Ofloxacin

Abstract

Ofloxacin is a fluoroquinolone whose primary mechanism of action is inhibition of bacterial DNA gyrase. In vitro it has a broad spectrum of activity against aerobic Gram-negative and Gram-positive bacteria, although it is poorly active against anaerobes. Ofloxacin, unlike most other broad spectrum antibacterial drugs, can be administered orally as well as intravenously. Penetration into body tissues and fluids is highly efficient. Clinical trials with orally and intravenously administered ofloxacin have confirmed its potential for use in a wide range of infections, where it has generally proved as effective as standard treatments. Ofloxacin is well tolerated, and in comparison with other available fluoroquinolones is less likely to cause clinically relevant drug interactions. Ofloxacin thus offers a valuable oral treatment (with an option for intravenous administration if necessary) for use in a wide range of clinical infections, but with a particular advantage in more severe or chronic infections when recourse to parenteral broad spectrum agents would normally be required, thereby providing cost savings and additionally allowing outpatient treatment. Ofloxacin is a fluoroquinolone, whose mechanism of action involves inhibition of bacterial DNA gyrase. It has a broad range of in vitro activity against aerobic Gram-negative and Gram-positive bacteria. Gram-negative bacteria are almost invariably susceptible, and usually highly susceptible, to ofloxacin, although a few such bacteria may show only moderate susceptibility, e.g. Pseudomonas stuartii, Providencia species and Gardnerella vaginalis MIC₉₀ values are some-what higher against Gram-positive bacteria, but these organisms are usually susceptible. However, Nocardia asteroides is resistant and some streptococcal and enterococcal species may show only moderate susceptibility and, occasionally, resistance. Many mycobacterial species are susceptible to ofloxacin, in particular Mycobacterium tuberculosis, with the exception of some rare species which may be resistant. Ofloxacin in common with other fluoroquinolones is not considered to be 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. Ofloxacin and ciprofloxacin show similar antimicrobial activities, provided MIC₉₀ values are related to susceptibility/resistance breakpoints, and both fluoroquinolones tend to exhibit better activity than norfloxacin, enoxacin and pefloxacin against some pseudomonal, streptococcal and staphylococcal strains. The antibacterial activity of ofloxacin is influenced little, if at all, by inoculum size, growth medium or the presence of serum. Acidic pH, or the addition of urine or magnesium may reduce the in vitro antibacterial activity of ofloxacin. Bacteriostatic and bactericidal activities are usually achieved at similar ofloxacin concentrations. Resistance to fluoroquinolones occurs at a low rate in vitro and is chromosomally mediated. High level resistance results from DNA gyrase mutation, requires multiple passage at high drug concentrations, and occurs infrequently in vivo Low level resistance results from cell-membrane changes and may occur during single-step exposure at low drug concentrations, generally only decreasing susceptibility. It may, however, produce clinical resistance in bacteria which were previously only moderately susceptible. There is usually cross-resistance for all fluoroquinolones. Plasmid-mediated resistance has not been noted. Ofloxacin usually has additive or indifferent effects when combined with other antibacterial agents in vitro but, may occasionally demonstrate synergy and only rarely antagonism. At therapeutic concentrations ofloxacin does not exert detrimental effects on the immune system in vitro or in vivo Ofloxacin rapidly eliminates aerobic Gram-negative microflora from the gastrointestinal tract and significantly reduces enterococci. However, obligate anaerobic Gram-negative and anaerobic Gram-positive flora are not substantially modified by ofloxacin, although yeast overgrowth is a rare occurrence. Toxicological studies indicate that ofloxacin has a low toxic potential, although ofloxacin (at high concentrations) and other fluoroquinolones can cause articular damage in juvenile animals. Ofloxacin is efficiently absorbed with an absolute bioavailability of tablet formulations approaching 100%. Maximum plasma concentrations are reached about 1 to 2 hours after oral administration and are linearly related to dose. Food may delay the rate of absorption but does not affect its extent. Steady state is reached after 2 to 4 doses at 12-hourly intervals. Following intravenous administration maximum plasma concentration can be up to 50% higher than after the same dose of ofloxacin administered orally. However, after the rapid initial distribution phase following 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. Ofloxacin is 20 to 25% protein bound, with the mean volume of distribution ranging from 1.3 to 1.7 L/kg. The drug penetrates rapidly and efficiently into body tissues and fluids (including breast milk and the placenta), and achieves effective antimicrobial concentrations in all tissues evaluated. The mean elimination half-life of ofloxacin is 5 to 8 hours. Mean body clearance ranges from 11 to 16 L/h and mean renal clearance is only slightly lower (9 to 11 L/h). Ofloxacin is almost exclusively excreted unchanged in urine, with negligible metabolism. The disposition of ofloxacin is unaffected by gender, and age-related changes in ofloxacin disposition appear highly correlated with creatinine clearance. Indeed, renal impairment can have a profound effect, decreasing renal clearance of ofloxacin and increasing elimination half-life. These changes become clinically significant when creatinine clearance is less than 3 L/h (50 ml/ min), and dosage adjustment is required in such patients. Ofloxacin is not efficiently removed by haemodialysis or peritoneal dialysis. Renal clearance of ofloxacin was reduced in patients with alcoholic cirrhosis; this was not always related to hepatic or renal function test values, although it was correlated with a decrease in tubular secretion. The broad spectrum of in vitro activity of ofloxacin against aerobic Gram-negative and Gram-positive bacteria combined with its efficient penetration into body tissues and fluids would suggest its clinical use in a wide range of infections. It would not, however, be expected to have any significant