of nonrenal clear­ance for ofloxacin (Chan et al. 1987; Flor 1989;Lameire et al. 1991; Passlick et al. 1989).

4.4.3 Hepatic ImpairmentSilvain et al. (1989) compared the pharmaco­

kinetics of a single oral dose of ofloxacin 200mgin 12 patients with alcoholic cirrhosis and 12healthy volunteers . Renal clearance of ofloxacin wassignificantly reduced in patients with cirrhosis (4.6vs 11.4 L'h) with a concomitant increase in plasmaconcentrations and elimination half-life. Thesechanges were not always correlated with hepaticfunction tests (this was not unexpected consideringthe small degree of biliary excretion of ofloxacinand lack of significant metabolism) or with renalfunction, but was in part related to an impairmentof tubular handling of the drug. It may thereforebe appropriate to monitor plasma ofloxacin con­centrations in patients with alcoholic cirrhosis.

Drugs 42 (5) 1991

4.4.4 Other ConditionsThe pharmacokinetics of ofloxacin do not ap­

pear different in patients with cystic fibrosis com­pared with healthy subjects (Pedersen et al. 1987).During repeated 12-hourly intravenous infusion ofofloxacin 3 mg/kg in intensive care patients therewas a significant accumulation of ofloxacin after Iweek of treatment in those who were receiving me­chanical respiratory support (Martin et al. 1990,1991). This appeared related to a reduction in renalelimination of ofloxacin, probably by saturation ofthe mechanisms of active tubular secretion.

5. Clinical Use

The clinical activity of ofloxacin was character­ised at.the time of the previous review (Monk &Campoli-Richards 1987), but numerous subse­quently published studies should allow better def­inition of the place of ofloxacin in therapy. Un­fortunately, results of many of these trials aredifficult to interpret because of methodologicalproblems. This reappraisal will therefore focus pri­marily on well-designed, comparative, statisticallyanalysed studies of therapy in large homogeneouspatient populations. Other less rigorously designedstudies will be used where they provide significantinformation, especially in therapeutic areas whereadequate controlled studies are lacking. Statisti­cally significant differences between treatments wereoccasionally found and when this occurred it isspecifically mentioned in the text.

It can also be assumed, unless specified other­wise, that ofloxacin was administered orally. Thedrug is also now available as a parenteral formu­lation , usually administered by slow intravenousinfusion over 30 minutes, which can be used in­terchangeably with oral administration at the samedosage, as these routes show pharmacokineticbioequivalence (section 4). The parenteral formu­lation therefore offers improved clinical utility, withconsiderable advantage in certain situations wherean oral formulation cannot be used, e.g. critical carepatients or in those with conditions affecting gas­trointestinal absorption. As soon as appropriate,

Ofloxacin : An Update

patients can be switched from intravenous to oraladministration, with considerable cost saving.

Indeed, many studies have used intravenous of­loxacin administration (either exclusively or witha change to oral administration after several days)and these are specified in the individual sectionson clinical use. Some studies have summarisedclinical experience gained with intravenous oflox­acin in large numbers of patients with severe in­fection (Graninger et al. 1990; Kanellakokoupou &Giamarellou 1990; Leroy et al. 1989b; Regamy &Steinbach-Lebbin 1990), but the variety of infec­tions treated and extensive use of concomitantantibacterial drugs precludes detailed analysis.

5.1 Genitourinary Infections

5.1.1 Urinary Tract InfectionsThe high and long-lasting urinary concentra­

tions achieved with ofloxacin (it is primarily ex­creted unchanged by the kidney; section 4.3) andits activity against usual community or hospital ac­quired urinary tract pathogens in vitro (generallyGram-negative bacteria; section 2.1.1) indicate thatofloxacin should be effective in the treatment ofurinary tract infections (UTIs). This has indeedproved to be the case for both uncomplicated andcomplicated U'Tls in comparative clinical trials(table IV).

In general, ofloxacin appeared more effectivethan pipemidic acid, nitrofurantoin, amoxicillin/clavulanic acid and carbenicillin, Ofloxacin wasusually at least as effective as, and occasionallymore effective than, cotrimoxazole or other fluor­oquinolones (ciprofloxacin, pefloxacin, norfloxacinand fleroxacin). Similar efficacy between ofloxacinand fosfomycin, aztreonam, piperacillin or ceftaz­idime was observed in isolated comparisons. Cip­rofloxacin appeared more effective than ofloxacinin the treatment of pseudomonal infection in par­aplegic patients with neurogenic bladder dysfunc­tion (Burgdorfer et al. 1991; table IV).

The usual dosage of ofloxacin was 100 or 200mgtwice daily for 3 to 10 days administered orally:100mg twice daily for 3 days was the most frequentregimen for uncomplicated lower UTI and 200mg

843

twice daily for 5 to 10 days for upper or compli­cated UTI. The drug was administered intraven­ously in some studies of patients with complicatedUTI (Cox 1991; Schalkhauser 1990). Several stud­ies used a once daily regimen (Basista 1991; Hoo­ton et al. 1991; RugendorfT 1987; Schalkhauser1990; Wittenberger 1986). The use of ofloxacin 100,200 or 400mg as a single dose in patients with un­complicated UTI has also been investigated innoncomparative or dose-finding studies (Raz et al.1988; Vogt et al. 1988) and in some comparativestudies listed in table IV (Homer 1987; Hooton etal. 1991; Knothe et al. 1985; Naber & Thyroff-Frie­singer 1990; Ode et al. 1987). A single dose of of­loxacin 100mg sometimes gave a low bacteriolog­ical response rate (70 to 80%), which was notconsidered adequate by some authors (Ode et al.1987). The higher single dose of ofloxacin 200mgappeared comparable in efficacy to fosfomycin 3gor cotrimoxazole (trimethoprim 160mg + sulpha­methoxazole 800mg) as single daily doses (Naber& Thyroff-Friesinger 1990). A single dose of oflox­acin 400mg was significantly (p < 0.05) less effec­tive than cotrimoxazole for 7 days in women withacute cystitis (Hooton et al. 1991). Single-dosetreatment with ofloxacin appears unlikely to offeran appropriate treatment for uncomplicated UTI.

Ofloxacin has been successfully used in renaltransplant patients with UTI during an open-labelstudy (Vogt et al. 1988) and in comparison withcotrimoxazole (Prati et al. 1988) [table IV].

Ofloxacin 400mg once daily for 3 weeks was sig­nificantly more effective than cotrimoxazole 320/1600mg once daily for 3 weeks in eradicating ur­inary bacteria in elderly patients with asympto­matic bacteriuria, although both groups showedhigh rates of reinfection and superinfection soonafter treatment (Giamarellou et al. 1991). Ofloxa­cin 200mg and cotrimoxazo1e 160/800mg, eachtwice daily for 3 to 7 days for acute cystitis, weresimilarly effective in reducing vaginal colonisationby E. coli for up to 30 days after therapy (Tartag­lione et al. 1988).

In comparative clinical trials listed in table IVpatients with pathogens resistant in vitro to theantibacterial agents evaluated were invariably ex-

844 Drugs 42 (5) 1991

Table IV. Summary of studies comparing ofloxacin (OFL) with other antibacterial agents in patients with urinary tract infection

Reference Urinary tract infection Dosagea Efficacyb

(no. of patients) (mg) (% responding)

Amoxicillin/clavulanic acid (AMO/CLA)

Knothe et al. (1985) Lower (50) OFL 100 sd 78AMO/CLA 500 tid x 3d 50

Knothe et al. (1985) Upper (50) OFL 200 bid x 7d 100AMO/CLA 500 bid x 7d 82

Aztreonam (AZM)

Arakawa et al. (1990) Uncomplicated (85) OFL 300 x 3d 911M AZM 1000 sd 86

Carbenicillin (CAR)

Cox (1989) Uncomplicated (38) OFL 200 bid x 10d 100"CAR 764 qid x 10d 75

Ceftazidine (CFZ)

Cox (1991) Pyelonephritis (68) IV OFL 200 bid x 5-9d 97IV CFZ 1000 bid x 5-9d 100

Ciprofloxacin (CIP)BurgdOrfer et al. (1991) Complicated with OFL 200 bid x 10-14d 46

Pseudomonas spp. (47) CIP 500 bid x 10-14d 77"

Kromann-Andersen et al. Complicated (61) OFL 100 bid x 7d 83

(1988) CIP 250 bid x 7d 68

Cotrimoxazole (TMP/SMX)

Basista (1991) Uncomplicated (97) OFL 200 od x 3d 87

TMP/SMX 160/800 bid x 7d 85

Cox et al. (1986) Uncomplicated (142) OFL 200 bid x 7d 92TMP/SMX 160/800 bid x 7d 96

Cox (1989) Complicated (125) OFL 200 bid x 10d 92TMP/SMX 160/800 bid x 10d 95

Hoff ler (1987) Various (40) OFL 100sd 70TMP/SMX 160/800 bid x 3d 60

Hooton et al. (1991) Cystitis (130) OFL 400 sd 81"OFL 200 od x 3d 89TMP/SMX 160/800 bid x 7d 98

Knothe et al. (1985) Lower (59) OFL 200 bid x 7d 94TMP/SMX 160/800 bid x 7d 81

Knothe et al. (1985) Upper (66) OFL 200 bid x 7d 72TMP/SMX 160/800 bid x 7d 91

Latham et al. (1986) Acute lower (60) OFL 200 bid x 7d 94

TMP/SMX 160/800 bid x 7d 93Naber & Thyroff-Friesinger Uncomplicated (158) OFL 200 sd 81(1990) TMP/SMX 160/800 sd 87Ode et al. (1987) Uncomplicated (137) OFL 100 sd 73

TMP/SMX 160/800 bid x 3-7d 93Prati et al. (1988) Complicated in renal OFL 200 bid x 10d 90

transplant patients (40) TMP/SMX 160/800 bid x 6d 76Velluci et al. (1987) Complicated (40) OFL 200 bid x 5-10d 100

TMP/SMX 160/800 bid x 5-10d 65Walstad et al. (1986) Cystitis (200) OFL 100 bid x 3d 92

TMP/SMX 80/400 bid x 3d 88

Ofloxacin: An Update 845

Table IV. Contd

Reference Urinary tract infection Dosagea Efficacyb

(no. of patients) (mg) (% responding)

Fleroxacin (FLE)

Kawada et al. (1990b) Complicated (243) OFL 200 tid x 5d 87

FLE 300 od x 5d 85

Naber &Sigl (1988) Complicated (65) OFL 200 bid x 7d 91

FLE 400 od x 7d 80

Fosfomycin (FOS)

Naber &Thyroff-Friesinger Uncomplicated (239) OFL 200 sd 81

(1990) FOS 3000 sd 82

Nitrofurantoin (NIT)

Ludwig & Pauthner (1987) Lower (78) OFL 100 bid x 3d 81

NIT 100 tid x 3d 66

Propaczy (1985) Lower (63) OFL 200 bid x 3-7d 82

NIT 100 tid x 3d 82

Norfloxacin (NFX)

Rugendorff (1987) Complicated (30) OFL 200 od x 7d 93

NFX 400 bid x 10d 80

Pefloxacin (PEF)

Magyar et al. (1989) Severe (55) OFL 200 bid x 6-14d 85

PEF 400 bid x 6-14d 86

Pipemidic acid (PA)

Kishi et al. (1984) Complicated (228) OFL 200 tid x 5d 89'PA 500 qid x 5d 72

Wittenberger (1986) Lower (50) OFL 100 od x 3-7d 81PA 400 bid x 7d 53

Piperacillin (PIP)

Schalkhiiuser (1990) Complicated (50) IV OFL 200 od x 7d 96IV PIP 4000 tid x 7d 82

a Administered orally unless otherwise specified.

b Wherever possible the bacteriological response rate was used at the longest follow-up. Clinical responses usually showed a

close correlation with bacteriological responses but there were greater differences between studies for clinical response, because

of the widely different definitions used for clinical cure/improvement in different countries.

