Dailymed

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Maxaquin and other antibacterial drugs, Maxaquin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description

Maxaquin (lomefloxacin HCl) is a synthetic broad-spectrum antimicrobial agent for oral administration. Lomefloxacin HCl, a difluoroquinolone, is the monohydrochloride salt of (±)-1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid. Its empirical formula is C₁₇H₁₉F₂N₃O₃•HCl, and its structural formula is:

Lomefloxacin HCl is a white to pale yellow powder with a molecular weight of 387.8. It is slightly soluble in water and practically insoluble in alcohol. Lomefloxacin HCl is stable to heat and moisture but is sensitive to light in dilute aqueous solution.

Maxaquin is available as a film-coated tablet formulation containing 400 mg of lomefloxacin base, present as the hydrochloride salt. The base content of the hydrochloride salt is 90.6%. The inactive ingredients are carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyoxyl 40 stearate, and titanium dioxide.

Clinical Pharmacology

Pharmacokinetics in healthy volunteers

In 6 fasting healthy male volunteers, approximately 95% to 98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid following single doses of 200 and 400 mg (T_max 0.8 to 1.4 hours). Mean plasma concentration increased proportionally between 100 and 400 mg as shown below:

Dose (mg)	Mean Peak PlasmaConcentration(µg/mL)	Area Under Curve(AUC)(µg∙h/mL)
100	0.8	5.6
200	1.4	10.9
400	3.2	26.1

In 6 healthy male volunteers administered 400 mg of lomefloxacin on an empty stomach qd for 7 days, the following mean pharmacokinetic parameter values were obtained:

Cmax	2.8 µg/mL
Cmin	0.27 µg/mL
AUC0–24 h	25.9 µg∙h/mL
Tmax	1.5 h
t1/2	7.75 h

The elimination half-life in 8 subjects with normal renal function was approximately 8 hours. At 24 hours postdose, subjects with normal renal function receiving single doses of 200 or 400 mg had mean plasma lomefloxacin concentrations of 0.10 and 0.24 µg/mL, respectively. Steady-state concentrations were achieved within 48 hours of initiating therapy with one-a-day dosing. There was no drug accumulation with single-daily dosing in patients with normal renal function.

Approximately 65% of an orally administered dose was excreted in the urine as unchanged drug in patients with normal renal function. Following a 400-mg dose of lomefloxacin administered qd for 7 days, the mean urine concentration 4 hours postdose was in excess of 300 µg/mL. The mean urine concentration exceeded 35 µg/mL for at least 24 hours after dosing.

Following a single 400-mg dose, the solubility of lomefloxacin in urine usually exceeded its peak urinary concentration 2- to 6-fold. In this study, urine pH affected the solubility of lomefloxacin with solubilities ranging from 7.8 mg/mL at pH 5.2, to 2.4 mg/mL at pH 6.5, and 3.03 mg/mL at pH 8.12.

The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing, with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide metabolite. The mean renal clearance was 145 mL/min in subjects with normal renal function (GFR = 120 mL/min). This may indicate tubular secretion.

Food effect

When lomefloxacin and food were administered concomitantly, the rate of drug absorption was delayed (T_max increased to 2 hours [delayed by 41%], C_max decreased by 18%), and the extent of absorption (AUC) was decreased by 12%.

Pharmacokinetics in the geriatric population

In 16 healthy elderly volunteers (61 to 76 years of age) with normal renal function for their age, the half-life of lomefloxacin (mean of 8 hours) and its peak plasma concentration (mean of 4.2 µg/mL) following a single 400-mg dose were similar to those in 8 younger subjects dosed with a single 400-mg dose. Thus, drug absorption appears unaffected in the elderly. Plasma clearance was, however, reduced in this elderly population by approximately 25%, and the AUC was increased by approximately 33%. This slower elimination most likely reflects the decreased renal function normally observed in the geriatric population.

Pharmacokinetics in renally impaired patients

In 8 patients with creatinine clearance (Cl_Cr) between 10 and 40 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 335% over the AUC demonstrated in patients with a Cl_Cr> 80 mL/min/1.73 m². Also, in these patients, the mean t_1/2 increased to 21 hours. In 8 patients with Cl_Cr< 10 mL/min/1.73 m², the mean AUC after a single 400-mg dose of lomefloxacin increased 700% over the AUC demonstrated in patients with a Cl_Cr> 80 mL/min/1.73 m². In these patients with Cl_Cr< 10 mL/min/1.73 m², the mean t_1/2 increased to 45 hours. The plasma clearance of lomefloxacin was closely correlated with creatinine clearance, ranging from 31 mL/min/1.73 m² when creatinine clearance was zero to 271 mL/min/1.73 m² at a normal creatinine clearance of 110 mL/min/1.73 m². Peak lomefloxacin concentrations were not affected by the degree of renal function when single doses of lomefloxacin were administered. Adjustment of dosage schedules for patients with such decreases in renal function is warranted. (See Dosage and Administration.)

Pharmacokinetics in patients with cirrhosis

In 12 patients with histologically confirmed cirrhosis, no significant changes in rate or extent of lomefloxacin exposure (C_max, T_max, t_1/2, or AUC) were observed when they were administered 400 mg of lomefloxacin as a single dose. No data are available in cirrhotic patients treated with multiple doses of lomefloxacin. Cirrhosis does not appear to reduce the nonrenal clearance of lomefloxacin. There does not appear to be a need for a dosage reduction in cirrhotic patients, provided adequate renal function is present.

