The U.S. clinical experience with lomefloxacin, a new once-daily fluoroquinolone

The U.S. Clinical Experience with Lomefloxacin, a New Once-Daily Fluoroquinolone EM AD RIZK, M.D., Sko/cie, ///inois

Lomefloxacin is a new fluoroquinolone antimicrobial agent that has undergone extensive worldwide clinical evaluation. This report sum- marizes the safety and efficacy of lomefloxacin in the treatment of uncomplicated urinary tract infections, complicated urinary tract infections, acute exacerbations of chronic bronchitis, and for prophylaxis during urinary tract surgery. The clinical data presented are an overview of all clinical studies conducted in the United States to date. The results have been derived from multiple studies in which patients received lomefloxacin or a comparative agent in either blinded or open-label studies. During the course of the clinical program in the United States, lomefloxacin has been compared with oral norfloxacin, ciprofloxacin, and cefaclor, as well as parenteral cefotaxime. In all instances, the once-daily oral administration of lomefloxacin was either equally effective or statistically significantly superior in clinical and/or bacteriologic efficacy to these comparative agents. In addition, the compara- tors were administered either two or three times per day, except in the surgical prophylaxis studies, in which single doses of each antibiotic were administered preoperatively. These results attest to the value of the convenience and simplicity of the oral dosing regimen for lomefloxacin. During the course of the clinical-program, lomefloxacin was well tolerated, with most adverse events of mild to moderate severity. In general, the incidence of adverse events for patients and subjects receiving lomefloxacin was comparable to that observed in patients treated with comparator drugs. The most common adverse events were related to the gastrointestinal tract (nausea and diarrhea), the skin and appendages (photosensitivity), and the central nervous system (dizziness and headache).

From Searle, Skokie, Illinois. Reprints should be addressed to Emad Rlzk. M.D.. Searle, 5200 Old Orchard

Road, Skokie, Illinois 60077.

A sub-analysis of adverse events in the respiratory studies demonstrated that concomitant administration of lomefloxacin and theophylline does not increase the incidence of adverse events when compared to lomefloxacin alone. An additional sub-analysis also showed that the incidence of adverse events in elderly patients was similar to that in younger patients. The results of the U.S. clinical program indi- cate that lomefloxacin administered orally once daily is effective and well tolerated in a variety of infections of bacterial origin.

L omefloxacin is a difluorinated quinolone that combines excellent pharmacokinetic character-

istics with a broad spectrum of antimicrobial activity [1,2]. Bactericidal in nature, lomefloxacin is highly active against nearly all enteric pathogens (including multiresistant strains), fastidious organisms (including P-lactamase-positive strains), staphylococci (including methicillin-resistant strains), and Legionella spp. Its activity in vitro also extends to such important pathogens as Pseu- domonas aeruginosa and Acinetobacter spp. It is moderately active against the streptococci (including enterococci), Ureaplasma spp. and Myco- plasma spp., and Chlamydia trachomatis.

This broad-spectrum activity in vitro is com- plemented by the nearly complete absorption of lomefloxacin from the gastrointestinal tract (>98%), which is followed by rapid and widespread tissue distribution [1,2]. A terminal half-life of ‘7-8 hours, a significant postantibiotic effect (PAE), and extended availability in the plasma and tissues coupled with low protein binding provide the basis for a dosing schedule that is less frequent than those of currently available quinolones. This report provides evidence for the clinical and bacteriologic efficacy of once-daily lomefloxacin in a variety of bacterial infections.

METHODOLOGY The clinical trials reviewed in this report include

the U.S. studies sponsored by Searle (Chicago, Illi- nois). In most studies, lomefloxacin was compared in a randomized, controlled fashion with another

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fluoroquinolone or other standard antimicrobial regimen. In addition, 570 subjects (416 treated with lomefloxacin) were involved in various pharmacokinetic and pharmacodynamic studies.

Clinical success was defined as “cure” (elimination of all baseline signs and symptoms) or “im- provement” (decrease of at least one severity grade in at least one baseline sign or symptom with none worsening). Bacteriologic “eradication” in urinary tract infections was defined as the absence of the baseline pathogen(s) (5 lo4 colony-forming units (CFU)/mL) at the end of treatment. In respiratory tract infections, bacteriologic eradication was defined as elimination of the baseline pathogen or the absence of suitable material for culture at the end of treatment. Prophylactic success was defined as the absence of a pathogen (<lo5 CFU/ml) from urine cultures obtained within 5 days following surgery.

