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REVIEW ARTICLE LEVOFLOXACIN: A POTENT ANTIBIOTIC INTRODUCTION

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REVIEW ARTICLE

LEVOFLOXACIN: A POTENT ANTIBIOTIC

Rahila Bano*, Adeel Arsalan, Iqbal Ahmad, Zufi Shad

ABSTRACT

Levofloxacin is a third generation fluoroquinolone antibacterial agent with a broad spectrum

activity against Gram-positive and Gram-negative bacteria and atypical pathogens. It shows its

bacteriocidal activity by inhibiting topoisomerase IV and DNA gyrase. Levofloxacin has shown

strong antibacterial activity against Staphylococcus species, Streptococcus pyogenes,

Streptococcus pneumoniae. Staphylococcus haemolyticus, Enterobacter species, Escherichia

coli, Salmonella species Klebsiella species Serratia species, Enterococcus species, Proteus.

Species, Pseudomonas aeruginosa, Haemophilus influenzae and Neisseria gonorrhoea.

Moreover, levofloxacin has showed antifungal activity against Chlamydia trachomatis. It is also

active against penicillin-resistant Streptococcus pneumoniae. It also possesses killing effect on

resistant mycobacteria like Mycobacterium tuberculosis and Mycobacterium leprae causing

tuberclosis and even Mycoplasma species of HIV infection. It is indicated in the treatment of

urinary tract infection, respiratory tract infection, biliary tract infection and other infection with

clinical efficacy of 80-92%.

*Corresponding author: rahee_qasim@hotmail.com

Baqai Institute of Pharmaceutical Sciences

2

INTRODUCTION

Antibiotics are among the most frequently prescribed medications in modern medicin, they cure

disease by killing or inhibiting bacteria. The first antibiotic was penicillin, discovered

accidentally from a penicillium notatum.1 Today, over 100 different antibiotics are available to

doctors to cure minor discomforts as well as life- threatening infections.

Although antibiotics are useful in a wide variety of infections, it is important to realize that

antibiotics not only treat bacterial infections but also used in the prevention of infection.

Antibiotics were once considered as “wonder drugs”. Antibiotics are used for decades to

effectively treat a number of bacterial infections. Unfortunately, due to the overuse and misuse of

antibiotics, the resistant of bacteria may develop globally. The resistant is now become a fire

alarm to health care professionals.

History of Antibiotics

Pasteure and Joubert were among the first to recognize the potential of microbial products as

therpeutic agents in 1877.1 Penicillin becomes available for clinical use in 1941. Streptomycin,

chloramphenicol, and clarithromycin were identified towards the end of or soon after world war

II.1 Then after, numerous classes of antimicrobial agents have been discovered. Antibiotic are

effecftive against a number of microorganisms. They are used in the treatment of different

bacterial infections such as respiratory tract, gastrointestinal tract, urinary tract, skin and soft skin

tissue infections, nose and throat infections, meningitis, gonorrhea and dental abscess, septiemia

and pneumnia etc.2

Quinolones and Fluoroquinolones

With the increasing number of available quinolone antibiotics, prescribing these drugs has

become a challenge. Compared with older quinolones such as norfloxacin and ciprofloxacin, the

newer agents have an expanded antimicrobial spectrum and new indications. The most recently

released agents have significant antimicrobial activity against Gram-positive, Gram-negative,

atypical pathogens and anaerobes. The new classification of quinolone antibiotics by generation

3

can help family physicians prescribe these agents appropriately and evaluate new drugs as they

are introduced.3

The fluoroquinolones are broad-spectrum antibiotics with particular activity against Gram-

negative organisms, especially Pseudomonas aeruginosa. These agents are well absorbed when

given orally. Because tissue and fluid concentrations often exceed the serum drug concentration,

these antibiotics are particularly useful for certain infections, such as pneumonia.4-5

History and Chemistry of Quinolone

The original quinolone antibiotics included nalidixic acid, cinoxacin and oxolinic acid. The

addition of fluoride to the original quinolone antibiotic compounds yielded a new class of drugs,

the fluoroquinolones, which have a broader antimicrobial spectrum and improved

pharmacokinetic properties.6

Mode of Action

Physical studies have further defined interactions of quinolones with their principal target, DNA

gyrase. The binding of quinolones to the DNA gyrase-DNA complex suggests two possible

binding sites of differing affinities. Mutations in either the gyrase A gene (gyrA) or the gyrase B

gene (gyrB) that affect quinolones susceptibility also affect drug binding, with resistance

mutations causing decreased binding and hypersusceptibility mutations causing increased

binding.7 Regulation of expression of membrane efflux transporters may contribute to quinolone

susceptibility in both Gram-positive and Gram-negative bacteria. The substrate profile of the

nalidixic acid efflux transporter of bacteria correlates with the extent to which the activity of

quinolone substrates is affected by over expression of nalidixic acid. In addition, the Emr

transporter of Escherichia coli affects susceptibility to nalidixic acid, and the MexAB OprK

transport system of P. aeruginosa affects susceptibility to ciprofloxacin.2

The fluoroquinolones are bactericidal antibiotics that act by specifically targeting DNA gyrase.8

