Levofloxacin, an oral fluoroquinolone antibacterial agent, is the optical S-(-) isomer of ofloxacin. In vitro it is generally twice as potent as ofloxacin. Levofloxacin is active against most aerobic Gram-positive and Gram-negative organisms and demonstrates moderate activity against anaerobes. Drug penetration into body tissues and fluids is rapid and widespread after oral administration. In clinical trials conducted in Japan, oral levofloxacin has demonstrated antibacterial efficacy against a variety of infections, including upper and lower respiratory tract, genitourinary, obstetric, gynaecological and skin and soft tissue. In comparative trials with ofloxacin, levofloxacin, at half the daily dosage of ofloxacin, showed equivalent efficacy and a reduced incidence of adverse effects in the treatment of lower respiratory tract and complicated urinary tract infections.
Levofloxacin has a tolerability profile similar to that of other oral fluoroquinolones, with gastrointestinal and central nervous system effects reported most commonly. Theophylline dosage adjustment does not appear to be necessary in patients receiving concomitant levofloxacin. Coadministration with antacids or with other drugs containing divalent or trivalent cations reduces levofloxacin absorption.
Thus, levofloxacin has potential as a broad spectrum antibacterial drug in the treatment of a variety of infections. However, clinical trials recruiting non-Japanese patients are in progress and these results will form a basis on which future recommendations for the broader use of levofloxacin can be made.
The mechanism of action of levofloxacin, like that of other fluoroquinolones, involves inhibition of bacterial deoxyribonucleic acid (DNA) gyrase, a type II topoisomerase. It has a broad range of in vitro activity against most aerobic Gram-negative bacteria, although some strains may show only moderate susceptibility (Providencia rettgeri and Pseudomonas aeruginosa) or resistance (Serratia marcescens). MIC90 values are somewhat higher against Gram-positive bacteria, but these organisms are usually susceptible. Levofloxacin, in common with other available fluoroquinolones, demonstrates only moderate activity against anaerobes
Mean MIC90 values for levofloxacin were about 50% lower than those observed for ofloxacin against both Gram-positive and Gram-negative bacteria and 3 to 4 times lower than those for ciprofloxacin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Mean MIC90 values for levofloxacin were approximately 50% higher than those observed for ciprofloxacin against most Gram-negative bacteria. Ciprofloxacin showed greater in vitro activity than levofloxacin against Pseudomonas aeruginosa.
Inhibition of bacterial multiplication by levofloxacin was not influenced by growth medium types while the presence of serum and inoculum size had equivocal effects. Acidic pH or the addition of urine may reduce the in vitro antibacterial activity of levofloxacin. Levofloxacin usually has additive or indifferent effects when combined with other antibacterial agents in vitro, but may occasionally show synergy or antagonism. A postantibiotic effect for levofloxacin has been exhibited against methicillin-susceptible and methicillin-resistant S. aureus, S. epidermidis, Enterococcus faecalis and Escherichia coli.
Resistance to fluoroquinolones occurs at a low rate in vitro and is chromosomally mediated. Changes to the A or B subunits of DNA gyrase or cell membrane porin channels are 3 possible mechanisms of chromosomal mutation which can confer bacterial resistance to the fluoroquinolones. Apart from 1 unconfirmed report in S. aureus, plasmid-mediated resistance has not been noted with fluoroquinolones. Although no specific data regarding its resistance pattern are available, levofloxacin will be likely to display a pattern similar to its racemate, ofloxacin.
Levofloxacin was generally as efficacious or more efficacious than ciprofloxacin, ofloxacin or norfloxacin in protecting mice against experimentally induced systemic infections, lower respiratory tract infections and pyelonephritis. At therapeutic concentrations, the drug penetrates into human phagocytes in vitro without affecting cell viability.