Abbreviations: od =once daily ; bid = twice daily ; tid =3 times daily; qid =4 times daily ; sd = single dose ; d =day; 1M= intramuscular;

IV = intravenous; , p < 0.05.

eluded from analysis. In some cases, it was clearthat exclusion because of resistance to ofloxacin wasless frequent than with the comparator agent (Cox1989; Naber & Thyroff-Friesinger 1990). Thiswould have clinical significance if ofloxacin wereto be used empirically for uncomplicated UTI ingeneral practice.

The consensus of recent reviews (Corrado 1991b;Krornann-Andersen & Nielsen 1990; Naber 1989;

Nicolle 1989; Nielsen & Madsen 1989) concerningthe use of ofloxacin or fluoroquinolones for thetreatment of UTIs is that current standard therapyfor simple uncomplicated lower UTI, such as ashort course of cotrimoxazole, is adequate at thepresent time, producing clinical and bacteriologicalcure in 85 to 100% of patients. However, ofloxacinoffers a valuable alternative for complicated andsevere forms of urinary tract infection, where intra-

846

venous and oral therapy can be used interchange­ably.

5.1.2 ProstatitisBacterial prostatitis occurs at a low frequency,

making clinical trials somewhat difficult to under­take. Penetration of many antibacterial drugs intoprostate tissue is low, and the clinical efficacy ofsome accepted agents such as carbenicillin and co­trimoxazole may be poor (Naber 1989; Nielsen &Madsen 1989). Ofloxacin has good penetration intoprostate tissue (section 4.2) and should offer an ef­fective alternative. Small open-label studies withofloxacin 300 to 600mg daily for 7 to 14 days inacute infection and for up to 2 months in chronicinfection have shown clinical and bacteriologicalcure rates of 80% or more (Guibert & Acar 1986;Suzuki et al. 1984; Tallarigo et al. 1989). 22 of 23patients (96%) with acute prostatitis, predomi­nantly caused by enteric Gram-negati ve bacteria,remained cured at 7 months' follow-up after of­loxacin 200mg twice daily for 24 to 90 days (Remyet al. 1988). Corrado (1991b) briefly summarisedresults of 117 patients treated with ofloxacin forprostatitis, but insufficient details were providedfor analysis. Cox (1989) found ofloxacin 300mgtwice daily was more effective than carbenicillin764mg 4 times daily (100% vs 57% clinical cure,p = 0.048) in 23 evaluable patients with chronicprostatitis treated for 6 weeks. The lower efficacywith carbenicillin may in part be related to poorcompliance, because of inconvenient adverse ef­fects. Ofloxacin may offer a suitable first-line treat­ment for acute and chronic prostatitis, but furtherstudy is required to determine recurrence rates andappropriate treatment dosage and duration.

5.1.3 Sexually Transmitted Diseases

Gonococcal InfectionsSingle oral doses of ofloxacin 100 to 600mg

(usually 200 or 400mg) were essentially 100% ef­fective bacteriologically in eradicat ing Neisseriagonorrhoeae in male and female patients with un­complicated gonorrhoea (urethritis or cervicitis)based on the results of dose-finding and compar-

Drugs 42 (5) 1991

ative clinical trials enroling more than 1000patientsin total (Ariyarit et al. 1986; Aznar et al. 1987;Blacket al. 1989; Blomer et al. 1988; Chan et al. 1986;Covino et al. 1990; Henderson 1987; Judson et al.1986; Lutz 1989; Rajakumar et al. 1988; Rich­mond et al. 1988; Smith et al. 1991 ; Tack et al.1989;Tanphaichitra et al. 1986).The drug also ap­peared effective in eradicating N. gonorrhoeae inpatients with associated pharyngeal or anorectal

gonorrhoea (Corrado 199Ia). Ofloxacin was equallyeffective against penicillinase- and non-penicilli­

nase-producing N. gonorrhoeae (Chan et al. 1986;Covino et al. 1990; Smith et al. 1991).

Clinical cure rates varied widely between stud­ies (80 to 100%), being dependent on many factors(definition , inclusion/exclusion criteria , durationoffollow-up, etc). Postgonococcal urethritis was re­ported in some trials, occurring in 24% of patientsstudied by Ariyarit et al. (1986). When concurrentChlamydia trachomatis infection was present,single-dose ofloxacin did not reliably cause chla­mydial eradication (Black et al. 1989; Blorner et al.1988; Covino et al. 1990; Smith et al. 1991 ).

The results of trials comparing single-dosetherapy with ofloxacin or other antibacterial drugsare summarised in table V. Ofloxacin was at leastas effective as the comparator drugs (amoxicillin,ceftriaxone and pivampicillin) . However, it is im­portant to note that, except for the comparison withintramuscular ceftriaxone, the studies occurred inareas where penicillinase-producing strains of N.

gonorrhoeae were not a major clinical problem.

Ofloxacin would therefore appear to offer a sim­ple single-dose oral treatment for gonorrhoea , inparticular in areas where resistance to standardtreatments has become a problem. However, theusual restriction of ofloxacin in children and preg­nant women may limit the usefulness of thistherapy for gonorrhoea (Black et al. 1989). Fur­thermore, reports with other fluoroquinolones havenoted the appearance of fluoroquinolone cross-re­sistant gonococci (Gransden et al. 1990; Jephcott& Turner 1990; Wagenvoort et al. 1986).

Ofloxacin: An Update 847

Abbreviation: 1M = intramuscular.

Table V. Summary of studies comparing oral ofloxacin (OFL)

with other agents as single-dose therapy in patients with un­

complicated gonorrhoea

Spectinomycin (SPT) or pivampicillin (PIV)

± probenecid (PRO)

Blomer et al. OFL 300 (124) 99

(1988) SPT 2000 or PIV 97

1400 + PRO 1000

(88)

Amoxicillin (AMO) + probenecid (PRO)

Black et al. (1989) OFL 400 (100) 99

AMO 3000 + PRO 96

1000 (101)

Lutz (1989) OFL 400 (70) 99

AMO 3000 + PRO 93

1000 (82)

U. urealyticum infection. Ofloxacin, usually 400 or600mg daily for 7 days, was almost 100%effectivein eradicating such infections bacteriologically andproduced similar results as treatment with doxy­cycline, minocycline and erythrom ycin, while ap­pearing more effective than ciprofloxacin. Indeed ,ciprofloxacin has been shown to have unacceptablyhigh relapse rates even at doses as high as 2g daily(Ahrned-Jushuf et al. 1988; Fong et al. 1987; Hoo­ton et al. 1990; van der Willingen et al. 1988). Of­loxacin was generally better tolerated than doxy­cycline, minocycline and erythromycin, all of whichproduced a high incidence of nausea and vomiting(Batteiger et al. 1989; Ibsen et al. 1989; Judson etal. 1986), Ofloxacin appeared similarly effective ineradicating C. trachomatis and U. urealyticum in­fection or during concurrent infection with these 2pathogens (Mogabgabet al. 1990;Vilata et al. 1989).However, a recent study indicated that neither of­loxacin nor doxycycline were particularl y effectivein eradicating U. ureaplasma when present con­comitantly with C. trachomatis (Faro et al. 1991).Neither ofloxacin, doxycycline nor erythrom ycinappeared effective in eradicating nongonococcalurethritis or cervicitis caused by Mycoplasmahom­inis (Faro et al. 1991 ; Moller et al. 1990), HoweverN. gonorrhoeae was successfully eradicated by of­loxacin when it was present concurrently with C.trachomatis (Boslego et al. 1988; Mogabgab et al.1990).

Bacteriological cure rates for proven infectionwere selected for determ ining efficacy in table VIas this was a more uniform means of comparisonbetween studies, despite the difficulty in distin­guishing failure from reinfection. Clinical cure ratesvaried widely between studies depending on manyfactors such as definition and duration of follow­up: despite being lower than microbiological curerates, intrastudy comparison of clinical cure ratesdid not reveal differences between the comparativeagents. In some studies (e.g. Kitchen et al. 1990)many additional patients were initially enroled withnongonococcal urethritis which was diagnosedclinically and without microbiological confirma­tion of C. trachomatis or U. urealyticum infection;

Bacteriological

cure rate (%)

100

98

Dose (mg) [no. of

patients evaluated]

OFL 400 (47)

1M CFX 250 (42)

Reference

Ceftriaxone (CFX)

Covino et al.

(1990)

Nongonococcal InfectionsNumerous open-label studies totalling many

hundreds of patients have examined the efficacy ofofloxacin in eradicating C. trachomatis infection inpatients with nongonococcal urethritis or cervicitis(Argenziano et al. 1989; Asano et al. 1989; Bischoff1986; Kawada et al. 1990a; Kawamura et al. 1989;Matsuda et al. 1988; Nayagam et al. 1988; Rich­mond et 'al. 1988; Watanabe et al. 1989; Yuri et al.1988). Ofloxacin 200mg twice or 3 times daily for5 to 21 days produced a bacteriological cure rateof 80 to 100%; the usual dosage of ofloxacin 200mgtwice daily for 7 to 14 days was generally 100%effective. Other studies in limited numbers ofpatients have also indicated that the same oflox­acin regimen may be effective in eradicating non­gonococcal infections caused by Ureaplasma urea­lyticum (Judson et al. 1986; Kawamura et al. 1989)or Staphylococcus aureus (Argenziano 1989).

Table VI summarises the results of studies com­paring ofloxacin with other antimicrobial agents inthe treatment of nongonococcal urethritis and cer­vicitis in patients with proven C. trachomatis or

848 Drugs 42 (5) 1991

Table VI. Summary of clinical trials comparing oral ofloxacin (OFL) with other antimicrobial agents in patients with nongonococcal

urethritis or cervicitis. Only patients with proven Chlamydia trachomatis or Ureaplasma urealyticum infections were included

Reference Condition Dosage (mg) Bacteriological[no. of patients evaluated] cure rate (%)

Ciprofloxacin (CIP)

Perea et at (1989) C. trechometis/U. urealyticum OFL 200 bid x 7d (19) 83(03) CIP 500 bid x 7d (25) 60

Doxycycline (DOX)

Batteiger et al. (1989) C. trachomatis OFL 300 bid x 7d (10) 100(s or 03) DOX 100 bid x 7d (8) 88

Blomer et at (1988) C. trachomatis OFL 200 or 400 bid x 9-10d (356) 99(~or 03) DOX 100mg od x 9-10d (177) 95

Boslego et aL(1988) C. trachomatis OFL 300 bid x 7d (18) 100(03) DOX 100 bid x 7d (10) 100

Faro et at (1991) C. trachomatis /U. urealyticum OFL 300 bid x 7d (20) 100 (7)3

(9) DOX 100 bid x 7d (20) 90 (25)3

Fransen et al. (1986) C. trachomatis OFL 200 bid x 9-10d (21) 95(9 or 03) DOX 200 od x 9-10d (19) 100

Judson et al. (1986) C. trachomatis OFL 300 bid x 7d (38) 82

(9 or 03) DOX 100 bid x 7d (34) 94

Kitchen et al. (1990) C. trachomatis OFL 400 od x 7d (17) 100(9 or 03) DOX 100 bid x 7d (8) 100

Mogabgab et al. (1990) . C. trschomstis/U. urealyticum OFL 300 bid x 7d (33) 97(9 or 03) DOX 100 bid x 7d (33) 97

Stein & Saravolatz (1989) C. trachomatis jU. urealyticum OFL 300 bid x 7d (16) 100(9 or 03) DOX 100 bid x 7d (18) 100

Erythromycin (ERY)Ibsen et at, (1989) C. trachomatis OFL 200 bid x 7d (43) 100

(03) ERY 500 bid x 7d (31) 97Ml2IlIer et at (1990) C. trachomatis OFL 200 bid x 7d (6) 100

(03) ERY 500 bid x 7d (31) 90

Minocycline (MIN)Vilata et al. (1989) C. trachomat is/U. urealyticum OFL 200 bid x 7d (40) 92

(03) MIN 100 bid x 7d (40) 90

a First results for C. trachomatis and in parentheses for U. urealyticum when present concomitantly with C. trachomat is.