In this review, patients who had a documented baseline pathogen but who did not have a recorded clinical or bacteriologic outcome were excluded from the evaluation for that outcome, whereas in other published reviews, these patients were counted as failures. This difference results in slightly different efficacy rates, particularly in acute exacerbation of chronic bronchitis. It is be- lieved that the data presented here may be more representative of the efficacy rates expected in ac- tual clinical use in patients infected with susceptible pathogens.

In all studies involving patients with infections

(except one dose-comparison study in acute exacerbation of chronic bronchitis), lomefloxacin was administered orally as a 400-mg dose once daily. The comparative antimicrobial agents utilized in these studies were administered at their usual doses two or three times daily. The duration of therapy for all studies was 7-14 days. In the studies evaluating the prevention of infection in transurethral surgery, lomefloxacin was administered as a single 400-mg oral dose 2-6 hours prior to surgery, whereas the comparative cephalosporins were given parenterally at their usual dose 30-90 minutes prior to surgery.

UNCOMPLICATED URINARY TRACT INFECTION In two randomized, controlled studies comparing

lomefloxacin (400 mg once daily) with norfloxacin (400 mg twice daily) in uncomplicated urinary tract infection, a total of 420 patients were evaluable for clinical efficacy, and 424 for bacteriologic efficacy (Table I). Lomefloxacin treatment resulted in clinical success in 99.1% of patients, whereas norfloxa- tin was clinically successful in 93.5% of patients. This difference was statistically significant (p = 0.002). The bacteriologic responses to the two treatments were similar, 98.2% for lomefloxacin and 96.3% for norfloxacin (p = nonsignificant). High pathogen eradication rates were also observed (Table II), including eradication of all strains of Staphylococcus saprophyticus.

TABLE I

Clinical and Bacteriologic Efficacy of Lomefloxacin and Norfloxacin in Evaluable Patients with Uncomplicated Urinary Tract Infections

Drug Dose (Oral) Patients

Evaluated

Clinical Outcome

Cured t Improved (%) p Value

Patients Evaluated

Bacteriologic Outcome

Pathogens Eradicated (%) p Value

q.d. = once dally; b.i.d. = twice daily; NS = not statistically significant.

Lomefloxacln 400 mg q.d. 218 216 98.2 Norfioxacin 400 mg b.1.d. 202 2 0.002 208 96.3 NS

TABLE II

Bacteriologic Eradication by Pathogen for Lomefloxacin and Notfloxacin in Patients with Uncomplicated Urinary Tract Infection

Pathogen

Eschenchti co2 Klebsiela pneumoniae Proteus mKabi/is Staphylococcus s-eprophflkus

Lomefloxacin

Pathogens Pathogens Eradicated Evaluated

(%I (4

98.3 173 100 7 100 16 100 13

Norfloxacin

Pathogens Eradicated

6)

97.1 85.7

100 100

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TABLE III

Clinical and Bacteriologic Efficacy of Lomefloxacin and Comparative Agents in Evaluable Patients with Complicated or Recurrent Urinary Tract Infection (Comparative and Noncomparative Studies)


Evaluated

Clinical Outcome


Patients Evaluated



Lomefloxacin 400 mgq.d. 92 Noriloxacin 400 mg b.i.d. 97

Lomefloxacin 400 mg q.d. Ciprofloxacin 500 mg b.i.d. ii

tomefloxacin 400 mgq.d. 63 I q.d. = once daily; b.i.d. = twxe daily; NS = not statistically significant.

88.0 893

98.6 95.7

92.1

NS

NS

-

92 97

:i

63

91.3 78.4

97.2 95.7

79.4

0.015

NS

-

TABLE IV

Bacteriologic Eradication by Pathogen for Lomefloxacin and Comparative Agents in Patients with Complicated or Recurrent Urinary Tract Infection (Comparative Studies)

Pathogen

Lomefloxacin

Pathogens Pathogens Evaluated Eradicated

(4 (%I

Nortloxacin

Pathogens E::: Eradicated

h) (%I

Lomefloxacin

Pathogens Pathogens Evaluated Eradicated

hl (%I

Ciprofloxacin

Pathogens EL%2 Eradicated

(d (%I

Escherichia co/i Klebsiella pneumoniae Proteus mifabilis k?udomonas aeruginosa Group D streptococci