application, at least as monotherapy, for the treatment of infections where anaerobic bacteria might be frequently encountered. Ofloxacin was administered orally in most clinical trials. However, the availability of the intravenous formulation and its interchangeability with the oral formulation allows improved versatility during ofloxacin treatment. The intravenous route can be used when oral therapy is inappropriate (e.g. critical care patients or conditions affecting absorption) but it is usual to switch to 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, more so than carbenicillin, in the treatment of acute or chronic bacterial prostatitis. Ofloxacin as single-dose treatment is bacteriologically 100% effective in eradicating Neisseria gonorrhoeae in uncomplicated gonorrhoeal cervicitis and urethritis, and also eradicates associated pharyngeal or anorectal infection. It is equally effective against β-lactamase-producing strains of N. gonorrhoeae Treatment with ofloxacin for 1 week is also effective in the treatment of nongonococcal urethritis and cervicitis caused by Chlamydia trachomatis, producing similar results to doxycycline; neither treatment, however, eradicated infections caused by Mycoplasma hominis, and results against Ureaplasma urealyticum were equivocal. As a short course (1 to 3 weeks) ofloxacin was also highly 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 gynaecological infections caused by other pathogens. Ofloxacin has proven effective in the treatment of acute or chronic lower respiratory tract infection (bronchitis and pneumonia), whether community or hospital acquired. It appeared at least as effective as other treatments such as erythromycin, doxycycline, cotrimoxazole, amoxicillin, amoxicillin/clavulanic acid, pivmecillinam, cefotaxime and other fluoroquinolones, and it was more effective than cefaclor. Ofloxacin was 80 to 100% effective bacteriologically against most common respiratory pathogens [Haemophilus influenzae, Klebsiella pneumoniae, Branhamella catarrhalis (Moraxella catarrhalis) and Staphylococcus aureus], while rates were lower against Streptococcus pneumoniae (70 to 75%) and Pseudomonas aeruginosa (about 50%). The relatively low eradication rate for S. pneumoniae might limit the use of ofloxacin when such an infection is clinically expected. However, the eradication rate for P. aeruginosa must be considered in relation to the recalcitrance of these infections even to other parenteral antibacterial agents. Of note, 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 successfully in combination with first- and second-line antitubercular drugs in patients with Mycobacterium tuberculosis pulmonary infection resistant to standard therapy. Limited experience with oral ofloxacin suggests it has clinical efficacy in adults and children with acute exacerbation of cystic fibrosis caused by P. aeruginosa or S. aureus, and when used in combination with other drugs such 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 determine its 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 topical otic formulation of ofloxacin is undergoing investigation for use in adults and children with otitis media. Oral ofloxacin was of similar efficacy to oral cefaclor or cephalexin in the treatment of mild to moderate skin and soft tissue infections (generally caused by staphylococci and streptococci). However, oral ofloxacin was more effective than intravenous cefotaxime in serious skin and soft tissue 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 1 to 2 weeks is essentially 100% effective clinically and bacteriologically in eliminating enteric infections caused by Salmonella and Shigella species, including those in patients unresponsive to standard therapies or with resistant strains. Ofloxacin has been studied in the treatment of other infections such as peritonitis and septicaemia with encouraging preliminary results. Ofloxacin has proven highly effective in the treatment and prophylaxis of immunocom-promised and cancer patients with respect to Gram-negative infections, but further investigation of ofloxacin in combination with other agents is required to extend the activity against Gram-positive bacteria. 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 has generally confirmed its favourable clinical tolerability. The most clinically significant adverse effects are neurological (psychosis, hallucinations and epilepsy), although these occur infrequently. The possible pharmacological mechanism appears to be common to all fluoroquinolones, and may involve GABA receptor antagonism and promotion of CNS excitation. Pseudomembranous colitis has also been rarely encountered. Because of the articular damage which has been noted in juvenile animals during toxicological studies, the use of fluoroquinolones is generally not permitted in children. However, ofloxacin has been used successfully in a few paediatric patients with cystic fibrosis without any evidence of joint toxicity. Studies indicate that ofloxacin has little or no propensity to interact with theophylline, caffeine or fenbufen. Other fluoroquinolones, however, and most notably enoxacin, may undergo a marked interaction with these drugs. Quinolones chelate with alkaline earth and transition metal cations, and should not be administered with antacids containing calcium, magnesium or aluminium, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc, as these may reduce absorption and plasma concentrations of ofloxacin. If required, antacids should be administered 2 hours before or after ofloxacin. Ofloxacin does not appear to interact with ranitidine, pirenzipine, cyclosporin, cefotaxime, clindamycin or metronidazole. The usual dosage for ofloxacin is 200 to 400mg orally every 12 hours for 7 to 14 days. Dosage recommendations can vary between different countries. The lower dosage of 200mg twice daily is 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 usually require 200 or 300mg twice daily, and for severe infections at least 2 weeks’ treatment with 300 to 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 same dosage recommendations as for oral regimens, as the formulations show bioequivalence. The intravenous route is only used when necessary, and a change to the oral route should be made as soon as practicable. An eye drop formulation is also available. Dose reduction and/or prolongation of the dose interval is necessary in patients with renal impairment.