Abbreviations: od = once daily; bid = twice daily; d = days.

many of these patients could show persistenceof their clinical signs regardless of the treatmentgiven.

Using a regimen of ofloxacin 600mg daily for 2weeks repeated as 3 courses with 3- to 4-week restperiods, Grima et aJ. (l99l) reported clinical plusbacteriological cure in 91% of 91 acute and 85% of48 patients with chronic C. trachomatis infection.They found ofloxacin more effective and better tol-

erated than the previous regimens (minocycline,rifampicin and miocamcyin) used in their depart­ment.

In conclusion, ofloxacin offers a valid and ef­fective alternative to standard therapy with doxy­cycline in patients with proven C. trachomatis ur­ethritis or cervicitis, but further study is requiredto determine its efficacy against infections causedby U. urealyticum.

Ofloxacin: An Update

Other Conditions

Weidner et al. (1990) determined the efficacy ofofloxacin 200mg twice daily for 2 weeks in 70 menwith uncomplicated acute epididymitis (including44 patients with definite bacterial aetiology - gen­erally C. trachomatis and/or other common urin­ary tract pathogens) . Six and 3 patients remainedculture posit ive at the end and 12 weeks after theend of treatment, respectively. At 12 weeks 14% ofall patients complained of persistent symptoms andin 20% the epididymitis was still infiltrative. Othernoncomparative studies, generally including smallnumbers of patients, have indicated that ofloxacin200mg twice daily for 2 to 3 weeks is highly effec­tive against acute or chronic epididymitis usuallycaused by C. trachomatis (Ekwere 1991; Melekos& Asbach 1987; Weidner et al. 1987).

All 30 women with acute salpingitis or endo­metritis primarily caused by C. trachomatis or En­terobacteriaceae were clinically and bacteriologi­cally cured after 21 days' treatment with ofloxacin200mg twice daily plus amoxicillin/clavulanic acid2 to 4 g/day (Verhoest et al. 1989). Ofloxacin ordoxycycline in combination with piperacillin werereported to be similarly effective (2 to 4% clinicalfailures) in 114 patients with acute salpingitiscaused by C. trachomatis with or without other pa­thogens, but this brief abstract did not state dos­ages or treatment duration (Judlin et al. 1988). Inanother study of 72 women with acute salpingitiscaused primarily by C. trachomatis and/or N.gonorrhoeae ofloxacin 400mg twice daily for 10days, or cefoxitin 2g intramuscularly plus proben­cid Ig orally followed by doxycycline 100mg twicedaily for 10 days, resulted in clinical cure in 95%and 97%, respecti vely (Wendel et al. 1989, 1991).Other than studies of ofloxacin in the treatment ofacute salpingitis caused by C. trachomatis or N.gonorrhoeae, there have been few recent investi­gations in other obstetric or gynaecological infec­tions except for a few patients in noncomparativetrials (Seiga et al. 1988).At the time of the previousreview (Monk & Campoli-Richards 1987) ofloxa­cin had been used successfully in a few such trialsin patients with adnexitis , intrauterine infection andparametritis. Also, a single double-blind trial com-

849

paring ofloxacin 200mg 3 times daily and amoxi­cillin 250mg 4 times daily each for 7 days in 257patients (primarily with moderately severe, un­complicated endometritis, salpingitis or Barthol­in's abscess caused mainly by E. coli. Staphylococ­cus epidermidis and Enterococcus faecalis) showedcomparable clinical and bacteriological efficacy(Takase et al. 1986).

5.2 Lower Respiratory Tract Infections

Ofloxacin has demonstrated considerable effi­cacy in the treatment of lower respiratory tract in­fections in small noncomparative open studies(Chidiac et al. 1989; Kikuchi & Onozaki 1988; LeChevalier et al. 1988, 1989; Moorhouse & Clarke1988; Muraki et al. 1988; Musial et al. 1988; San­chez Gascon et al. 1989; Tanaka et al. 1989). A fewdeserve special mention because of the unusualconditions treated or their specific mode of admin­istration.

Sato et al. (1991) treated 18 patients with diffusepanbronchiolitis with ofloxacin 600 mg/day for 3to 6 months when acute exacerbations occurredduring a 4-year period. Compared with the 2 yearsbefore and the 2 years after the introduction of of­loxacin, marked clinical improvement in pulmo­nary function and a significant reduction in thenumber of acute exacerbations were noted duringtreatment. Meek et al. (1989) treated 40 patientswith acute infectious exacerbations of chronic ob­structive pulmonary disease caused by Pseudo­monas aeruginosa using the high dosage of oflox­acin 800mg twice daily for 7 days. The outcomewas: eradication (23), superinfection (6), recurr­ence (5), persistence (3) and none valuable (3). Of­loxacin resistance did not develop . Somewhat bet­ter results were gained by Dopff et al. (1990) in 38patients with severe community-acquired pneu­monia who were treated with intra venous ofloxa­cin 200mg twice daily for II days (mean) plusintravenous penicillin 12 x 106 U/day for 5 days(mean). Patients were changed to oral ofloxacin 3.5days on average after the onset of treatment, usu­ally 2 days after apyrexia. 85% of 33 evaluable caseswere clinically cured.

850

Uncommon respiratory pathogens which wereisolated in many open-label and some controlledclinical trials were almost invariably eradicated byofloxacin . These included Mycoplasma pneumon­iae (Dopff et al. 1990; Forsberg et al. 1989; Kikuchiet al. 1990; Kikuchi & Onozaki 1988; Leroy et al.1989a), Chlamydia psittaci (Dopffet al. 1990; Hay­ashi et al. 1989; Kikuchi & Onozaki 1988; Leroyet al. I989a), Chlamydia pneumoniae (Lipsky et al.1990), Mycobacterium fortuitum (Yew et al. 1990b);Coxiella burnetii (Leroy et al. 1989a) and Legi­onella pneumophila (Leroy et al. 1989a), The latterpathogen was also successfully eradicated by oflox­acin in renal transplant patients (Wynckel et al.1991).

Table VII summarises the results of dose-find­ing and comparative clinical trials of ofloxacin ver­sus other antibacterial agents in patients with lowerrespiratory tract infections. In general, ofloxacin wasat least as effective clinically and bacteriologicallyas other agents including erythromycin, doxycy­line, cotrimoxazole, amoxicillin, amoxicillin/cla­vulanic acid, pivmecillinam, cefotaxime and otherfluoroquinolones (ciprofloxacin, pefloxacin , enox­acin , fleroxacin and tosufloxacin). The only studyto show a statistically significant superior clinicaland bacteriological efficacy for ofloxacin was incomparison with cefaclor (Fujimori et al. 1984).Definition of clinical cure and improvement var­ied considerably between studies and consequentlyso did rates ofclinical improvement or cure. Whilebacteriological eradication rates provide a moreobjective assessment of response, they were not al­ways determined because of the technical difficul­ties involved in pathogen isolation during lowerrespiratory tract infection (viral infection may befrequent). When bacteriological efficacy was deter­mined, pathogens were usually identified in only alimited number of patients assessed clinically.

Ofloxacin was usually administered orally, al­though the intravenous route has been used withsuccess compared with amoxicillin/clavulanic acid(Khajotia et al. 1990) and cefotaxime (Freytag &Zichner 1990) in more severe infections in hospi­talised patients. The usual dosage of ofloxacin was400 to 600 rug/day (occasionally 800 mg/day) for

Drugs 42 (5) 1991

10 to 14 days, divided into 2 or 3 equal daily doses.A once-daily regimen with ofloxacin has also beensuccessfully used (Maesen et al. 1987; Punakivi etal. 1990; Rademaker et al. 1990).

Studies which isolated large numbers of patho­gens (Grassi et al. 1987) or cumulated data frommany trials (Ball 1990) showed that ofloxacin pro­duced 80 to 100% eradication of most commonrespiratory pathogens including Haemophilus in­fluenzae, Klebsiella pneumoniae, Branhamella ca­tarrhalis (Moraxella catarrhalis) and S. aureus,while rates were lower for Streptococcus pneumon­iae (70 to 75%) and P. aeruginosa (about 50%).Several authors have commented on the relatively

low eradication rate for S. pneumoniae (Le Chev­

alier et al. 1989; Rademaker et al. 1990; Thys etal. 1991) and occasionally patients with suspectedS. pneumoniae infection were excluded (Forsberget al. 1989).

Gaffuri Riva et al. (1990) examined the pro­phylactic efficacy ofofloxacin in a randomised trialin 60 patients with chronic obstructive pulmonarydisease. Patients received ofloxacin 300mg twicedaily, amoxicillin Ig twice daily or placebo for aweek during each of 3 consecutive winter months.While the number of monthly infections appearedreduced with ofloxacin (0.5) and amoxicillin (0.8)compared with placebo (1.7), statistical signifi­cance was not reached.

In conclusion, ofloxacin prov ides an effectivetreatment for community- or hospital-acquiredlower respiratory tract infections, including acuteexacerbation ofchronic bronchitis and pneumonia,and it may be considered as an alternative tostandard therapies for these conditions. Howeverreservation must be expressed concerning its usewhen S. pneumoniae infection is suspected or insituations where such infection might be expectedwith some frequency . Ofloxacin has a clearer roleto play in the treatment of severe respiratory in­fections where pathogen susceptibility is proven andagainst usual respiratory pathogens, especially sincethe drug can be used both orally and intravenously.

Ofloxacin: An Update

5.2.1 Pulmonary TuberculosisAlthough preliminary study has indicated that

ofloxacin is effective when combined with otherstandard antitubercular drugs in the primary treat­ment of pulmonary tuberculosis (Tsukamura et al.1986), this approach has not been pursued or ad­vocated as standard agents (rifampicin, isoniazidand pyrazinamide) are effective and well-estab­lished. Nevertheless, ofloxacin may have a role toplay in the treatment of intractable tuberculosiswhere resistance has developed to standard agentsor where toxicity precludes their use.

The effects of ofloxacin 300 to 800 mg/day (onceor twice daily) for longer than 6 months have beenexamined in several open-label studies totallingseveral hundred patients resistant to standard an­titubercular therapy (Besozzi et al. 1991; Matsu­moto et al. 1988; Nakae et al. 1991; Truffot-Pernotet al. 1990; Tsukamura et al. 1985; Tsunekawa etal. 1987; Yew et al. 1990a). Invariably, the patientsreceived concomitant antitubercular therapy witheither continuation of established drugs and/or ad­dition of second-line agents . Not surprisingly, spu­tum culture conversion rates varied widely be­

tween studies from 14 to 67% (mean 40 to 50%).The variability probably depended on many fac­tors, including disease severity and concomitantmedication. When negative conversion did takeplace it occurred within 3 to 5 months of the onsetof ofloxacin treatment. Lack of conversion wasoften associated with the acqu isition of resistanceto ofloxacin by Mycobacterium tuberculosis (Nakaeet al. 1991; Truffot-Pernot et al. 1990; Yew et al.1990a). Yew et al. (l990a) also found that sputumconversion was more rapid with ofloxacin 800mg

once daily than with 300mg once daily, and thehigher dose tended to be more effective (67% vs

50%). In a briefly reported study (Hellstrom et al.1990), treatment failure or chronic infection withmultiresistant strains ofM. tuberculosis were treatedwith either ofloxacin or cycloserine, in combina­tion with capreomycin, para-aminosalicylic acidand protioamide. Ofloxacin 12 mg/kg once dailyproduced greater than 90% conversion by the fourthmonth, with similar efficacy to cycloserine, but the

851

latter drug, unlike ofloxacin, was not well toler­ated.

Giogis et al. (1988) treated 7 tuberculosis patientswith renal insufficiency with ofloxacin 300mg oncedaily or every other day for 6 to 15 months in com­bination with standard agents . All patients wereclinically and microbiologically cured, and oflox­acin was well tolerated.

In an isolated case report, a patient with severemiliary tuberculosis with liver involvement devel­oped hepatic, ocular and vestibular toxicity duringtreatment with isoniazid, rifampicin, streptomycinand ethambutol. Substitution with ofloxacin 200mg3 times daily plus cycloserine led to rapid resolu­tion of adverse effects and sputum conversion.Treatment was continued for 9 months with no ad­verse effects and the patient remained cured at 9months' follow-up (Alegre et al. 1990).