In contrast to amino glycosides and beta lactams, some fluoroquinolones are active against

dormant and replicating bacteria.9 Fluoroquinolones exhibit a post-antibiotic effect following

bacterial exposure to inhibitory concentrations. The antibacterial effect continues for

4

approximately two to three hours after bacteria are exposed to these drugs, despite sub-inhibitory

concentrations. The duration of the post-antibiotic effect may be increased with longer bacterial

drug exposure and higher drug concentrations.

Classification of Quinolone Antibiotics

First Generation

The first-generation agents include cinoxacin and nalidixic acid, which are the oldest and least

often used quinolones. Because minimal serum levels are achieved, use of these drugs has been

restricted to the treatment of uncomplicated urinary tract infections.

Second Generation

Second generation agents include ciprofloxacin, enoxacin, lomefloxacin, norfloxacin and

ofloxacin. These quinolones have increased Gram-negative activity, as well as some Gram-

positive and atypical pathogen coverage. Compared with first-generation drugs and considered as

a group, these agents have broader clinical applications in the treatment of complicated urinary

tract infections and pyelonephritis, sexually transmitted diseases, selected pneumonias and skin

infections. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa.10-11

Because

of its good penetration into bone Ciprofloxacin and ofloxacin are the most widely used second-

generation quinolones because of their availability in oral and intravenous formulations.

Third Generation

The third generation quinolones currently include levofloxacin, gatifloxacin, moxifloxacin and

sparfloxacin. These agents are separated into a third class because of their expanded activity

against Gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant

Streptococcus pneumoniae, and atypical pathogens such as Mycoplasma pneumoniae and

Chlamydia pneumoniae.5, 10, 12

Although the third-generation quinolones retain broad Gram-

negative coverage. Because of their expanded antimicrobial spectrum, third-generation

quinolones are useful in the treatment of community-acquired pneumonia, acute sinusitis and

acute exacerbations of chronic bronchitis.

5

Fourth Generation

Trovafloxacin, currently the only member of the fourth-generation class, adds significant

antimicrobial activity against anaerobes while maintaining the Gram-positive and Gram-negative

activity of the third-generation quinolone.

LEVOFLOXACIN

Levofloxacin is the optical S- (-) isomer of ofloxacin which has been developed by the Daiichi

Seiyaku Pharmaceutical Co. Ltd, in Japan. Ofloxacin is a racemic mixture, but the S-isomer has

antibacterial activity 32- to 128-fold more potent than the R-isomer – hence most of the

antibacterial activity of ofloxacin is due to the S-isomer. Levofloxacin has been developed to

take advantage of this antibacterial potency while requiring only about half the usual dose of

ofloxacin to achieve similar efficacy, but potentially with an improved toxicity profile.13-17

Mechanism of Action

Levofloxacin is the L-isomer of the racemate, ofloxacin, and a quinolone antibacterial agent. The

antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of

levofloxacin and other quinolone antibacterials involves inhibition of DNA gyrase, an enzyme

required for DNA replication, transcription, repair and recombination. Levofloxacin has in vitro

activity against a wide range of Gram-negative and Gram-positive micro-organisms.

Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory

concentrations.18-19

Antibacterial Activity

Levofloxacin is a broad-spectrum antibacterial agent against Gram-positive and Gram-negative

bacteria including anaerobes. Levofloxacin has shown strong antibacterial activities against

Staphylococcus species, Streptococcus pyogenes, Streptococcus pneumoniae. Staphylococcus

haemolyticus, Enterobacter species, Escherichia coli, Salmonella species Klebsiella species

Serratia species, Enterococcus species, Proteus. species and other glucose non fermentive Gram-

negative rod Pseudomonas aeruginosa, Haemophilus influenzae and Neisseria gonorrhoea.