Metabolism and pharmacodynamics of lomefloxacin

Lomefloxacin is minimally metabolized although 5 metabolites have been identified in human urine. The glucuronide metabolite is found in the highest concentration and accounts for approximately 9% of the administered dose. The other 4 metabolites together account for < 0.5% of the dose.

Approximately 10% of an oral dose was recovered as unchanged drug in the feces.

Serum protein binding of lomefloxacin is approximately 10%.

The following are mean tissue- or fluid-to-plasma ratios of lomefloxacin following oral administration. Studies have not been conducted to assess the penetration of lomefloxacin into human cerebrospinal fluid.

Tissue or Body Fluid	Mean Tissue- or Fluid-to-Plasma Ratio
Bronchial mucosa	2.1
Bronchial secretions	0.6
Prostatic tissue	2.0
Sputum	1.3
Urine	140.0

In two studies including 74 healthy volunteers, the minimal dose of UVA light needed to cause erythema (MED-UVA) was inversely proportional to plasma lomefloxacin concentration. The MED-UVA values (16 hours and 12 hours postdose) were significantly higher than the MED-UVA values 2 hours postdose at steady state. Increasing the interval between lomefloxacin dosing and exposure to UVA light increased the amount of light energy needed for photoreaction. In a study of 27 healthy volunteers, the steady state AUC values and C_min values were equivalent whether the drug was administered in the morning or in the evening.

Microbiology

Lomefloxacin is a bactericidal agent with in vitro activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin results from interference with the activity of the bacterial enzyme DNA gyrase, which is needed for the transcription and replication of bacterial DNA. The minimum bactericidal concentration (MBC) generally does not exceed the minimum inhibitory concentration (MIC) by more than a factor of 2, except for staphylococci, which usually have MBCs 2 to 4 times the MIC.

Lomefloxacin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections: (See Indications and Usage.)

Gram-positive aerobes

•  Staphylococcus saprophyticus

Gram-negative aerobes

•  Citrobacter diversus
•  Enterobacter cloacae
•  Escherichia coli
•  Haemophilus influenzae
•  Klebsiella pneumoniae
•  Moraxella catarrhalis
•  Proteus mirabilis
•  Pseudomonas aeruginosa (urinary tract only—See Indications and Usage and Warnings)

The following in vitro data are available; however, their clinical significance is unknown.

Lomefloxacin exhibits in vitro MICs of 2 µg/mL or less against most strains of the following organisms; however, the safety and effectiveness of lomefloxacin in treating clinical infections due to these organisms have not been established in adequate and well-controlled trials:

Gram-positive aerobes

•  Staphylococcus aureus (including methicillin-resistant strains)
•  Staphylococcus epidermidis (including methicillin-resistant strains)

Gram-negative aerobes

•  Aeromonas hydrophila
•  Citrobacter freundii
•  Enterobacter aerogenes
•  Enterobacter agglomerans
•  Haemophilus parainfluenzae
•  Hafnia alvei
•  Klebsiella oxytoca
•  Klebsiella ozaenae
•  Morganella morganii
•  Proteus vulgaris
•  Providencia alcalifaciens
•  Providencia rettgeri
•  Serratia liquefaciens
•  Serratia marcescens

Other organisms

•  Legionella pneumophila

Beta-lactamase production should have no effect on the in vitro activity of lomefloxacin.

Most group A, B, D, and G streptococci, Streptococcus pneumoniae, Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis, and anaerobic bacteria are resistant to lomefloxacin.

Lomefloxacin appears slightly less active in vitro when tested at acidic pH. An increase in inoculum size has little effect on the in vitro activity of lomefloxacin. In vitro resistance to lomefloxacin develops slowly (multiple-step mutation). Rapid one-step development of resistance occurs only rarely (< 10^–9) in vitro.

Cross-resistance between lomefloxacin and other quinolone-class antimicrobial agents has been reported; however, cross-resistance between lomefloxacin and members of other classes of antimicrobial agents, such as aminoglycosides, penicillins, tetracyclines, cephalosporins, or sulfonamides has not yet been reported. Lomefloxacin is active in vitro against some strains of cephalosporin- and aminoglycoside-resistant gram-negative bacteria.

Susceptibility tests

Diffusion techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standardized procedure¹ that has been recommended for use with disks to test the susceptibility of organisms to lomefloxacin uses the 10-µg lomefloxacin disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for lomefloxacin.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-µg lomefloxacin disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥ 22	Susceptible (S)
19–21	Intermediate (I)
≤ 18	Resistant (R)

A report of "susceptible" indicates that the pathogen is likely to be inhibited by generally achievable drug concentrations. A report of "intermediate" indicates that the result should be considered equivocal, and, if the organism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that achievable drug concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control organisms. The 10-µg lomefloxacin disk should give the following zone diameters:

Organism	Zone Diameter (mm)
S aureus (ATCC 25923)	23–29
E coli (ATCC 25922)	27–33
P aeruginosa (ATCC 27853)	22–28

Dilution techniques

Use a standardized dilution method² (broth, agar, or microdilution) or equivalent with lomefloxacin powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (µg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard lomefloxacin powder should provide the following MIC values:

Organism	MIC (µg/mL)
S aureus (ATCC 29213)	0.25–2.0
E coli (ATCC 25922)	0.03–0.12
P aeruginosa (ATCC 27853)	1.0–4.0