A combination of ofloxacin and isoniazid afterbronchoscopic examination may be useful in pre­venting exacerbation of pulmonary tuberculosis(Sakatani et al. 1988).

In conclusion, ofloxacin would appear to offera useful second-line agent for the treatment of in­tractable or resistant tuberculosis and when stand­ard therapy is not well tolerated. However, optimaldosage and treatment duration need to be defined.

5.2.2 In Patients with Cystic FibrosisSeveral authors have examined the use of of­

loxacin 400mg twice daily for several weeks in rel­atively small numbers ofcystic fibrosis patients withinfectious exacerbations caused by P. aeruginosaor S. aureus in open-label studies (Foucaud et al.1987; Meyer 1987), or in comparisons with cip­rofloxacin (Jensen et al. 1987a,b, Kurz et al. 1986)which produced similar results to ofloxacin.

The efficacy of ofloxacin appeared promisingbased on clinical improvement (e.g. lung function,clinical signs); pathogen eradication would notusually be expected with any antibacterial treat­ment. However, occasional eradication was seen insome studies. Notably, complete eradication of allmethicillin-resistant S. aureus isolates (as well asall H. influenzae strains) was seen when ofloxacinwas combined with fosfomycin and 90% eradica-

852 Drugs 42 (5) 1991

Table VII. Summary of dose- finding and comparative trials of ofloxacin (OFL) compared with other antibacterial agents in patients

with lower respiratory tract infections

Reference Diagnosis Dosagea Efficacy (% patients)

(no, of patients (mg)clinical cure + bacteriologicalevaluated)improvement cure(cured alone)

Dose-f inding studyGrassi et al. (1987) Mainly acute or chronic OFL 200 bid 91 (36)

bronchitis, pneumonia (667) OFL 300 bid x m 8,7d 93 (54) 78

OFL 400 bid 92 (48)

Amox icillin (AMO)

Devogelaere & Maes Acute, acute or chronic OFL 200-300 bid x 8-22d 94 (89) 95

(1986) bronch itis (33) AMO 1000 bid or tid x 6-15d 73 (60) 73

Stocks et al. (1989) Pneumonia, acute bronchitis OFL 400 bid x 10d 93 (65) 96

(82) AMO 500 tid x 10d 92 (67) 85

Amoxicillin/clavulanic acid (AMO/CLA)

Khajotia et al. (1990) Lower respiratory tract IVb OFL 400-800 daily x 7-10d 100 (27) 95

infection (92) IVb AMO/CLA 1000-6000 daily x 94 (30) 82

7-10d

Rademaker et al, Acute or chronic bronchitis OFL 400 od x 10d 84

(1990) (95) AMO/CLA 500 bid x 10d 89

Cefaclor (CFC)Fujimori et at, (1984) Acute or chronic bronchitis OFL 200 tid x 14d 80 90

(103) CFC 250 tid x 14d 57 50

Cefotaxime (CTX)Freytag & Zichner Acute or chronic bronchitis, IV OFL 200 bid x 5-12d 90 (75)(1990) pneumonia (40) IV CTX 2000 tid x 6-17d 90 (80)

Ciprofloxac in (CIP)Kardos & Gebhardt Acute or chronic bronch itis OFL 200 bid x 5-10d 93 (36)

(1989) (29) CIP 250 bid x 3-10d 93 (53)

Ciprofloxacin (CIP), enoxacin (ENO) and pef loxacin (PEF)Maesen et al. (1987) Acute or chronic bronchitis OFL 200 bid or 400-800 od x 7-10d 81

ENO 200-300 bid x 10d 59PEF 200 bid x 10d 68CIP 250-500 bid x 10d 51

Cotrimoxazole (TMP/SMX)De Simone et al. Acute or chronic bronchitis, OFL 300 bid x 5-12d 93 (80) 86(1991) pneumonia (28) TMP/SMX 160/800 bid x 5-17d 86 (86) 79

Doxycycline

Harazim et al. (1987) Acute or chronic bronch itis, OFL 200-400 bid x 10d 94 (46)

pneumonia (219) DOX 100 bid x 10d 92 (50)Punakivi et al. (1990) Acute or chronic bronchitis OFL 400 od x 10-14d 99 (77)

(178) DOX 100 od x 10-14d 96 (63)

Erythromycin (ERY)

Forsberg et al. (1989) Pneumonia excluding OFL 200 bid x 5-10d 85 83S, pneumoniae (68) ERY 500 bid x 5-10d 82 75

Ofloxacin: An Update 853

Table VII. Contd

Reference Diagnosis Dosage a Efficacy (% patients)

(no. of patients (mg)clinical cure + bacteriological

evaluated)improvement cure

(cured alone)

Fleroxacin (FLE)

Hara et al. (1990) Chronic bronch itis, OFL 200 bid x 14d 77 84bronchiectasis (129) FLE 200 od x 14d 90 75

FLE 300 od x 14d 62 80

Hara et al. (1991) Pneumonia . chronic OFL 200 bid x 14d 84 70

respiratory tract infection FLE 300 od x 14d 82 75

(281)

Pivmecillinam (PIV)

Egede & Kristensen Acute or chronic bronchitis OFL 200 bid x 14d (97) 94

(1990) (81) PIV 700 bid x 14d (98) 97

Tosufloxacin (TOS)

Fujimori et al. (1989) Acute or chron ic bronchitis, OFL 200 tid x 14d 83 85

pneumonia (273) TOS 150 bid x 14d 82 79

a Treatment given orally unless otherwise stated .

b High IV dosage for 2-3 days generally changed to lower oral dosage subsequently,Abbreviations: od = once daily ; bid = twice daily : tid = 3 times daily; m = mean; d = days ; IV = intravenous.

tion of P. aeruginosa isolates when it was com­bined with azlocillin or ceftazidime (Foucaud et aI.1987). However, development of resistance couldoccur in P. aeruginosa infection (Foucaud et al.1987).

The role of fluoroquinolones in cystic fibrosishas been reviewed (Grenier 1989). The generalconclusions were that the fluoroquinolones appearto offer an effective oral therapy versus traditionalparenteral therapy with {1-lactams or aminoglyco­sides. Further study is warranted in larger numbersof patients: the clinical significance of fluoroquin­olone resistance development in P. aeruginosaneeds to be better defined and strategies developedto limit this, and the use of fluoroquinolones inchildren with cystic fibrosis warrants investigation.Some studies of ofloxacin (Foucaud et al. 1987;Meyer 1987)enroled cystic fibrosis patients aged 5to 18 years, without notable toxicity (especial1y ar­ticular, see section 6).

5.3 Otorhinolaryngological Infections

Many open-label studies have indicated that of-

loxacin (usual1y 300 to 600mg daily for 1 to 2weeks) can be effective in the treatment of variousotorhinolaryngological infections, including otitismedia, tonsillitis, pharyngitis, sinusitis and oralcavity disease (Bernabei et al. 1989; Honmura etal. 1984; Iwasawa 1984; Lenarz 1986; Pappalardoet al. 1989; Sanbe et al. 1984; Sugita et al. 1984;Yamamoto et al. 1984). Almost invariably smallnumb ers of patients were enroled which precludedany definite conclusions. Compiled data for largernumbers of patients were discussed previously byMonk and Campoli-Richards (1987). At that timeofloxacin 300mg 3 times daily had been shown tobe comparable c1inical1y and bacteriological1y toamoxicillin 250mg 3 times daily in tonsillitis (Sa­saki et al. 1984) and pipemidic acid 500mg 4 timesdaily in otitis media (Kawamura et al. 1984). Fewnotable studies have been published subsequently.A double-blind comparison of ofloxacin 200mg 3times daily and talampicillin 250mg 4 times dailyfor 3 to 7 days in 300 patients with periodontalinfections, pericoronitis or osteitis of the jaw

854

showed 79% clinical efficacy with both treatments(Sasaki et al. 1987). Two open studies of patientswith chronic otitis media or externa caused by P.aeruginosa have indicated erad ication rates of 44%(Geyer 1988) and 95% (Oberascher & Karas 1988).Clearly, this eradication of P. aeruginosa with anoral medication deserves further study, as thosepatients would normally only have recourse to par­enteral therapy. Ofloxacin deserves further con­trolled study in the otorhinolaryngological field toallow definitive conclusions as to its potential placein therapy .

5.3.1 Topical TreatmentKimura et al. (1991) have recently studied a

controlled-release periodontal insert of ofloxacin(PT-Ol) in 27 patients with periodontitis. Whenused weekly in combination with supragingivalscaling it significantly reduced subgingival floracompared with placebo or untreated controls.However, it no longer produced a significant effectwhen used in combination with root planing andsubgingival scaling, which alone was very effectivein eliminating subgingival microflora.

Several studies have examined the efficacy of anew otic solution of ofloxacin in patients with oti­tis media. A preliminary dose-finding study in 52patients with suppurative otitis media revealedsimilar clinical efficacy rates with 0.3% and 0.5%solutions but somewhat lower efficacy with a 0.1%solution (Kawamura et aI. 1990). A more detailedcomparison of 0.3% and 0.5% solutions in 170patients with acute or chronic suppurative otitismedia also found equivalent clinical and bacter­iological efficacy with the 2 formulations (Baba etal. 1990c), and the 0.3% solution has been subse­quently used. Suzuki et aI. (1991) recommendednot exceeding 2 weeks' continuous treatment as be­yond this there was no increase in bacterial erad­ication rate, but risk of fungal superinfection wasincreased .

Preliminary studies in children with purulentotitis media and externa showed that the 0.3% so­lution applied once or twice daily produced similareffects, with greater than 90% 'excellent or good'

Drugs 42 (5) 1991

clinical responses and 93% bacterial eradication(Baba et al. 1990b; Ohyama et al. 1990).

Baba et al. (1990a) compared 0.3% ofloxacin so­lution with placebo in 204 evaluable patients withchronic suppurative otitis media, all of whom werereceiving oral cephalexin concomitantly. Thisdouble-blind comparison showed significantlyhigher clinical response (72 vs 50%) and bacterio­logical eradication (80 vs 46%) with the ofloxacinotic solution .

Comparison with other topical antibacterialtreatments for otitis media and externa are war­ranted for this ofloxacin otic solution

5.4 Skin and Soft Tissue Infections

Ofloxacin has been used to treat a wide varietyof skin and soft tissue infections of mild to mod­erate severity. Cumulated data for a large numberof Japanese patients were discussed in the previousreview of ofloxacin (Monk & Campoli-Richards1987), and there have also been a number of open­label studies in limited numbers of patients (DiPrima et aI. 1988; Fritzen et aI. 1986). Compara­tive studies discussed previously indicated that of­loxacin 200mg twice daily was at least as effectiveas doxycycline or cotrimoxazole at usual dosagesin the treatment of surgical wound infections (Roe­kaerts & Deleers 1985),but only a few patients wereassessed. Ofloxacin 200mg 3 times daily was at leastas effective as cefaclor 250mg 3 times daily in a 2­week double-blind comparison in 241 patients withuncomplicated moderately severe suppurative skinand soft tissue infections (Fujita et aI. 1984). Morerecently, ofloxacin 300 or 400mg twice daily andcephalexin 500 to 1000 rug/day for 10 days pro­duced identical clinical response rates (95%) in 72patients with mild to moderate soft tissue infection(Powers 1990). As noted by Fong (1989) most mildto moderate skin and soft tissue infections can befavourably treated with local debridement anddrainage without antibacterial therapy . In addi­tion, the use of a broad spectrum agent like oflox­acin as empirical treatment has been questioned,as the infecting pathogens are almost invariablystreptococci and staphylococci (Fong 1989; Powers

Ofloxacin: An Update

et al. 1990). Skin and soft tissue infections in dia­betic patients are more often mixed, including P.

aeruginosa. S. aureusand B. fragilis, and ofloxacinmight be considered appropriate in these patients(Leslie et al. 1989; Sapico 1989).