40 15 10 6 5

95.0 93.3

loo.0 83.3 60.0

83.0 75.0 80.0 87.5 66.7

66 6

- - -

97.0 100.0 - - -

65 95.4 4 100.0

- - - - - -

COMPLICATED OR RECURRENT URINARY TRACT ACUTE EXACERBATION OF CHRONIC INFECTION BRONCHITIS

In complicated or recurrent urinary tract infection, lomefloxacin (400 mg once daily) was compared in three randomized, controlled studies to norfloxacin (400 mg twice daily), and ciprofloxacin (500 mg twice daily). In the two norfloxacin comparison studies, the bacteriologic eradication rate for the 92 evaluable patients treated with lomefloxa- tin (91.3%) was significantly superior (p = 0.015) to that observed for the 97 evaluable patients treated with norfloxacin (78.4%) (Table III). Lomefloxacin was very effective in eradicating Escherichia coli and other enteric pathogens. The clinical outcome for the two treatments was similar. No difference was observed in the study comparing once-daily lomefloxacin with twice-daily ciprofloxacin. Both treatments resulted in outstanding clinical and bacteriologic efficacy (Table III). Eradication of the causative pathogens was also comparable (Table IV).

In respiratory tract infection (acute exacerbation of chronic bronchitis), lomefloxacin (400 mg once daily) was compared to cefaclor (250 mg three times daily) in two comparative, multicenter studies. Bacteriologic success rates for lomefloxacin were numerically superior in both studies, and the difference was statistically significant in one study (96.3% for lomefloxacin and 82.2% for cefaclor, p = 0.05).

One dose-ranging study involving 96 evaluable patients demonstrated no significant differences in either bacteriologic or clinical outcome between two dosage regimens of lomefloxacin (400 mglday or twice daily) (Table V).

PROPHYLAXIS IN TRANSURETHRAL SURGERY

Among 63 clinically evaluable patients treated with lomefloxacin in a noncomparative study in complicated urinary tract infections,. 92.1% were treated successfully.

Lomefloxacin was compared to an injectable cephalosporin in two randomized, controlled studies with the objective of preventing urinary tract infection following transurethral surgery. Two studies (499 patients) compared a single oral dose of lomefloxacin (400 mg) given 2-6 hours prior to surgery with a single intramuscular or intravenous



TABLE V

Clinical and Bacteriologic Efficacy of Lomefloxacin and Comparative Agents in Evaluable Patients with Acute Exacerbation of Chronic Bronchitis (Comparative Studies)


Evaluated

Clinical Outcome


Patients Evaluated



Lomefloxacln Cefaclor 400 mg q.d. 250 mg t.i.d. 92.6 96.3 2 93.3 NS iz 82.2 0.05

Lomefloxacin 400 mgq.d. 92.2 Cefaclor 250 mg

t.1.d. 87.0

Lomefloxacin 400 mg q.d. 95.9 Lomefloxacin 400 mg b.i.d.

:; 97.9

q.d. = once daily; b.i.d. = twice dally; t.i.d. = three bmes dally; NS = not statistically signifxant.

NS

NS 49 47

98.0 87.0

85.1 91.5

NS

NS

TABLE VI

Prevention of Infection in Evaluable Patients Following Transurethral Surgery by Lomefloxacin or Comparative Agents (Comparative Studies)

Drug Dose

Lomefloxacin 400mgSD Cefotaxime 1gSD

IM = intramuscularly; IV = mtravenously; SD = single dose.

Route

Oral IV or IM

Patients Evaluated

207 206


Prophylactic Success (%)

98.6 95.1

p Value

0.047

dose of cefotaxime (1 g) given 30-90 minutes prior related to drug treatment (occurring in ~1% of to surgery. In the pooled results from these two 3,399 patients and subjects) were nausea (1.9%), studies (413 evaluable patients), lomefloxacin was -photosensitivity (1.7%), headache (l.l%), and dizzi- significantly superior (p = 0.047) to cefotaxime in ness (1.0%). The majority of the reported events preventing infection (Table VI). Three pathogens were considered mild or moderate in severity. In were isolated from the three patients who became general, the incidence of adverse events considered infected in the lomefloxacin group, whereas 12 to be probably related to drug treatment in patients pathogens were isolated from the 10 patients who or subjects receiving lomefloxacin was comparable became infected in the cefotaxime group. to that for comparator drugs.

SAFETY Results from the worldwide clinical studies pro-

vide evidence for the safety of lomefloxacin. It has been generally well tolerated by the patients in the studies presented in this report, as well as by subjects who received it in pharmacokinetic and pharmacodynamic studies.