More over levofloxacin has shows antibacterial activity against Chlamydia trachomatis.19-20

6

Gram-Negative Bacteria

Levofloxacin is about two-folds more active than ofloxacin and generally two to four fold less

active than ciprofloxacin against most Enterobacteriaceae and P.aeruginosa. The MIC90 of

levolfoxacin against P.aeruginosa is generally 4-8 µg per ml. Similary, levofloxacin is

comparable with, or one-or two dilutions inferior to ciprofloxacin in its activity against H.

influenzae, N. gonorrhoeae and Moraxella caterhalis, with MIC90 values of 0.015 -0.06 µg per

ml.21-24

Similar levofloxacin activity has been noted against Gram-negative pathogens isolated

from cancer patients-a clinical setting in which levofloxacin may have a future role.22

Levofloxacin has good activity against both Pasteurella species and Eikenella corrodens with

MIC90 values of 0.015 µg per ml.25

The MIC90 of levofloxacin against Legionella pneumophila is

0.125 µg per ml, compared with 0.25 µg per ml for ofloxacin.26

Levofloxacin is slightly more active against Bacteroides fragilis than ciprofloxacin with an

MIC90 2 µg per ml; but in general, levofloxacin can only be considered to have low activity

against anaerobes Fusobacterium species are resistant (MIC90 64µg per ml).21,27

Gram-Positive Bacteria

Levofloxacin is about two fold more active than ciprofloxacin against penicillin-susceptible and

resistant S. pneumoniea (MIC90 2µg per ml) and two to four fold more active against methicillin-

susceptible Staphlococcus aureus (MIC90 0.5µg per ml) Activity against methicillin-resistant

S.aureus (MRSA) is less impressive with MIC90 16µg per ml. concentrations of 1-2 µg per ml

inhibit 90% of Streptococci, while the MIC90 against Enterotoccus faecalis is generally no better

than 2µg per ml. Indeed, 28

found only 39% of vancomycin-susceptible and 11% vancomycin-

resistant strains of Enterococci were susceptible to <2 mg per ml levofloxacin. Levofloxacin has

variable activity against Listeria monocytogenes (MIC90 2-8 µg per ml) and is poorly active

against Corynebacterium jeikeium (MIC90 > 64 µg per ml).22-24, 29-31

Levofloxacin has variable activity against Gram-positive anaerobes, with MIC90 8µg per ml

against Peptostreptococcus species and broadly similar activity against Clostridium species.21, 25,

27

7

Mycobacteria

In vivo studies of Mycobacterium tuberculosis suggest that levofloxacin activity is comparable

with that produced by two-folds greater dosage of ofloxacin, although the MIC90 values for both

drugs are similar at 1 µg per ml. Sparfloxacin has better activity with MIC90 0.5µg per ml.32

Several workers have found similar findings in vitro.33-34

Rifampicin and isoniazid were more

active than levolfoxacin in a murine model of tuberculosis, but there was little difference in

activity between levofloxacin and ethambutol or pyrazinabide.35

Levofloxacin (MIC90 0.75 µg

per ml) has two fold greater bactericidal activity against Mycobacterium leprae then ofloxacin.36

Mycoplasma

Levofloxacin is active against Mycoplasma fermentans, the Mycoplasma species isolated in

patients with HIV infection, with MIC90 0.078 µg per ml.37

Pharmacokinetics

Absorption

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak

plasma concentrations are usually attained one to two hours after oral dosing. The absolute

bioavailability of a 500 mg oral dose of levofloxacin is approximately 99%.2 Levofloxacin

pharmacokinetics is linear and predictable after single and multiple oral dosing regimens. Steady

state is reached with in 48 hours following a 500 mg once-daily regimen. The peak and through

plasma concentrations attained following multiple once-daily oral 500 mg regimens were

approximately 5.7 and 0.5 mcg/ml, respectively.38

Oral administration with food slightly prolongs the time to peak concentration by approximately

1 hour and slightly decreases the peak concentration by approximately 14%. Therefore

levofloxacin can be administered without regard to food. The plasma concentration profile of

levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to

that observed for levofloxacin tablets when equal doses (mg/ml) are administered. Therefore, the

oral and IV routes of administration can be considered interchangeable.39-41

Distribution

8

The mean volume of distribution of levofloxacin generally ranges from 89 to 112 L after single

and multiple 500 mg doses, indicating widespread distribution into body tissues. Penetration of

levofloxacin into blister fluid is rapid and extensive.2 Levofloxacin also penetrates well into lung

tissues. Lung tissue concentrations were generally two to five folds higher than plasma

concentrations and ranged from approximately 2.4 to 11.3 mcg/ml over a 24-hour period after a

single doseof 500mg oral dose.42-43

Levofloxacin is approximately 24 to 38% bound to serum

proteins across all species studied, as determined by the equilibrium dialysis method.

Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum

proteins is in dependent of the drugs concentration.44-48

Metabolism

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to

its enantiomer, D-ofloxacin.19

Levofloxacin undergoes limited metabolism in humans and is

primarily excreted as unchanged drug in urine. Following oral administration, approximately

87% of an administered dose was recovered as unchanged drug in urine within 48 hours.2

Excretion

Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma

elimination half-life of levofloxacin ranges from approximately six to eight hours following

single or multiple doses of levofloxacin give orally or intravenously. The mean apparent total

body clearance and renal clearance range from approximately 144 to 226 ml/min and 95 to 142

ml/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that

tubular secretion of levofloxacin occurs in addition to its glomerular filtration.18, 49-51

Concomitant administration of either cimetidine or probenecid results in approximately 24% and

35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of

levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of

the urine samples freshly collected from subjects receiving levofloxacin.2

Therapeutic Uses

Therapeutically it is used for urinay tract infection, sinusitis, and chronic bronchitis.

Uncomplicated mild to moderate infection of skin and skin structure including abscesses,

cellulitis and wound infection, acute mild to moderate pyelonephritis against a variety of aerobic

9

Gram-positive and Gram-negative bacteria, including Tubercle bacilli, P. aeruginosa and

Enterococus faecalis are only moderately susceptible. Levofloxacin is also administered

topically as 0.5% eye drop for the treatment of bacterial conjunctivitis.2, 19

Urinary Tract Infections and Prostatitis

Various Japanese studies of levofloxacin 100-200 mg thrice daily for 3-14 days suggest rates of

clinical efficacy of 85-100% in the treatment of uncomplicated and complicated urinary tract

infections.52

Found levofloxacin in 250mg daily for 10 days to have similar efficacy of either

ciprofloxacin 500 mg twice daily for 10 days, or lomefloxacin 400 mg daily for 14 days, in the

treatment of acute pyelonephritis.

Levofloxacin in the treatment of acute and chronic prostatitis, epidiymitis and gonococcal and

chlamydial urethritis.16

in a small open study of 23 patients with acute epididymitis treated with

levofloxacin 100 mg two or three times daily for 14 days, overall clinical efficacy was 100%.53

A

5-day course of 300mg per day levofloxacin was effective in a small study of gonococcal

urethritis.54

Respiratory Tract Infections

Levofloxacin to be effective in the treatment of respiratory tract infections when used in doses

ranging from 200 mg once daily to 200mg thrice daily.16

In one study, treatment of 12 patients

with various lower respiratory tract infections with levofloxacin 200mg once-daily for 7-14 days

resulted in 100% efficacy.17

Other authors using various regimens, including 100-200mg thrice-

daily, have found less satisfactory results with approximately only 50% patients classified as

having a 'good' or 'excellent' clinical outcome. As might be expected, knowing the in vitro

activity of levofloxacin, the rate of P. aeruginosa eradication was low in the 300 mg per day

group, but approached 75% in patients receiving 200 mg thrice daily.55-57

In one of the largest

studies reported, 58

examined the efficacy of either 300 or 600 mg per day in 87 patients who

were managed either as outpatients (300 mg per day for 3 days) or as inpatients (200 mg thrice-

daily for 7 days). Eradication of responsible pathogens was noted in 80% cases by day 7, and

among patients with, pneumonia, clinical efficacy was noted in about 89% cases. A 7- to l4-day

course of levofloxacin 500 mg once-daily appears to be as effective as coftriaxone (l-2 g per

10

day)/cefuroxime (500 mg twice-daily) for community-acquired pneumonia, and cefaclor 250 mg

twice-daily for acute exacerbations of chronic bronchitis.59-60

Biliary Tract Infections

Among 11 patients with biliary tract infections (six cholecystitis; three cholangitis;

cholecystocholangitis and liver abscess) treated with levofloxacin l00-200mg thrice daily for 3-

14 days, clinical outcome was good in eight patients (73%) and in the remainder.61

Other Infections

Non-comparative studies of levofloxacin 100mg thrice-daily for soft tissue and skin infections,

obstetric and gynecological infections and ear, nose and throat infections (occasionally requiring

200mg thrice-daily) have demonstrated overall clinical efficacy in about 80-92% cases.16