Ofloxacin may , however, offer an advantage inmore severe skin and soft tissue infections whereGram-negative aerobic bacteria, as well as strep­tococci and staphylococci, are the major patho­gens. Hospitalisation is frequently required to ad­minister parenteral antibacterial therapy" In a pilotstudy (Lentino et al. 1991) 18 of 21 patients (86%)with serious skin and soft tissue infection (mainlycellulitis) were cured after treatment with ofloxacin400mg twice daily for up to 14 days , initially ad­ministered intravenously and changing to the oralroute after at least 3 days. Gentry et al. (1989) com­pared oral ofloxacin 400mg twice daily and intra­venous cefotaxime 2g 3 times daily for an averageof 12 days in 93 evaluable patients with seriousskin and soft tissue infections (mainly wound in­fections and abscesses). Multiple pathogens werecommonly isolated, including S. aureus, E. coli,Klebsiella spp. , P. aeruginosa, Serratia marcescens,Proteus/Providencia spp. and Enterobacter spp. Pa­thogen persistence after therapy occurred in 22.5%of cefotaxime-treated patients compared with 10%of ofloxacin recipients. More patients receiving of­loxacin were cured (84 vs 58%) and the remainderwere improved except for I failure in each group.In conclusion, ofloxacin was at least as effective ascefotaxime in serious skin and soft tissue infectionbut has the advantage of oral administration, whichmay allow outpatient treatment, shortening theduration of hospitalisation and permitting consid­erable cost saving.

Several other studies in more specific , unusualindications deserve mention. Yew et al. (1989a)successfully treated 8 of 9 patients with Mycobac­teriumfortuitum sternotomy wound infection withofloxacin 300 to 1200 rug/day for 3 to 6 monthsin combination with amikacin 500 rug/day for 3to 8 weeks. They subsequently successfully treated3 (Yew et al. 1989b) and 7 (Yew et al. 1990d)patients with the same condition with otloxacin600mg once daily alone for approximately 3 to 6

855

months (usually for 3 months after wound heal­ing).

A preliminary study of ofloxacin 400mg or pe­floxacin 800mg once daily as monotherapy dem­onstrated similar and significant clinical improve­ment of 17 patients with leprosy who had not beenpreviously treated (Grosset et al. 1990). Mono­therapy with 22 consecutive doses eradicated 99.9%of the initial Mycobacterium leprae load. Furtherexamination of tluoroquinolones as an adjunct tostandard leprosy therapy would therefore seem jus­tified.

5.5 Bone and Joint Infections

Dellamonica et al. (1989) treated 17 patientswith chronic osteomyelitis with ofloxacin 200mgtwice or 3 times daily for 4 to 7 months; 2 patientsalso received amoxicillin. Outcome with long termfollow-up included 12 patients cured, I superinfec­tion and 4 primary failures. Brouqui et al. (1989)used the same ofloxacin regimen, usually in com­bination with other antibacterial agents, in 23patients with osteitis. The outcome for 12 evalu­able patients with adequate long term follow-up in­cluded 8 cures, I superinfection, 2 primary failuresand 1 relapse. 115 patients with post-traumatic os­teomyelitis received ofloxacin 200mg 3 times dailyfor an average of 22.4 days , usually as monother­apy (Ketterl et al. 1988). Expected pathogens wereencountered, primarily S. aureus, S. epidermidis,streptococci, and P. aeruginosa, and more than 90%were eradicated at the end of treatment. Long termfollow-up revealed 98 cures (85%), 4 improve­ments, 5 primary failures, 2 superinfections and 6reinfections. More recently, Scully et al. (1991)treated 16 patients with osteomyelitis caused bymultiresistant bacteria using ofloxacin 400mg twicedaily for a mean duration of 121 days. 14 patientswere clinically cured at the end of treatment and2 showed relapse during a mean 28-month follow­up period.

5.6 Enteric Infections

Studies in patients with enteric infections causedby Salmonella spp. (usually S. typhi, S. typhimu­rium, S. enteritidis. S. paratyphii or Shigella spp.

856

(S; flexneri, S. dysenteriae) have shown that oflox­acin (usuaIly 400 rug/day, occasionally up to 800rug/day) for I to 2 weeks was essentiaIly 100% ef­fective clinicaIly and bacteriologically in eliminat­ing infection (Akhtar et al. 1989; Biron et al. 1990;Lang et al. 1990; Lo 1988; Ohnishi & Murata 1990;Sabbour & Osman 1990; Stahl et al. 1986b; Tan­phaichitra & Srimuang 1988; Tigaud et al. 1989;

Ulutan et al. 1988; Wang et al. 1989; Yousaf &Sadick 1990). Most of these studies were noncom­

parative and included patients who had been pre­viously unresponsive to chloramphenicol (Ohnishi

& Murata 1990; Yousaf & Sadick 1990) or isolatesresistant to other antibiotics (chloramphenicol,ampicillin, cotrimoxazole) [Akhtar et al. 1989;Wang et al. 1989]. All studies of enteric infectionused the oral route of administration for ofloxacin;the parenteral formulation has not been used.

Comparison of ofloxacin 200mg twice daily

(n = 35) and chloramphenicol 500 to 750mg 4 timesdaily (n = 38) each for 2 weeks revealed equivalent

100% efficacy in patients with S. typhi typhoid fe­ver (Akhtar et al. 1989). However, 85% of oflox­

acin recipients were afebrile within 3 days whilemore than 7 days was required for a similar pro­

portion of patients receiving chloramphenicol tobecome afebrile .

Thus, ofloxacin offers an effective therapy forpatients with salmonellosis or shigellosis. It should,however, be noted that fluoroquinolone cross-re­sistance has emerged in S. typhimurium duringtreatment with ciprofloxacin (Howard et al. 1990;

Piddock et al. 1990).

A single study has indicated that a l-day courseof ofloxacin 200mg 8-hourly and even a single doseof 400mg can be effective in the treatment of shi­gellosis (Akalin et al. 1989). This simplified regi­men deserves further study because of its promo­tion of compliance and improved economy.

Ofloxacin does not appear particularly effectivein eradicating Helicobacter pylori in patients withgastritis or gastrointestinal ulceration (Bayerdorfferet al. 1987a, b; Burette et al. 1990; Glupczynski etal. 1987).

Drugs 42 (5) 1991

5.7 Peritonitis in CAPD Patients

Chan and colleagues have published severalstudies evaluating orally administered ofloxacin forthe empirical treatment of peritonitis in CAPDpatients. Usual pathogens (most commonly S. au­reus, S. epidermidis, streptococci, Pseudomonas andAcinetobacter species) were encountered. Treat­ment of 10 episodes of peritonitis with ofloxacin400mg followed by 200mg daily for a total of 10days resulted in a 50% cure rate compared with an83% cure rate for 18 episodes treated with oflox­acin 400mg foIlowed by 300mg daily for a total of10 days (Chan et al. 1988). This latter regimen wasused in their subsequently reported comparativetrials. The ofloxacin regimen proved superior tointraperitoneal tobramycin 8 mg/L for 10 days in46 assessable episodes (cure rates 75 and 52%, re­spectively) [Chan et al. 1989a], but somewhat lesseffective than intraperitoneal vancomycin 30 mg/L plus aztreonam 250 mg/L for 10 days in 45 as­sessable episodes (cure rates 77 and 87%, respec­tively) [Cheng et al. 1991]. However, in 110 as­sessable episodes, the cure rate of 78% with thisofloxacin regimen was not significantly improvedby concomitant administration of rifampicin 300mgdaily for 10 days (81%) and was not significantlydifferent from combined intraperitoneal adminis­tration of cephalothin 250 mg/L plus tobramycin8 mg/L for 10 days (81%) [Chan et al. 1990]. It isrecommended that oral therapy with ofloxacin beused as an alternative empirical treatment for peri­tonitis in CAPD patients while culture results arepending.

5.8 Septicaemia

88 patients with septicaemia (primarily causedby Gram-negative bacteria and/or Gram-positivecocci) received intravenous ofloxacin 200mg 12­hourly for 10 days (mean) [Doco-Lecompte & Mo­dai 1989]. 62 patients received monotherapy andthe remainder received an arninoglycoside con­comitantly. 89 of 94 pathogens were eradicated(95%) and clinical cure was obtained in 81 patients(92%). Death occurred in 3 patients, relapse in 2,

Ofloxacin: An Update

superinfection in I and persistence in I (acquisi­tion of resistance by S. epidermidisi.

5.9 Immunocompromised andCancer Patients

5.9.1 TreatmentIn a briefly reported study (Sawada et al. 1991b)

II of 17 patients with haematological malignancyand secondary infection (65%) were clinically curedafter treatment with ofloxacin 200mg 3 times daily(duration not stated). Maiche (1989) treated 31cancer patients with infection (urinary tract, res­piratory tract or skin) caused by multiresistant pa­thogens (S; aureus, S. epidermidis, K. pneumoniae,Pseudomonas spp .) with ofloxacin 200mg twicedaily for 6 to 15 days. 29 patients (94%) were bac­teriologically cured and the other 2 developed S.epidermidis septicaemia. The same group (Maiche& Teerenhovi 1989) randomly assigned 16 cancerpatients with septicaemia or pneumonia to receiveoral ofloxacin 200mg plus intravenous cefotaxime2g each twice daily or intravenous tobramycin pluscefotaxime 2g twice daily ; cure rates were 83 and90%, respectively. Raffi et al. (1990) performed apreliminary study of the combination of oral of­loxacin 200mg twice daily plus intravenous piper­acillin 4g 3 times daily as empirical treatment of24 febrile episodes in 21 neutropenic patients. 19of 22 evaluable cases (86%) responded with an im­mediate success rate (no fever within 48 hours) of46%. The combination would appear to deservefurther study.

5.9.2 ProphylaJCisOpen-label studies in neutropenic patients have

indicated a potential role for ofloxacin in the pre­vention of fever and infection (Maiche 1989; Sa­wada et al. 1991). Ofloxacin was significantly moreeffective than norfloxacin in preventing develop­ment of fever or microbiologically documented in­fection in 71 granulocytopenic patients with hae­matological malignancies after cytostatic treatment(D' Antonio et al. 1991). Arning et al. (1990) com­pared 3 different prophylactic regimens during 88neutropenic episodes in 59 patients undergoing

857

cytotoxic therapy: ofloxacin 200mg twice daily ,ciprofloxacin 500mg twice daily , and cotrimoxa­zole 160/800mg twice daily plus colistin 2 X 106U3 times daily. The median time from the onset ofneutropenia (and treatment) to the first febrile epi­sode was similar in all 3 group (15, 12 and 20 days,respectively) as were the rates of microbiologically­proven infection (23, 23 and 32%), which were pri­marily caused by Gram-positive cocci in all groups.Liang et al. (1990) also achieved positive results forofloxacin 300mg twice daily when compared withcotrimoxazole 160/800mg twice daily in 102 neu­tropenic patients following cytotoxic therapy forhaematological malignancies. Ofloxacin was clearlysuperior to cotrimoxazole with respect to the oc­currence of fever (22 vs 48%, p < 0.025) and de­velopment ofGram-negative bacteraemia (2 vs17%,p < 0.05). Similar results were obtained by Kernand Kurrle (1991) comparing ofloxacin 200mg 3times daily and cotrimoxazole 160/800mg 3 timesdaily in 128 neutropenic patients following cyto­toxic therapy for acute leukaemia. Fewer patientsreceiving ofloxacin were colonised by Enterobac­teriaceae (13 vs90%, p < 0.001) and P. aeruginosa93 vs 14, p = 0.025), or developed Gram-negativebacterial infection (4 vs 26%, p = 0.002). In theabove mentioned studies ofloxacin was better tol­erated than cotrimoxazole, which produced sig­nificantly more toxic and frequent skin reactions,often necessitating its discontinuation.