Following oral administration of levofloxacin 50 to 200mg in healthy volunteers, mean maximum plasma concentrations ranging from 0.57 to 2.04 mg/L were achieved within 0.8 to 2.4 hours; these parameters are linearly related to dose. Food does not appear to affect the absorption of levofloxacin, which has an oral bioavailability approaching 100%. The apparent mean volume of distribution of levofloxacin ranges from 1.09 to 1.26 L/kg after administration of single 50, 100 or 200mg doses to healthy volunteers. Oral levofloxacin penetrates rapidly and efficiently throughout the body, achieving concentrations in tissues or body fluids which are generally higher than those observed in plasma
Within 24 hours of an administered oral dose, about 80 to 85% of the drug is excreted unchanged in the urine. The mean plasma elimination half-life of levofloxacin is 4 to 7 hours. The elimination half-life and the area under the plasma concentration-time curve (AUC) of levofloxacin increase proportionally as creatinine clearance decreases. Therefore, prolongation of the normal dosage interval and/or dosage reduction of levofloxacin is necessary in patients with impaired renal function.
The efficacy of oral levofloxacin (mostly 100mg 3 times daily) has been investigated in both noncomparative trials and controlled comparative studies with ofloxacin in Japanese patients with a variety of infections. In comparisons with ofloxacin, levofloxacin was mostly administered at half the daily dosage of ofloxacin
Levofloxacin has proven effective in the treatment of acute or chronic lower respiratory tract infections (bronchitis and pneumonia) and was as effective as ofloxacin in comparative trials. Eradication rates for levofloxacin against common respiratory pathogens [Haemophilus injluenzae, Moraxella (Branhamella) catarrhalis, S. aureus and Streptococcus pneumoniae] were 80 to 100%, while those against P. aeruginosa were lower (about 30%).
In patients with either complicated (upper) or uncomplicated (lower) urinary tract infections, levofloxacin achieved clinical and bacteriological efficacy rates that ranged from 80 to 100%. In women with uncomplicated cystitis, single dose levofloxacin 200mg yielded clinical efficacy rates of 100% on day 3 and 94% on days 7 and 14. Levofloxacin 200 to 300 mg/day displayed clinical and bacteriological efficacy rates comparable to treatment with ofloxacin 400 to 600 mg/day in patients with complicated urinary tract infections. Clinical and bacteriological efficacy rates of 100% were achieved for levofloxacin 200 to 400 mg/day administered for 3 days to patients with gonococcal urethritis and 14 days to patients with nongonococcal (chlamydial) urethritis. Levofloxacin showed clinical efficacy in men with acute prostatitis (100%), chronic prostatitis (74%) and acute or chronic epididymitis (88%). The short duration of levofloxacin therapy (<15 days) used in the treatment of chronic prostatitis may have limited its effectiveness.
Skin and soft tissue infections were responsive to treatment with levofloxacin (clinical efficacy rates 80 and 91% in 2 large trials), while eradication rates for methicillin-susceptible S. aureus and coagulase-negative staphylococci were approximately 90%.
Clinical cure/improvement was observed in 93% of women with various obstetric and gynaecological infections treated with levofloxacin 200 to 300 mg/day. Eradication rates of > 90% were observed for commonly isolated pathogens which included C. trachomatis, E. coli, S. aureus, Streptococcus spp., Peptostreptococcus spp. and E. faecalis.
Clinical efficacy rates of 74 to 92% have been achieved with levofloxacin in noncomparative studies of patients with a variety of ear, nose and throat infections. Overall bacteriological eradication rates were 100% for H. influenzae and M. catarrhalis, 97% for Streptococcus spp. and 93% for methicillin-susceptible and methicillin-resistant S. aureus, with lower rates observed for coagulase- negative staphylococci (75%) and P. aeruginosa (66%). Levofloxacin has also displayed clinical efficacy in bacterial enteritis (97% of patients cured or improved) and in ocular infections (92%), odontogenic infections (83%) and biliary tract infections (73%) investigated in single clinical trials.
Levofloxacin is generally well tolerated, with most adverse effects being mild to moderate in severity and transient in nature. In 5 comparative trials with ofloxacin which recruited a total of 918 patients, a lower incidence of gastrointestinal symptoms (1.2 vs 5.2%) [abdominal discomfort, anorexia or diarrhoea] and central nervous system effects (0.8 vs 2.2%) [insomnia, headache or dizziness] was observed in levofloxacin recipients. In comparative trials, the overall incidence of abnormal laboratory findings (mostly transient elevations of liver function tests, eosinophilia or leucopenia) with levofloxacin (2.4 to 15.5%) was similar to that observed with ofloxacin (4.3 to 18.2%)
Levofloxacin, in common with other fluoroquinolones, has been shown to cause articular damage in animal studies at high dosages. In addition, the phototoxic potential of levofloxacin as assessed in mice appears to be similar to that of ofloxacin and ciprofloxacin and lower than that of lomefloxacin, enoxacin and nalidixic acid.