Levofloxacin 500 mg once daily for 7 days appears to have efficacy comparable with

ciprofloxacin 500mg twice-daily for 7 days in the treatment of skin and skin structure infections,

with reported rates of cure/improvement in 96.1 % versus 93.5% cases, respectively.62

In one Japanese study of 22 patients with obstetric and gynecological infections, the clinical

efficacy of levofloxacin 200-600mg daily for 3-14 days was 95%.63

In a study of 114 patients

with bacterial enteritis levofloxacin 200-300mg per day for 3-5 days was associated with clinical

cure rate of 97% .16

Toxicity

Doses of 200-600 mg levofloxacin per day appear to be well tolerated with side effects largely

consisting of those noted with all fluorquinolones, such as55, 64-65

Shock: Since shock symptoms may rarely occur, observe patients carefully .if any abnormalities

are observed, discontinue the medication and take appropriate measure.

Hypersensitivity: Anaphylactoid symptoms (erythema, chills, dyspnea), edema, urticaria,

feeling of warmth or photosensitivity may rarely occur and rash or pruritus may infrequently

occur. In the event of such symptoms, discontinue the medication.

11

Dermatological: It has been reported that ofloxacin may rarely cause lyell syndrome or stevens

Johnson syndrome.

Psychoneurological: Convulsion, tremor or numbness may rarely occur, and insomnia,

dizziness or headache may infrequently occur.

Renal: An increase in BUN may infrequently occur it has been reported that ofloxacin may

rarely cause acute renal failure.

Hepatic: An increase in SGOT, SGPT, Alkaline phosphatase, y-GT or total biliribin may

infrequently occur.

Hematologic: A decrease in leukocytes, erythrocytes, hemoglobin or homatocrit or an increase

in eosinophils may infrequently occur. Observe patient carefully, and if any abnormality is

observed, discontinue the medication.

Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea, anorexia, abdominal pain

or enlarged feeling of abdomen may infrequently occur. Since it has been reported that ofloxacin

may rarely cause severe colitis, with blood in the stool, such as pseudomembranous colitis, in the

event of abdominal pain or frequent diarrhea take appropriate measures, including

discontinuation of the medication.

Mascular: Since rhabdomyolysis with rapid deterioration of renal function characterized by

myalgia, weakness, increase in CPK or myoglobin in blood or urine may occur, patient should be

cautioned.

Drug Interactions

Since it has been reported that other quinolones used in combination with non steroidal anti-

inflammatory drugs of phenylacetic/ propionic acid derivatives, such as fenbufen, may rarely

cause convulsions, this product should be administered carefully.66

Antacids containing aluminium or magnesium and drugs containing iron may interfere with the

absorption of levofloxacin resulting in attenuation of the efficacy of levofloxacin. These agents

should be taken atleast two hours before or two hours after levofloxacin administration.2

12

Mode of Administration and Dosage

Oral Administration

The optimal dosage of levofloxacin for various patient populations has yet to be determined, but

most Japanese studies have used 100 mg thrice-daily (occasionally 200 mg thrice-daily) for the

treatment of a variety of infections, including respiratory, skin, biliary genitourinary,

obstetric/gyneocology and eye infections. The usual duration of treatment is single-dose therapy

for women with uncomplicated cystitis, 3-5 days for other urinary tract sepsis or gonococcal

urethritis and 7-14 days therapy for most other indications except for prostatitis, when longer

courses may be needed.16

Patients with Renal Failure

Since levofloxacin is mainly excreted unchanged in the urine. Serum levels are sensitive to

changes in renal function. Thus, dosage reduction is required in patients with renal impairment.

In Japanese patients, doses are reduced as follows; glomerular filtration rate (GFR) 40-70 ml per

min, 100 mg twice-daily; GFR 20-40 ml per min, 100mg daily; GFR <20 ml per min, 100mg

every 48 hours.16, 67

No information is available regarding the need for any dosage adjustment in

the elderly or in patients with hepatic failure.

CONCLUSIONS

Levofloxacin is a broad-spectrum antibiotic possess activity against Gram-positive and Gram-

negative and atypical microbes. Due to its lethal action on microorganisms, it has been widely

prescribed in respiratory tract infections, biliary tract infections and urinary tract infections with

clinical efficacy of 80-92%. It shows its bactericidal action on atypical pathogens like

Mycobacteria species and Mycoplasma species. It also possesses its action on resistant bacteria

like penicillin-resistant S. pneumoniae, Salmonella species Pseudomonas aeruginosa,

Haemophilus influenzae. Levofloxacin is well tolerated, and is associated with minimum side

effects.

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13

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