Gluckman et al. (1991) compared an absorbableand nonabsorbable regimen for prophylaxis in 44patients receiving conditioning therapy for bonemarrow transplantation: ofloxacin 400 mg/day plusamoxicillin 20 g/day versus vancomycin 450 mg/day plus tobramycin 450 rug/day plus colistin 4.5x 106 Ll/day, Mean duration of fever was shorterwith the ofloxacin regimen (9.2 vs 13.7 days, p =0.05). Gastrointestinal colonisation was preventedin a similar percentage of patients with the oflox­acin (73%) and vancomycin (68%) regimens, beingcaused primarily by Gram-positive bacteria in theformer and Gram-negative bacteria in the latter.Sepsis occurred in 5 and 12 patients, respectively,the difference in frequency being mostly due to a

858

reduction of S. epidermidis sepsis in the ofloxacingroup.

Ofloxacin 300mg twice daily was compared withvancomycin 500mg 3 times daily plus polymyxin500mg 3 times daily administered from the onsetof chemotherapy in 62 patients with haematolog­ical malignancies (Winston et al. 1990). The groupreceiving ofloxacin acquired a lower number ofGram-negative bacillary organism types per patient(0.13 vs 1.37, p < 0.00005) with a lower rate ofdocumented infection (37 vs 66%, p = 0.04) andGram-negative septicaemia (0 vs 16%, p = 0.05).the ofloxacin regimen was better tolerated, pro­ducing fewer gastrointestinal adverse effects, thusimproving compliance. With the exception of a re­duction in S. aureus colonisation and infection byofloxacin, neither regimen was considered effectiveagainst other Gram-positive organisms.

In conclusion, ofloxacin regimens appear effec­tive as prophylaxis against Gram-negative infec­tions in neutropenic patients and are generally bet­ter tolerated than standard therapies. Investigationof ofloxacin in combination with other agents toextend activity against Gram-positive bacteriawould be expected in future .

In the above mentioned studies development ofresistance to ofloxacin did not appear to occur.During prophylactic administration of ofloxacinpneumococcal pneumonia developed in I patient,but it was unproven whether resistance had beenacquired by the S. pneumoniae isolate (Saito et al.1990). .

5.10 Other Infections

Administration of ofloxacin 400 to 800 rug/dayfor about 10 days (sometimes administered intra­venously for the first few days) has proven 100%effective in the treatment of infections caused byRickettsia conorii (Bouton neuse fever, Mediterra­nean spotted fever) and C. burnetii (Q fever) [Ber­nard et al. 1989; Bertrand et al. 1988; Lecour et al.1989]. Ofloxacin 400 rug/day for 4 weeks has alsobeen used with success to treat 12 patients withBrucella melitensis infection (Baykal et al. 1989).However, Khuri-Bulos and Shaker (1991) noted

Drugs 42 (5) 1991

prompt relapse in 3 of 5 patients with B. melitensisinfection after initial resolution of symptoms fol­lowing a 3-week course of ofloxacin 400 mg/day,Furthermore, fluoroquinolone resistance has beennoted to develop in B. melitensis during treatmentwith ciprofloxacin (Acocella et al. 1990; AI-Sibai &Qadri 1990), and fluoroquinolones do not appearto attain bacteric idal intracellular concentrationsagainst B. melitensis (Garcia-Rodriguez et al. 1991).

In reviewing published Japanese data , Borr­mann and Leopold (1988) noted that ofloxacin 0.3%eyedrops decreased the clinical signs of infectionand eradicated the pathogen in 98% of 325 casesofexternal ocular infections treated, including 92%of the patients with corneal ulcers. Only 0.7% ofpatients developed side effects, an incidence com­paring favourably with the 5 to 10%adverse eventrate usually associated with aminoglycoside eye­drops. Hirose et al. (1989) successfully used topicalofloxacin in a patient with severe corneal ulcerscaused by P. aeruginosa resistant to every otherantimicrobial agent used in their hospital. Oflox­acin and gentamicin were effective in preventingophthalmia neonatorum in 123/129 cases (95%)and116/131 cases (89%), respectively, when instilledusing Crede's method (Seiga et al. 1990).

6. Clinical Tolerability

The tolerability profile of ofloxacin, based onthe results of clinical trials, was well established atthe time of the previous review (Monk & Campoli­Richards 1987), with the incidence of adverseevents in phase II to IV trials (approximately 16000patients) ranging from 2.5 to 8.5%, probably de­pending on variations in reporting methods. Ingeneral, ofloxacin was well tolerated, with severeadverse reactions necessitating drug withdrawalbeing infrequent. The most common clinical ef­fects were gastrointestinal complaints (pain/dis­comfort, nausea/vomiting, diarrhoea, anorexia),CNS effects (headache, dizziness, insomnia) andcutaneous reactions (rash, pruritus), and were ofmild to moderate intensity (Monk & Campoli­Richards 1987).

This favourable profile has been confirmed in

Ofloxacin: An Update 859

Adverse reaction

Gastrointestinal f-------~-----~

Nervous L==========:::::J

infrequent and when they did occur were probablyrelated to pathological states. This confirms pre­vious data (Monk & Campoli-Richards 1987),which showed only minor, clinically insignificantreductions in red blood cell count and haemoglo­bin as related to ofloxacin. The tolerability of of­loxacin administered orally or intravenously dur­ing phase IV studies in France has recently beenreported (Jourdan et al. 1991): 157 of 4196 patients(3.7%) experienced adverse effects and 63 (1.5%)discontinued treatment. These rates appear some­what lower than in the previously mentioned USreport , possibly being related to lower dosage in theFrench report and differences in reporting meth­ods. The nature of the adverse effects were never­theless similar.

Postmarketing surveillance of ofloxacin hasprovided significant information concerning thetolerability of the drug during clinical use in Ger­many (Jungst & Mohr 1988, 1989; Jungst et al.1990)and Japan (Sawada et al. 1991 a). These stud­ies are more likely to reveal severe and unusualadverse reactions (or interactions) of clinical sig­nificance than controlled trials, which are usuallyperformed in selected patient populations. In acomprehensive report from Germany (Hingst et al.1990), physicians reported a total of 4659 adverseevents in 1691 patients from an estimated popu­lation of 6.4 million patients treated with ofloxacin400 rug/day (assumed mean) for 7 days (assumedmean) [table VIII]. All adverse events were re­corded regardless of the considered relationship toofloxacin; for events with sufficient data to makesuch an assessment, about 25% were consideredunrelated or only remotely related to ofloxacin(Jungst & Mohr 1988). The adverse events attract­ing the most attention were hallucinations and psy­chotic reactions. There have also been case reportsof neurological problems including organic psy­chosis (Zaudig et al. 1989)and visual plus auditoryimpairment (Brensing et al. 1989). Severe renaldysfunction and a predisposition to epilepsy maybe associated risk factors (Sawada et al. 199Ia).Based on in vitro and animal studies it appears thatthe pathogenic mechanism involves bind ing of of­loxacin to the benzodiazepine-Gabaj,-receptor

65432

Incidence (% patients)

Body system

o

Nausea~=======:::JInsomnia ~==::J

Headache ~!:!!:Z:3

Dizziness ~::::!~Female genital

pruritusDysgeusia

Vaginitis

Diarrhoea

Gastrointestinaldistress

Vomiting

a summary of adverse effects reported duringclinical trials in the USA (Tack & Smith 1989). 270of 2197 patients (12.3%) treated with ofloxacin(generally 400 to 800 rug/day for 3 to 10 days) hadadverse events considered definitely or probablyrelated to treatment. This incidence of 12.3% mightbe considered high compared with previous re­ports. Figure 4 shows the rates of adverse reactionsby body system and the most frequent adverseevents. 85 patients (3.9%) discontinued treatmentbecause of adverse reactions. There was no trendtoward an increased incidence of adverse reactionsin the elderly. Laboratory test abnormalities were

Fig.4. Incidence ofadverse reactions reported in 2197 patientstreated with ofloxacin in clinical trials (Tack & Smith 1989).

GeOllal/reprodUCltve f----- --'

Skin/subcutaneous 1---_--'

Spec,al senses

Body as a whole

Nutntional/metabolic

Cardiovascular

Respiratory

860 Drugs 42 (5) 1991

Table VIII. Adverse events reported during postmarketing surveillance of ofloxacin in Germany (after Jungst et al. 1990)

Category No. of adverse events Three commonest adverse events (no.)(no. of patients)a

first second third

Nervous system 1829 (833) Nervousness (140) Hallucination (121) Sleep disorder (118)

Hypersensitivity 852 (462) Rash (137) Dyspnoea (105) Pruritus (99)

Gastrointestinal 455 (293) Nausea (125) Abdominal pain (73) Gastrointestinal disorder (62)

Cardiovascular 234 (171) Tachycardia (56) Cardiovascular disorder Hypotension (25)

(28)

Joint and muscle 160 (123) Arthralgia (40) Myalgia (29) Joint disorder (25)

Blood cells 129 (93) Thrombopenia (27) Leucopenia (26) Agranulocytosis (13)

Headache 119 (119) Headache (116) Migraine (3)

Liver 114 (76) Test abnormal (58) Liver damage (11) Hyperbilirubinaemia (7)Coagulation and 106 (77) Petechiae (20) Purpura (9) Gastrointestinal haemorrhage

haemorrhage (9)

Skin 103 (101) Increased sweating Skin disorder (19) Mucous membrane disorder

(30) (11)

Kidney and urinary 87 (60) Increased creat inine Kidney failure (11) Abnormal function (10)

tract (15)

Respiratory tract 46 (42) Pharyngitis (6) Voice alteration (5) Pneumonia (5)

Drug interaction 40 (34) Theophylline (8) Coumarins (5) Insulin (5)

Endocrine 10 (10) Metrorrhagia (4) Thyroid disorder (2) Menstrual disorder (2)

Other 375 (286) Condition worsened Asthenia (42) Death (42)

(68)

Total 4659 (1691)

a Several events may be reported for each patient.

complex, thereby acting as a GABA antagonist andpromoting CNS excitation (Davey 1988; Halliwellet al. 1991 ; Segev et al. 1988; Tsuji et al. 1988a;Unseld et al. 1990). Indeed, the CNS-stimulatingeffects of ofloxacin can be reversed by coadmin­istration of the benzodiazepine agonist, midazolam(Unseld et al. 1990).

The Japanese postmarketing monitoring studyof ofloxacin (Sawada et al. 1991a) encountered ad­verse events of a similar nature to that seen in theGerman study (Jungst et al. 1990), although at alower frequency - probably reflecting national dif­ferences in spontaneous adverse event reporting byphysicians.

Pseudomembranous colitis has been infre­quently associated with ofloxacin (Chew et al. 1990;Dan & Samra 1989; Gineston et al. 1989; Roblinet al. 1990; Taupin et al. 1991), and there has beenone reported case of photo-onycholysis (Baran &

Brun 1986). Recently, Scully et al. (1991) reportedsleep disturbance in 27 of 99 patients (27%)duringtong term treatment with the relatively high dosageof ofloxacin 800 rug/day for severe infection. Dos­age reduction led to resolution of the insomnia in5 patients, while it persisted in another 5 andeventually necessitated cessation of ofloxacintherapy. Photosensitivity was also noted in 2patients .

Crystalluria has been reported for some otherfluoroquinolones, but Verho et al. (1988) were un­able to detect ofloxacin crystals in urine or anychange in renal function after drug administrationto healthy subjects. There have been no reportedcases ofcrystalluria with ofloxacin in the literature .

Ofloxacin, and other fluoroquinolones, are notusually administered to children (or to nursingmothers or during pregnancy) because articulardamage has been induced in juvenile animals dur-

Ofloxacin: An Update

ing high-dose ofloxacin administration in toxico­logical studies (Davis & McKenzie 1989). Arthral­gia has been reported in a few adults duringpostmarketing monitoring of ofloxacin (Jungstetal. 1990). Ofloxacin has been used in some child­ren with cystic fibrosis with no clear evidence ofjo int problems - no articular complications wereseen in 37 children and adolescents aged 2 to 20years in a retrospective analysis of such patientstreated with ofloxacin (Pertuiset et al. 1989). In thesame study 9 of 63 patients (14%) treated with pe­floxacin showed arthropathy. Some relaxation ofthe contraindication for ofloxacin in children mighttherefore be considered (with strict on-going moni­toring) in view of the potential value of ofloxacinas an oral treatment in children with cystic fibrosis.