Dosage and Administration
In Japanese studies, the most frequently used dosage was 100mg 3 times daily for the treatment of a variety of infections, including respiratory, genitourinary, obstetric, gynaecological, skin, oral, ear, nose, throat, enteral, biliary tract and eye infections. Treatment duration ranged from 7 to 14 days, although a shorter duration (3 to 5 days) was sufficient for the treatment of urinary tract infections (uncomplicated and complicated) or gonococcal urethritis. A single 200mg dose has been successfully used for women with uncomplicated cystitis.
Dosage reduction is required in patients with renal impairment. Patients should not receive concomitant levofloxacin and mineral supplements, vitamins with iron or other minerals, antacids, or sucralfate. If required, these drugs should be administered at least 2 hours before or after levofloxacin. The pharmacokinetics of theophylline are not significantly affected by levofloxacin; however, patients receiving this combination should still be monitored for clinical signs of theophylline toxicity.
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- Acer JF, O’Brien TF, Goldstein FW, Jones RN. The epidemiology of bacterial resistance to quinolones. Drugs 45 (Suppl. 3): 24–28, 1993Google Scholar
- Akabane K, Kato M, Takayama S. Involvement of inhibitory and excitatory neutrotransmitters in levofloxacin- and ciprofloxacin-induced convulsions in mice. Antimicrobial Agents and Chemotherapy 37: 1764–1770, 1993Google Scholar
- Baba S. Clinical studies on DR-3355 in the field of otorhinolaryngology. Poster: Proceedings of the 17th International Congress of Chemotherapy, Berlin, pp. 2110–2111, 1991Google Scholar
- Baba S, Miyamoto N, Vnno T, Naito Y, Yanai O, et al. Clinical evaluation of the effect of levofloxacin on sinusitis. Chemotherapy 40 (Suppl. 3): 365–378, 1992aGoogle Scholar
- Baba S, Miyamoto N, Yanai O, Tamura Y, Tokoro Y, et al. Study on the penetration of levofloxacin (DR-3355) into the otorhinolaryngeal tissues and discharges in patients. In Japanese. Chemotherapy 40 (Suppl. 3): 326–333, 1992bGoogle Scholar
- Bellido F, Pechère J-C. Laboratory survey of fluoroquinolone activity. Reviews ofInfectious Diseases 11 (Suppl. 5): S917-S924, 1989Google Scholar
- Chida T, Shibaoka H, Ishizuka I, Nakaya R. The effect of DL-8280, a new antimicrobial agent of pyridone-carboxylic acid derivative, on human fecal flora. In Japanese. Chemotherapy 32 (Suppl. 1): 109–117, 1984Google Scholar
- Foleno BD, Lafredo SC, Fu KP. In vitro activity of levofloxacin, ofloxacin and other quinolones against coagulase-negative staphylococci. Microbiology (Basel) 39: 120–123, 1993Google Scholar
- Fu KP, Grace ME, Hsiao CL, Hung PP. Elimination of antibiotic-resistant plasmids by quinolone antibiotics. Chemotherapy (Basel) 34: 415–418, 1988Google Scholar
- Fujimoto T, Mitsuhashi S. In vitro antibacterial activity of DR-3355, the S-(-)-isomer of ofloxacin. Chemotherapy (Basel) 36: 268–276, 1990Google Scholar
- Furuhama K, Akahane K, Tawara K, Takayama S. Interaction of the new quinolone antibacterial agent levofloxacin with fenbufen in mice. Arzneimittel-Forschung 42: 406–408, 1992Google Scholar
- Gaja M, Higa F, Yamashiro T, Nakamoto A, Miyara T, et al. Penetration of levofloxacin, a new quinolone antibacterial agent, into human neutrophils. In Japanese. Chemotherapy 40 (Suppl. 3): 64–67, 1992Google Scholar
- Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, et al. Pharmacokinetics of three newer quinolones in pregnant and lactating women. American Journal of Medicine 87 (Suppl. 5A): 49–51, 1989Google Scholar
- Goto S, Miyazaki S, Ishida Y. In vitro and in vivo antibacterial activities of a new quinolone, levofloxacin (DR-3355). In Japanese. Chemotherapy 40 (Suppl. 3): 14–26, 1992Google Scholar
- Guay DRP. Fluoroquinolone drug-drug interactions. Hospital Therapy 15: 825–832, 1990Google Scholar
- Guay DRP. The role of the fluoroquinolones. Pharmacotherapy 12 (Suppl.): 7IS-85S, 1992Google Scholar
- Higa F, Gaja M, Kusano N, Kitsukawa K, Shigeno Y, et al. Effect of glucocorticoid on the uptake of antibiotics by human polymorphonuclear leukocytes. Poster: Proceedings of the 17th International Congress of Chemotherapy, Berlin, pp. 152–153, 1991Google Scholar
- Inoue S, Misaki M, Matsumura K. Intraocular penetration of DR-3355. In Japanese. Journal of the Eye 9: 487–490, 1992Google Scholar
- Ishii T, Takayama M. Phase III clinical study oflevofloxacin in otitis media and otitis externa. Chemotherapy 40 (Suppl. 3): 334–351, 1992Google Scholar
- Ito K, Mikamo H, Izumi K, Tamaya T, Hirose R, et al. Penetration of levofloxacin into gynecological tissues. In Japanese. Chemotherapy 40 (Suppl. 3): 306–310, 1992Google Scholar
- Iwamoto K, Naora K, Katagiri Y, Ichikawa N, Hayashibara M, et al. Comparative neurotoxicity study of ciprofloxacin and sparfloxacin after coadministration with fenbufen in rats. Drugs 45 (Suppl. 3): 290–291, 1993Google Scholar
- Jones RN, Wiedemann B, Simone DE, Monteil H, Yamaguchi K. International surveillance of ofloxacin resistance. 18th International Congress on Chemotherapy, Stockholm, June/July 1993Google Scholar
- Kato M, Furuhama K, Woolley APAH, Ashby R, Fowler JSL, et al. Twenty-six-week oral toxicity of the new quinolone antibacterial agent levofloxacin in rats and cynomolgus monkeys. Arzneimittel-Forschung 42: 367–373, 1992Google Scholar
- Kawada Y, Kumamoto Y, Aso Y, Machida T, Saito I, et al. Comparative study on levofloxacin and ofloxacin in complicated urinary tract infections. In Japanese. Chemotherapy 40 (Suppl. 3): 230–248, 1992aGoogle Scholar
- Kawada Y, Kumamoto Y, Aso Y, Machida T, Saito I, et al. Dose-finding study on levofloxacin in complicated urinary tract infections. In Japanese. Chemotherapy 40 (Suppl. 3): 210–229, 1992bGoogle Scholar
- Kawada Y, Murakami S, Aso Y, Machida T, Saito I, et al. Studies on the clinical value of levofloxacin in the treatment of genitourinary tract infections. In Japanese. Chemotherapy 40 (Suppl. 3): 249–269, 1992cGoogle Scholar
- Lafredo SC, Foleno BD, Fu KP. Induction of resistance of Streptococcus pneumoniae to quinolones in vitro. Microbiology (Basel) 39: 36–39, 1993Google Scholar
- Lewin CS, Amyes SGB, Smith JT. Bactericidal activity of enoxacin and lomefloxacin against Escherichia coli KL16. European Journal of Clinical Microbiology 8: 731–733, 1989Google Scholar
- Lewin CS, Morrissey I, Smith JT. The mode of action of quinolones: the paradox in activity of low and high concentrations and activity in the anaerobic environment. European Journal of Clinical Microbiology and Infectious Diseases 10: 240–248, 1991bGoogle Scholar