Adverse event information has been analyzed for 3,399 patients and subjects treated with lomefloxacin in the initial clinical program. For the 2,869 patients treated with lomefloxacin, the most preva- lent adverse events, regardless of attribution to treatment, were related to the gastrointestinal system (nausea in 3.7% of patients and diarrhea in 1.4%), skin and skin appendages (photosensitivity in 2.4%), and central and peripheral nervous sys- tems (headache in 3.2% and dizziness in 2.3%). Adverse events judged by the investigators to be

The incidence of adverse events in elderly patients treated with lomefloxacin was similar to that observed in younger patients. Concurrent administration of theophylline did not increase the incidence of adverse events. This was determined by analysis of the subset of studies in which theophylline usage was likely, specifically those involving acute exacerbations of chronic bronchitis. In this analysis, 103 patients treated with lomefloxacin plus theophylline were compared with 150 patients who received lomefloxacin without concurrent theophylline. A similar incidence of probably related adverse events (7.0%) occurred in both groups. In addition, none of the patients in the lomefloxacin plus theophylline group experienced any central nervous system-related adverse event attributable to treatment.

None of the observed laboratory abnormalities that were attributable to lomefloxacin were clini-

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tally significant, nor were any serious enough to interrupt therapy. Changes in laboratory parameters listed as adverse events for patients who received lomefloxacin, without regard to relation- ship to treatment, were: hepatic, elevations of ala- nine aminotransferase (ALT)/serum glutamic py- ruvic transaminase (SGPT) (0.4%), aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) (0.4%), bilirubin (0.1%) and alkaline phosphatase (0.1%); hematologic, monocy- tosis (0.4%), decreased blood platelets (O.l%), decreased hemoglobin (0. I%), and elevated erythro- cyte sedimentation rate (ESR) (0.1%); renal, elevated blood urea nitrogen (BUN) (0.2%) and decreased potassium (0.1%).

Crystalluria, although reported for other quinolones [3-51, has not been observed in clinical trials with lomefloxacin.

During the clinical investigation of lomefloxacin, increases in minimum inhibitory concentration (MIC) values were infrequently observed for those few pathogens that persisted during therapy [2]. Super-infections occurred in 4.2% of the patients treated with lomefloxacin in the clinical trials, a rate not dissimilar to that observed with the comparative agents (6.0%) [21.

COMMENT This overview of the clinical efficacy of lome-

floxacin demonstrates its efficacy as a 400-mg oral dose in a wide variety of bacterial infections. Lomefloxacin was at least as effective as standard antimicrobial therapy in these infections, while of- fering the convenience of a once-daily dosing regimen.

The broad-spectrum activity in vitro of lomefloxacin has been demonstrated in two large studies [2], one involving 295 centers in 39 countries that tested the susceptibilities of nearly 600,000 clinical isolates. In this study, 93% of 369,000 gram-negative isolates were susceptible to lomefloxacin and another 2% were moderately susceptible. Of the 213,000 gram-positive isolates, 67% were susceptible and 13% were moderately susceptible.

Lomefloxacin is bactericidal, and the concentration at which killing occurs is generally equal to or no more than two-fold higher than the MIC value [6-81. In vitro studies have also shown that bacterial killing is rapid, with a 99% reduction in CFU of most organisms within 2 hours at two times the MIC [7-g].

As with other quinolones, the antimicrobial activity of lomefloxacin results primarily from the selec- tive inhibition of bacterial DNA gyrase [lo]. How- ever, the demonstrated ability of lomefloxacin to

reduce bacterial virulence factors and enhance phagocytic killing by polymorphonuclear leukocytes may also play a role in its clinical efficacy [11,123.

The efficacy of lomefloxacin in urinary tract infections is not unexpected, given its in vitro activity against nearly all urinary tract pathogens coupled with concentrations in the urine that are more than 100 times simultaneous concentrations in the plasma [2]. Even at the end of a 24-hour dosing pe- riod, urine concentrations significantly exceed the MIC values of nearly all urinary pathogens.

Efficacy in urinary tract infections extends to the prevention of such infections in patients undergoing transurethral surgery. Evidence is presented here that indicates that lomefloxacin may offer superior efficacy to that provided by injectable cephalosporins in this indication. In addition to having an oral agent that can be administered as much as 6 hours prior to surgery, the potential cost savings of preventing an infection that would require additional hospitalization is of particular significance.