7. Drug Interactions7.1 Theophylline and Caffeine

The potential for ofloxacin to interact withtheophylline and caffeine has been studied becauseof the ability of other fluoroquinolones, particu­larly enoxacin , to cause severe drug interactionswhich may lead to serious neurological complica­tions (Davey 1988).

Studies in animals have shown that ofloxacin,unlike enoxacin or norfloxacin, has no effect on theelimination half-life of concomitantly admini­stered theophylline (Nakanishi & Okuno 1990), al­though in most studies norfloxacin also had littleor no effect on theophylline pharmacokinetic prop­erties (reviewed in Janknegt 1990). Similarly, moststudies in healthy subjects and patients have shownofloxacin has no significant effect on plasma con­centrations of concomitantly administered theo­phylline (Anon 1989; Fourtillan et al. 1986; GaffuriRiva et al. 1991 ; Sano et al. 1988; Wijnands et al.1986, 1989) or caffeine (Harder et al. 1988; Staibet al, 1987). When compared with other fluoro­quinolones in these studies, the comparative agents,and in particular enoxacin, usually caused signifi­cant and sometimes profound increases in plasmatheophylline or caffeine concentrations. However,in some studies ofloxacin has had a significant ef­fect on some aspects of theophylline pharmacoki-

861

netics. For example, the renal clearance of theo­phylline was reduced by ofloxacin (-13%) [Sano etal. 1989], although this had no signifi­cant effect on theophylline plasma concentra­tions (Sano et al. 1988), while in another study of­loxacin increased steady-state plasma concentra­tions of theophylline by about 10%(Gregoire et al.1987), although this was not thought to be of majorclinical importance by the authors. A few cases ofsevere neurologicalcomplaints during ofloxacin andtheophylline coadministration have been noted inpostmarketing surveillance studies (Jungst & Mohr1988; Sawada et al. 199Ia), although a causal re­lationship was not established. Indeed, Tack andSmith (1989) noted no clinically significant inter­action between methylxanthines (theophylline andcaffeine) and ofloxacin in their safety review of thedrug. Thus, ofloxacin would appear to have a neg­ligible propensity to interact with methylxanthines,unlike other available fluoroquinolones. Indeed, arecent meta-anal ysis of quinolone-theophylline in­teractions (Parent & leBel 1991) confirmed thatthere was little evidence of interaction for ofloxa­cin (or fleroxacin and lomefloxacin), whereas en­oxacin, norfloxacin and ciprofloxacin showed def­inite and significant interaction. They concludedthat ofloxacin would be a preferable fluoroquino­lone to use in patients receiving theophylline com­pared with the latter agents.

Two mechanisms may be involved in the inter­action of fluoroquinolones and methylxanthines(Davey 1988). A pharmacokinetic interaction in­volving inhibition of cytochrome P450-mediatedN-demethylation and 8-hydroxylation may occur.However , in vitro and in vivo studies indicate thatofloxacin has no effect on cytochrome P450-me­diated methylxanthine metabolism (Fuhr et al.1990; Graber et al. 1989;Nakanishi & Okuno 1990),unlike other fluoroquinolones. Furthermore, oflox­acin undergoes minimal hepatic metabolism (seesection 3.3).

The pharmacodynamic interaction involvessynergism between methylxanthines and fluoro­quinolones each acting on GABA-receptor antag­onists , thereby suppressing the inhibitory activityof GABA and promoting CNS excitation (Davey

862

1988). In vitro, such an interaction has been dem­onstrated between ciprofloxacin and theophylline(Segev et al. 1988).

7.2 Other Drugs

Patients receiving enoxacin and fenbufen con­comitantly can develop severe convulsions (Moritaet al. 1988). In vitro and animal studies (Halliwellet al. 1991; Hirai et al. 1989; Tsuji et al. 1988b)suggest a pharmacodynamic interaction with themain metabolite of fenbufen, biphenyl acetic acid,and fluoroquinolones acting synergistically againstthe GABA receptor and promoting eNS excitationin a similar manner to the interaction betweenmethylxanthines and fluoroquinolones (section 7.1).However, no significant pharmacokinetic interac­tioa appears to occur between ofloxacin and fen­bufen (Katagiri et al. 1989), and a recent analysisof adverse effects in phase IV trials found patientsreceiving ofloxacin concomitantly with nonster­oidal anti-inflammatory drugs (NSAIDs) did nothave an increased risk of psychotic effects [Jungstet al. 1991).

Quinolones chelate with alkaline earth and tran­sition metal cations and should not be coadmin­istered with antacids containing calcium, magnes­ium or aluminium, with sucralfate, with divalentor trivalent cations such as iron, or with multivi­tamins containing zinc, as these may reduce ab­sorption and thus plasma concentrations (data onfile, Ortho). Coadministration of magnesium andaluminium antacids can markedly inhibit the ab­sorption of ofloxacin (Hoffken et al. 1986; Mat­sumoto et al. 1984). However, adm inistration ofcalcium carbonate or magnesium-aluminium hy­droxide 2 hours before or 2 hours after ofloxacinadministration did not have a clinically significanteffect on the bioavailability of ofloxacin (Flor et al.1990).

Ranitidine and pirenzipine had no significanteffect on the bioavailability of ofloxacin (Hoffkenet al. 1986).

Verho et al. (1987) reported that ofloxacin 200rug/day for 7 days did not affect the anticoagulantresponse to phenprocoumon in healthy subjects.

Drugs 42 (5) 1991

Also, ofloxacin (unlike enoxacin) had no signifi­cant effect on 7-ethoxycoumarin O-desethylase ac­tivity in hepatic microsomes in vitro (Nakanishi &Okuno 1990). In patients, interaction between of­loxacin and coumarins or warfarin has been re­ported in isolated cases (Jungst & Mohr 1988; Leor& Matetzki 1988), but a causal relationship wasnot definitely established .

An absence of pharmacokinetic interaction hasbeen reported when ofloxacin is used concurrentlywith cefotaxime (Weber et al. 1989), metronidazoleor clindamycin (Boeckh et al. 1988), or with cyclo­sporin (Wynckel et al. 1991).

Isolated instances of suspected drug interactionsbetween ofloxacin and various agents (insulin , B2­sympathomimetics, tiaprofenic acid, maprotiline,levonorgestrel plus ethinylestradiol, nifedipine,mexiletine , isosorbide dinitrate, and ethanol) havebeen reported during postmarketing surveillance inGermany (Jungst & Mohr 1988), but it is import­ant to note that in no case was a definite causalrelationship established.

8. Overdosage

Gastric lavage is recommended in the event ofacute ofloxacin overdosage, with maintenance ofadequate hydration. Ofloxacin is not efficiently re­moved by haemodialysis or peritoneal dialysis (dataon file, Ortho).

Koppel et al. (1990) described a patient who de­liberately overdosed with ofloxacin, diphenhydra­mine and chlormezanone. Measurement of plasmadrug concentrations revealed overdose with oflox­acin and ingestion of therapeutic doses of diphen­hydramine and chlormezanone. Psychosis andanticholinergic symptoms persisted for 2 days butrapidly resolved on the third day after 2 intraven­ous injections of physostigmine 2mg. The authorsnoted that overdose , but not therapeutic concen­trations of diphenydramine and chlormezanome,may induce anticholinergic action. Psychosis iscommon under diphenhydramine overdose . Theauthors considered that ofloxacin overdose mayhave potentiated the anticholinergic actions of di­phenhydramine and chlormezanone.

Ofloxacin: An Update

There has been a recent report of an accidentaloverdose with intravenous ofloxacin 3000mg(Kohler et al. 1991). The patient experienced mod­erately severe CNS symptoms which rapidly re­solved without any specific treatment. The peakserum ofloxacin concentration was 39 mg/L,

9. Dosage and Administration

The usual dosage for ofloxacin is 200 to 400mgorally every 12 hours for 7 to 14 days dependingon the type of infection. Dosage recommendationscan vary between different countries . Generally, thelower dosage of 200mg twice daily is sufficient forUTI , with only 3 days' treatment being necessaryfor simple cystitis. A single 400mg dose may beused for uncomplicated gonorrhoea. Other infec­tions usually require 200 or 300mg twice daily, andfor severe infection may require treatment for atleast 2 weeks with 300 to 400mg twice daily, e.g.up to 6 weeks for chronic prostatitis.

A once-daily dosage regimen (400mg daily) hasalso been successfully used in various clinical trials.Importantly, the drug can be administered intra­venously using the same dosage recommendationsas for oral administration, as the formulations showbioequivalence. The intravenous route may beadopted for critical care patients and other patientswhere gastrointestinal absorption might be im­paired, usually switching to the oral route in a fewdays. An eye drop formulation is also available.

Dosage reduction is required in patients withrenal impairment. The normal 12-hourly dose in­terval is reduced to 24-hourly if creatinine clear­ance is reduced to 10 to 50 ml/rnin, and one-halfthe recommended dose 24-hourly if creatinineclearance is less than 10 mljmin.

Ofloxacin is not usually administered to child­ren or adolescents, during pregnancy or to breast­feeding mothers. Patients should not receive min­eral supplements, vitamins with iron or other min­erals, or antacids 2 hours before or after receivingofloxacin. Patients should be made aware of thepossibility of CNS reactions which may affect psy­chomotor performance.

863

10. Place of Ofloxacin in Therapy

The broad spectrum of activity of ofloxacinagainst aerobic Gram-negative and Gram-positivebacteria, combined with its excellent penetrationinto body tissues and fluids, would suggest a wideapplication in the treatment of bacterial infections,although its generally poor activity against anaer­obic bacteria would preclude its use as monother­apy in conditions where these bacteria might befrequently encountered.

Clinical trials have shown that ofloxacin is in­deed effective in a wide range of infections includ­ing:• uncomplicated and complicated upper and lower

UTI, prostatitis (where it is more effective thancarben icillin), cervicitis , urethritis and salpingitiscaused by Neisseria gonorrhoeae and/or Chla­mydia trachomatis;

• acute or chronic lower respiratory tract infection(pneumonia and bronchitis) caused by commun­ity and hospital acquired pathogens;

• enteric infections caused by Salmonella and Shi-gella species;

• skin and soft tissue infections;• bone and joint infections ;• peritonitis and septicaemia.

Ofloxacin may be a useful treatment for acutebacterial exacerbations of cystic fibrosis in adultsand children, as a second-line treatment of therapy­resistant tuberculosis, and for treatment or pro­phylaxis of infections in immunocompromised orcancer patients. However , further study is requiredto provide a better definition of the efficacy of of­loxacin in these conditions. A few studies haveshown a relatively low eradication rate for S. pneu­moniae during respiratory tract infection, with someauthors suggesting caution in using ofloxacin whensuch infection is suspected or in situations whereit might be frequently encountered.

Although ofloxacin is effective in acute uncom­plicated infections (genitourinary, respiratory,otorhinolaryngological, enteric or skin and soft tis­sue), it is generally no more effective than olderantimicrobials. While it can be considered as aneffective alternative in these conditions, its choice

864

in clinical practice would depend on many factors,e.g. local microbiological flora, impact of resistanceon other antimicrobials, economics. However, of­loxacin has a clear advantage in the oral treatmentof more severe or chronic infections such as com­plicated UTI, chronic bronchitis or hospital-ac­quired pneumonia, septicaemia, peritonitis, andserious skin and soft tissue or bone and joint in­fection. In these situations it has a high degree ofclinical and bacteriological efficacy against bothcommon and many uncommon or unusual Gram­negative and Gram-positive pathogens, conditionswhich frequently necessitate recourse to parenteraltherapy. Ofloxacin provides considerable cost sav­ings in these circumstances, because of its oraladministration, which also facilitates outpatienttreatment.

In some countries, ofloxacin is also available asan intravenous formulation, which can be used in­terchangeably with oral ofloxacin without dosageadjustment. This flexibility of administration routeprovides an advantage for patients who cannot re­ceive oral treatment, e.g. critical care patients orthose with problems affecting gastrointestinal ab­sorption. Changeover to the oral route in clinicallyappropriate situations provides equal efficacy.