- Lewin CS, Smith JT. Interactions of 4-quinolones witb other antibacterials. European Journal of Medical Microbiology 29: 221–227, 1989Google Scholar
- Madinger NE, McGregor JA, McKinney PJ, Dembeck ST, Haskell CS, et al. Comparative antibiotic susceptibilities of anaerobes associated witb infections of the female reproductive tract. Clinical Infectious Diseases 16 (Suppl. 4): S349-S352, 1993Google Scholar
- Marchbanks CR. Drug-drug interactions witb fluoroquinolones. Pharmacotherapy 13: 23S-28S, 1993Google Scholar
- Matsuda S, Oh K, Hirayama H, Shimizu T, Kimura H, et al. Clinical study of levofloxacin (LVFX) on the infectious diseases in the field of obstetrics and gynecology. In Japanese. Chemotherapy 40: 311–325, 1992Google Scholar
- Morrissey I, Lewin CS, Smith JT. The influence of oxygen upon bactericidal potency. In Crumplin (Ed.) The 4-quinolones: Antibacterial agents in vitro, pp. 23–36, Springer-Verlag, London, 1990Google Scholar
- Morrissey I, Smith JT. The effect of inoculum size on 4-quinolone uptake by Escherichia coli KL-16. Journal of Pharmacy and Pharmacology 45 (Suppl): 1106, 1993Google Scholar
- Murata M, Ohnishi K, Irimajiri S, Matsuoka Y, Obana M, et al. Clinical trial of levofloxacin (DR-3355) and fecal drug concentration and change in the fecal microflora in infectious enteritis. In Japanese. Chemotherapy 40 (Suppl. 3): 170–187, 1992Google Scholar
- Nakashima M, Uematsu T, Kanamaru M, Okazaki O, Hakusui H. Phase I study of levofloxacin, (S)-(-)-ofloxacin. Japanese Journal of Clinical Pharmacology and Therapeutics 23: 515–520, 1992Google Scholar
- National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; Fourth Information Supplement. NCCLS Document MI00-S4, NCCLS, Villanova, Pennsylvania, 1992Google Scholar
- Neu HC. Synergy and antagonism of combinations of quinolones. European Journal of Clinical Microbiology and Infectious Diseases 10: 255–261, 1991Google Scholar
- Nielsen KT, Madsen PO. Quinolones in urology. Urology Research 17: 117–124, 1989Google Scholar
- Nix DE, Watson WA, Lerner ME, Frost RW, Krol G, et al. Effects of aluminum and magnesium and ranitidine on the absorption of ciprofloxacin. Clinical Pharmacy and Therapeutics 46: 700–705, 1989bGoogle Scholar
- Ohi Y, Goto T, Kawahara K, Kawahara M, Kawabata T, et al. Penetration of fluoroquinolones into human spinal fluid. In Japanese. Chemotherapy 40: 469–473, 1992Google Scholar
- Ohyama M, Nobori T, Shima T, Matsunaga S, Ohno F, et al. A clinical study on levofloxacin in treatment of tonsillitis, pharyngitis and sialadenitis. Chemotherapy 40 (Suppl. 3): 352–364, 1992Google Scholar
- Okimoto N, Niki Y, Soejima R. Effect of levofloxacin on serum concentration of theophylline. In Japanese. Chemotherapy 40 (Suppl. 3): 68–74, 1992Google Scholar
- Ooishi M, Miyao M, Oomomo A, Hosaka A, Hirokawa H, et al. Clinical efficacy of levofloxacin in bacterial infections of the eye. In Japanese. Journal of the Eye 9: 475–481, 1992Google Scholar
- Saito A, Irabu Y, Fuknhura H, Motomiya M, Oizumi K, et al. Dose finding comparative study on levofloxacin (LVFX) in chronic respiratory tract infection. In Japanese. Chemotherapy 40 (Suppl. 3): 75–96, 1992aGoogle Scholar
- Saito A, Oguchi K, Harada Y, Shinoda I, Komeda H, et al. Pharmacokinetics of levofloxacin in patients witb impaired renal function. In Japanese. Chemotherapy 40 (Suppl. 3): 188–195, 1992bGoogle Scholar