For infections outside the urinary tract, the nearly complete (>98%) oral bioavailability of lomefloxacin is an important factor. Although the MI& values of lomefloxacin for many organisms are higher than those for ciprofloxacin, the excel- ,lent pharmacokinetics of lomefloxacin suggest the likelihood of comparable clinical efficacy [13]. Cou- pled with higher plasma concentrations, the longer elimination half-life of lomefloxacin provides for a substantially greater area under the serum concentration-time curve than that of ciprofloxacin [2,13]. The concentration of lomefloxacin in tissues and body fluids generally exceeds the corresponding plasma concentration [2]. In fact, high concentrations of lomefloxacin are found in polymorphonuclear leukocytes [11,12], which are attracted to the site of an infection. The excellent efficacy of lomefloxacin in the various infections described in this report is consistent with these theoretical con- siderations.

The utility of some other fluoroquinolones in respiratory tract infections is limited by their interaction with methylxanthines, such as theophylline and caffeine [14-181. Extensive pharmacologic investigation has shown that this interaction does not occur with lomefloxacin [2,19-251, a result that is confirmed by the low frequency of central nervous system toxicity in patients treated with lomefloxacin in the clinical program. The interaction of lomefloxacin with antacids or anti-ulcer medica- tions containing aluminum or magnesium cations is comparable to most other quinolones [2,26-331. In fact, clinically insignificant reductions in the bioa-



SYMF’OSIUM ON ONCE-A-DAY QUINOLONE / RIZK

vailability of lomefloxacin occur in patients taking Maalox@ or sucralfate if they are administered 2 hours before or 2 hours after lomefloxacin [34,35].

A potentially important patient population that may benefit from the simplicity and convenience that lomefloxacin offers is the elderly. The pharmacokinetic parameters of lomefloxacin are only slightly altered in these patients [2]. No dosage ad- justment is required in the elderly (or in younger patients) unless the creatinine clearance is ~30 mL/ min/l. 73 m2.

In conclusion, consistently excellent clinical and bacteriologic results have been obtained to support the use of once-a-day lomefloxacin in the treatment of patients with bacteriologically proven complicated, recurrent, and uncomplicated urinary tract infections, in acute exacerbations of chronic bronchitis caused by susceptible pathogens, and in the prevention of post-surgical urinary tract infection in patients undergoing transurethral surgery.

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26. Hoffkin G, Borner K, Glatzel PD, Koeppe P, Lode H. Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur J Clin Microbial 1985; 4: 345-8. 27. Frost RW, Lettieri JT, Noe A, Shamblen EC, Lasseter K. Effect of aluminum hydroxide and calcium carbonate antacids on ciprofloxacin bioavailability. Clin Phar- macol Ther 1989; 45: 165. 28. Badran M, Eckert HG, Malerczyk V, Meyer BH, Muller FO, Niehsen W. Influence of antacids as concomitant medication on ofloxacin pharmacokinebcs in healthy volunteers. Eur J Clin Pharmacol 1989; 36 (Suppl): 11-35. 29. Grasela TH Jr, Schentag JJ, Sedman Al, et al. Inhibition of enoxacin absorption by antacids or ranitidine. Antimicrob Agents Chemother 1989; 33: 615-7. 30. Parpia SH, N.X DE, Hejmanowski LG. Goldstein HR, Wilton JH, Schentag JJ. Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrob Agents Chemother 1989; 33: 92-102. 31. Ryerson B, Toothaker R, Schleyer I, Sedman A, Colburn W. Effect of sucralfate on enoxacin pharmacokinebcs [Abstract 2141. In: Program and Abstracts of the Twenty-Ninth Interscience Conference on Antimrcrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1989 32. Garrelts JC, Godley PJ, Peterie JD, Gerlach EH, Yakshe CC. Sucralfate signifr- cantly reduces ciprofloxacin concentrations in serum. Antimicrob Agents Chemo- ther 1990; 34: 931-3. 33. Kunka RL, Wong YY, Lyon JL. Effect of antacid on the pharmacokrnetics of lomefloxacin. Pharm Res 1988; 5 (Suppl): S165. 34. Foster T, Blouin R. The effect of antacrd timing on lomefloxacin bioavailability [Abstract 12771. In: Program and Abstracts of the TwentyNinth interscience Confer- ence on Antimicrobial Agents and Chemotherapy. Washington, DC: American Soci- ety for Microbiology, 1989 35. N-X D, Schentag J. Lomefloxacin absorption kinebcs when administered with ranitidine and sucralfate [Abstract 12761. In: Program and Abstracts of the Twenty- Ninth Interscience Conference on Antimicrobial Agents and Chemotherapy. Wash- ington, DC: American Society for Microbiology, 1989.

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