There is increasing evidence that fluoroquino­lone cross-resistance can develop in various bac­terial species during treatment with these agents.While this does not yet appear to be a major clinicalproblem, experience with other antimicrobial drugclasses would suggest the need for some degree ofcaution with respect to indiscriminate drug use.Strategies should also be developed to limit the po­tential for resistance emergence, for example, theuse of ofloxacin concomitantly with other agentsin pseudomonal infections.

Within the fluoroquinolones as a group, oflox­acin offersan advantage over other available agents,as it is the least likely to undergo interaction withconcomitantly administered drugs such as theo­phylline, caffeine, fenbufen, anticoagulants, andcyclosporin.

In conclusion, ofloxacin is a valuable broadspectrum orally administered antibacterial drug(with an option for intravenous treatment if nee-

Drugs 42 (5) 1991

essary) for use in a wide range of clinical infections,but with a particular advantage in more severe orchronic infections where usual recourse is to par­enterally administered drugs.

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Ofloxacin: An Update

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Biron F, Boibieux A, Tigaud S, Peyramond D. Salmonellos is andshigellosis treatment with new quinolones. Pathologie Biologie38: 894-898, 1990

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Blomer R, Bruch K, Klose V. Ofloxacin in the treatment of gono­coccal and chlamydial urethritis. Clinical Therapeutics 10: 263­165, 1988

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Brattstrom C, Malmborg A-S, Tyden G. Penetration of cipro­floxacin and ofloxacin into human allograft pancreatic juice.Journal of Antimicrobial Chemotherapy 22: 213-219, 1988

Brensing KA. Ruddel H. Schmieder RE. Schutte W. Visus • undHorverlust als Komplikation der Therapie mit Ofloxacin.Medizinische Welt 40: 748-751, 1989

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Brook I, Ledney GD. Oral ofloxacin therapy of Pseudomonasaeruginosa sepsis in mice after irradiation. Antimicrobial Agentsand Chemotherapy 34: 1387-1389, 1990

Brouqui P, Aubaniac JM, Curvale G, Groulier P, Raoult D.Traitement des infections osteo-articulaires par l'ofloxacine.Pathologie Biologie 37: 468-471, 1989

Burgdorfer H, Schmidt-Bachaly D, Doring G. Behandlung vonPseudomonas-Infektionen bei neurogener Blaserstorung, Ver­gleichsstudie: Ciprofloxacin vs Ofloxacin. Miinchener Medi­zinische Wochenscrift 133: 313-318, 1991

Brun-Pascaud M, Fay M, Zhong M, Guyot A, Pocidalo JJ. Acomparative study of six quinolones in the prophylaxis ofPneumocystis carinii pneumonia in rats. American Review ofRespiratory Disease 143: 715, 1991

Burette A, Glupczynski Y, Deprez e. Combined therapy with of­loxacin and amoxycillin in the eradication of Helicobacter py­lori. Abstract. Gastroenterology 98: 26, 1990

Campoli-Richards DM, Monk JP , Price A, Benfield P, Todd PA,et al. Ciprofloxacin: a review of its antibacterial activity, phar­macokinetic properties and therapeutic use. Drugs 35: 373-447,1988

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Chan MK, Chau PY, Chan WWN. Ofloxacin pharmacokineticsin patients on continuous ambulatory peritoneal dial ysis.Clinical Nephrology 28: 277-180, 1987

Chan MK, Chau PY, Chan WWN . Oral treatment of peritonitisin CAPD patients with two dosage regimens of ofloxacin . Jour­nal of Antimicrobial Chemotherapy 22: 371-375, 1988

Chan MK, Chau PY, Chan WWN , Cheng IKP . Randomized con­trolled trial of oral ofloxacin vs intraperitoneal tobramycin forthe treatment of peritonitis in patients on continuous ambu­latory peritoneal dialysis . Reviews of Infectious Diseases II(Suppl. 5): 1292, 1989a

Chan M-K, Cheng IKP, Ng WSF. A randomized prospective trialof three different regimens of treatment of peritonitis in patientson continuous ambulatory peritoneal dialysis. American Jour­nal of Kidney Diseases 15: 155-159, 1990

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Chin A, Okamoto MP, Gill MA, Sclar DA, Berne TV, et al. In­traoperative concentrations of ofloxacin in serum , bile fluid,and gallbladder wall tissue . Antimicrobial Agents and Chemo­therapy 34: 2354-2357, 1990

Chin NX, Neu He. Combination of ofloxacin and other anti­microbial agents . Journal of Chemotherapy 2: 343-347, 1990

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Corrado ML. Worldwide clinical experience with ofloxacin inurologic cases. Urology 37 (Suppl.) : 28-32, 199tb

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Cox CEo Ofloxacin in the management of complicated urinarytract infections, including prostatitis. American Journal ofMedicine 87 (Suppl. 6C): 61-68, 1989

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Crowle AJ, Elkins N, May MH. Effectiveness of ofloxacin againstMycobacteriumtuberculosis and Mycobateriumavium, and rif­ampicin against M. tuberculosis in cultured human macro­phages. American Review of Respiratory Disease 137: 1141­1146, 1988

Cruciani M, Monzillo V, Navarra A, Tinelli C, Concia E. Anti­bacterial activity after a single-does of norfloxacin , ofloxacinand pipemidic acid detected in urine of volunteers. Drugs un­der Experimental and Clinical Research 14: 533-537, 1988

Dagrosa EE, Verho M, Malerczyk V, de Looze S, Hajdu P, et al.Multiple-dose pharmacokinetics of ofloxacin , a new broadspectrum antimicrobial agent. Clinical Therapeutics 8: 632-645,1986

Dan M, Samra Z. Clostridium difficile colitis associated with of­loxacin therapy . American Journal of Medicine 87: 479, 1989

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Davey PG. Overview of drug interactions with the quinolones.Journal of Antimicrobial Chemotherapy 22 (Suppl . C): 97-107,1988

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Davis GJ , McKenzie BE. Toxicologic evaluation of ofloxacin.American Journal of Medicine 87 (Suppl. C): 6-43, 1989

Davis RL. Drug interactions with fluoroquinolone antibiotics.Drug Interactions Newsletter 8: 27-30, 1988

De Bernardis E, Bonaccorsi S, Carlino S, Picari M, Rizza V. Phar­macokinetics and tissue distribution of ofloxacin in humansubjects during a multiple-dose regimen . International Journalof Clinical Pharmacology Research 8: 239-245, 1988

Dellamonica P, Bernard E, Estesse H, Garraffo R, Drugeon HB.Evaluation of pefloxacin, ofloxacin and ciprofloxacin in thetreatment of thirty-nine cases of chronic osteomyelitis. Euro­pean Journal of Clinical Microbiology and Infectious Diseases8: 1024-1030, 1989

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Ofloxacin: An Update

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Fitzgeorge RB, Featherstone ASR, Baskerville A. The effect ofofloxacin on the intracellular growth of Legionella pneumo­phila in guinea pig alveolar phagocytes. Journal of Antimi­crobial Chemotherapy 22 (Suppl. C): 53-57, 1988

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Freytag F, Zichner M. Bronchopulmonale Infektionen . Verglei­chende Untersuchung zur klinischen Wirksamkeit von Cefo­taxim versus Ofloxacin parenteral. Medizinische Welt41 : 72­75, 1990

Freymann H, Stapel A, Ruge W. Pharmacokinetics and efficacyof ofloxacin in patients with chronic bronchitis. Reviews ofInfectious Diseases I I (Suppl. 5): 1107, 1989

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Fu KP, Grace ME, Hsiao CL, Hung PP. Elimination of antibiotic­resistant plasmids by quinolone antibiotics. Chemotherapy(Basel) 34: 415-418, 1988

Fu KP, Hilliard J, Isaacson D, Tobia AJ, Rosenthale ME, et al.In-vivo evaluation of ofloxacin in Salmonella typhimurium in­fections in mice. Journal of Antimicrobial Chemotherapy 25:263-268, 1990

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Fuchs PC, Jones RN, Barry AL, Gavan TL, The CollaborativeAntimicrobial Susceptibility Test Group. Ofloxacin suscepti­bility testing quality control parameters for microdilution anddisk diffusion, and confirmation of disk diffusion interpretivecriteria. Journal of Clinical Microbiology 27: 49-52, 1989

Fuhr Y, WolffT, Harder S, Schymanski P, Staib AH. Quinoloneinhibition of cytochrome P-450-dependent caffeine metabol ­ism in human liver microsomes. Drug Metabolism and Dis­position 18: 1005-1010, 1990

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Fujimori I, Saito A, Nakayama M, Tomisawa M, Takebe K, etal. Comparative study of T-3262 (tosulfoxacin tosilate) andofloxacin in respiratory tract infection by double-blind method.Chemotherapy (Tokyo) 37: 1086-1118, 1989

Fujita K, Munakata A. Serum and prostatic tissue concentrationsof ofloxacin . Clinical Therapeutics 10: 32-35, 1988

Fujita K, Nakano M, Nonami E, Shishiba T, Katsumata M, etal. Comparative clinical study of DL-8280 and cefaclor forsuppurative skin and soft tissue infections by a double-blindmethod. Kansenshogaku-Zasshi 58: 793-819, 1984

Fujiwara S, Usui T, Seo K, Nishimoto K. Susceptibility to of­loxacin of clinical isolates from wire. Chemotherapy (Tokyo)39: 124-128, 1991

Fukada T. The factors affecting antibacterial activity of quino ­lones in urine. Journal of Tokyo Women's Medical College 58:1092-1102, 1988

Gaffuri Riva Y, Crippa F, Guffanti EE. Theophylline interactionwith new quinolones and macrolides in COPD patients. Ab­stract . American Review of Respiratory Disease 143: 498, 1991

Gaffuri Riva Y, Piazza G, Galzavara MP, Crippa F, Montoli C.Comparison between ofloxacin and amoxycillin to prevent in­fective episodes in COPD. Abstract P287. European Respira­tory Journal 3 (Suppl. 10): 117, 1990

Garcia-Rodriquez JA, Garcia Sanchez JE, Trujillano I. Lack ofeffective bactericidal activity of new quinolones against Bru­cella spp. Antimicrobial Agents and Chemotherapy 35: 756­759, 1991

Garvez MD, Francisco RS, Co SL, Tupasi TE. Clinical utilization. of the quinolones: its impact on the resistance patterns of com­monly isolated pathogens. Chemotherapy (Tokyo) 39: 614, 1991

Gentry LO, Rodriguez-Gomez G. Ofloxacin versus parenteraltherapy for chronic osteomyelitis. Antimicrobial Agents andChemotherapy 35: 538-541, 1991

Gentry LO, Rodriguez-Gomez G, Zeluff BJ, Khoshdel A, et al.A comparative evaluation of oral ofloxacin versus intravenouscefotaxime therapy for serious skin and skin structure infec­tions. American Journal of Medicine 87 (Suppl, C): 57-60, 1989

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Giamarellou H, Iakovou M, Pistoni M, Petrikkos G, Dontas A,et al. Kinetics and comparative efficacy of ofloxacin versus co­trimoxazole in the asymptomatic bacteriuria of elderly sub­jects. Chemotherapy (Basel) 37 (Suppl. I): 19-24, 1991

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Glupczynski Y, Labbe M, Burette A, Delmee M, Avensani Y, etal. Treatment failure of ofloxacin in Campylobacter pylori in­fection. Lancet I: 1096, 1987

Goldstein EJC, Citron DM. Comparative activities of cefurox­ime, amoxicillin-c1avulanic acid, ciprofloxacin , enoxacin, andofloxacin against aerobic and anaerobic bacteria isolated frombite wounds. Antimicrobial Agents and Chemotherapy 32: 1143­1148, 1988

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Correspondence: Diana Faulds. Adis Interna tional Limited, 41Centorian Drive, Private Bag, Mairangi Bay, Auckland 10, NewZealand .