- Saito A, Shigeno Y, Irabu Y, Fukuhara H, Saito A, et al. Clinical study on levofloxacin in the field of internal medicine. In Japanese. Chemotherapy 40 (Suppl. 3): 147–169, 1992cGoogle Scholar
- Sasaki J, Morishima T, Shiiki K, Yamane N, Sakamoto H, et al. Clinical study of levofloxacin in treatment of odontogenic infections. In Japanese. Chemotherapy 40 (Suppl. 3): 379–391, 1992Google Scholar
- Smith JT, Lewin CS. Chemistry and mechanisms of action of the quinolone antibacterials. In Andriole VT (Ed.) The quinolones, pp. 23–82, Academic Press, London, 1988Google Scholar
- Soejima R, Kawane H, Okimoto N, Umeki S, Sumi M, et al. Comparative study of levofloxacin and ofloxacin in bacterial pneumonia by the double-blind method. In Japanese. Chemotherapy 40 (Suppl. 3): 121–146, 1992aGoogle Scholar
- Soejima R, Kawane H, Okimoto N, Umeki S, Sumi M, et al. Comparative study of levofloxacin and ofloxacin in chronic respiratory tract infections by the double-blind method. In Japanese. Chemotherapy 40 (Suppl. 3): 97–120, 1992bGoogle Scholar
- Takahashi H, Mogi S, Kobayashi M, Fukaya T, Ohkawara A, et al. Assay of skin level and clinical investigation oflevofloxacin in the treatment of skin infections. In Japanese. Chemotherapy 40 (Suppl. 3): 286–305, 1992Google Scholar
- Tanaka M, Ishii H, Sato K, Osada Y, Nishino T. Characterization of high-level quinolone-resistance in methicillin-resistant Staphylococcus aUreus. Abstract no. 808, p. 233. 31st ICAAC, Chicago, 1991aGoogle Scholar
- Tanaka M, Otsuki M, Nishino T. Bactericidal activities of ofloxacin and its optically active isomer (DR-3355) on non-growing cells of Escherichia coli and Pseudomonas aeruginosa. Chemotherapy (Basel) 38: 21–27, 1992Google Scholar
- Tanimura H, Ohnishi H, Okamura T, Uenishi M, Ichimiya G, et al. Chemotherapy of biliary tract infections (XXXVII). Excretion into bile and gallbladder tissue levels of levofloxacin and its clinical effect in biliary tract infections. In Japanese. Japanese Journal of Antibiotics 45: 557–568, 1992PubMedGoogle Scholar
- Tomii T, Fukuda M, Sasaki K. Penetration of l-ofloxacin (DR-3355) into the lacrimal fluid. In Japanese. Japanese Journal of Clinical Ophthalmology 45: 1607–1610, 1991Google Scholar
- Van Siooten AD, Nix DE, Wilton JH, Love JH, Spivey JM, et al. Combined use of ciprofloxacin and sucralfate. Drug Intelligence and Clinical Pharmacy 25: 578–582, 1991Google Scholar
- Wagai N, Yoshida M, Takayama S. Phototoxic potential of the new quinolone antibacterial agent levofloxacin in mice. Arzneimittel-Forschung 42: 404–405, 1992Google Scholar
- Watanabe K, Kato N, Muto Y, Bandou K, Ueno K. Antibacterial activity of levofloxacin, S-isomer of ofloxacin, against anaerobic bacteria. In Japanese. Chemotherapy 40 (Suppl. 3): 57–63, 1992Google Scholar
- Yamashita M, Sawada K, Chokyu H, Miyazaki S, Kuwayama M, et al. Prostatic tissue levels oflevofloxacin. In Japanese. Chemotherapy 40 (Suppl. 3): 203–209, 1992Google Scholar
- Yokota T, Suzuki E, Arai K, Kanda K. In vitro antibacterial activity of levofloxacin, its selective toxicity and influence on axon dendrites. In Japanese. Chemotherapy 40 (Suppl. 3): 27–35, 1992Google Scholar
- Yura J, Shinagawa N, Ishikawa S, Mashita K, Suzui K, et al. Clinical evaluation of levofloxacin, a new quinolone, in patients with surgical infections. In Japanese. Chemotherapy 40 (Suppl. 3): 271–286, 1992Google Scholar