What Is Levofloxacin Hemihydrate?

One of quinolones, which has a broad-spectrum antibacterial effect and strong antibacterial effect, against most enterobacteriaceae bacteria, such as Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella and Gram-negative bacteria such as Haemophilus influenzae, Legionella pneumophila, and Neisseria gonorrhoeae have strong antibacterial activity. It also has antibacterial effects on Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Mycoplasma pneumoniae, Chlamydia pneumoniae, but it has a poor effect on anaerobic bacteria and enterococci.

Chinese name: Levofloxacin
Foreign name: Levofloxacin Tablets
Molecular formula: C18H20FN3O41 / 2H2O

Molecular weight: 370.38
Main ingredients: Levofloxacin
Character: This product is yellow or grayish yellow crystalline powder

Levofloxacin compounds

Levofloxacin Basic Information

Chinese name: Levofloxacin

Chinese alias: levofloxacin lactate; levofloxacin hydrate; levofloxacin hydrochloride 1/2 hydrate;

Chemical name: (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyridine Acene [1,2,3-de]-[1,4] benzoxazine-6-carboxylic acid hemihydrate

English name: Levofloxacin Hemihydrate

English alias: Levofloxacin hemihydrate; Levofloxacin; (S) -9-Fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido (1,2, 3-de) -1,4-benzoxazine-6-carboxylic acid hydrate (2: 1);

CAS number: 138199-71-0

Molecular formula: C ₁₈ H ₂₂ FN ₃ O ₅

Molecular weight: 379.38300

Exact mass: 379.15400

PSA: 84.24000

LogP: 1.48260

Physical and Chemical Properties of Levofloxacin

Properties: This product is yellow or grayish yellow crystalline powder; odorless, bitter. Slightly soluble in water, acetone, ethanol, methanol, and easily soluble in acetic acid.

Density: 1.48g / cm ³

Melting point: 214-216 ° C

Boiling point: 571.5ºC at 760mmHg

Flash point: 299.4ºC

Vapor pressure: 6.7E-14mmHg at 25 ° C

Levofloxacin Safety Information

Safety instructions: S24 / 25

Levofloxacin production method

The racemic ofofloxacin is directly resolved into a levorotide through a high-performance liquid chromatography column packed with a special stationary phase; or ofloxacin is treated with hydroxylamine sulfate and acidified with hydrochloric acid to obtain the hydrochloride salt, which is alkaline. After treatment with an ion exchange column, the amphoteric compound obtained is added with (S)-(+)-mandelic acid, which forms a crystal after forming a salt with the (-)-isomer. The product can be obtained through ion exchange resin and then deaminated by reduction. . Or use 2,3,4,5-tetrafluorobenzoic acid as raw material to prepare 2- (ethoxymethylene) -3-oxo-3- (2,3,4,5-tetrafluorophenyl) After ethyl propionate, it is reacted with (S) -2-aminopropanol to introduce asymmetric carbon atoms, which is obtained by ring closure, hydrolysis, and introduction of methylpiperazine. It can also use 2,3, -difluoro-6-nitrophenol as a raw material and react with glycidyl p-toluenesulfonate in the R configuration in the presence of a phase transfer catalyst to form an optically active compound, which is then reduced and reacted with ethoxylate. Diethyl methylene malonate (EMME) was condensed, and finally treated with reagents, ring closure, hydrolysis, and introduction of piperazinyl.

Levofloxacin uses

This product has the characteristics of broad antibacterial spectrum and strong antibacterial effect, and it is effective against most enterobacteriaceae bacteria, such as Klebsiella pneumoniae, Proteus, Salmonella typhimurium, Shigella, influenza bacilli, some E. coli, green pus Bacillus, Neisseria gonorrhoeae, etc. have strong antibacterial activity, and also have good antibacterial effect on some Staphylococci, Streptococcus pneumoniae, Chlamydia, etc. ^[1] .

Levofloxacin Pharmacopoeia Standard

Levofloxacin source (name), content (potency)

This product is (1)-(S) -3-methyl-9-fluoro-2,3-dihydro-10- (4-methyl-1-piperazinyl) -7oxo-7H-pyrido [1,2,3-de] -1,4benzoxazine-6-carboxylic acid hemihydrate. Calculated as anhydrous, the content of levofloxacin (C18H20FN3O4) shall not be less than 98.5%.

Levofloxacin traits

This product is off-white to light yellow crystalline powder, odorless and bitter.

This product is slightly soluble in water, very slightly soluble in ethanol, insoluble in ether; easily soluble in glacial acetic acid, slightly soluble in 0.1mol / L hydrochloric acid solution.

Specific rotation

Take this product, accurately weigh it, add methanol to dissolve and quantitatively dilute it to make a solution containing about 10mg per 1ml, and measure it according to the law (Appendix VIE of Part Two of the Pharmacopoeia, 2010 Edition). The specific rotation should be -92 ° to -99 °.

Levofloxacin identification

(1) Take an appropriate amount of this product and ofloxacin reference substance, add the mobile phase under the optical isomer to dissolve and dilute it to make a solution containing 0.02mg and 0.04mg per 1ml, as the test solution and control Product solution. According to the method under the optical isomer test, the retention time of the main peak of the test solution should be consistent with the retention time of the levofloxacin peak (back) in the main peak of the reference solution.

(2) Take an appropriate amount of this product, add 0.1mol / L hydrochloric acid solution to dissolve and dilute it to make a solution containing about 5g per 1ml, and measure according to ultraviolet-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of the 2010 edition). There is a maximum absorption at a wavelength of 294 nm, and a minimum absorption at a wavelength of 263 nm.

(3) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs" 1128).

Levofloxacin test

Take this product, add water to make a solution containing 10mg per 1ml, and measure it according to law (Appendix VI H of the second edition of the Pharmacopoeia 2010), the pH value should be 6.8 ~ 8.0.

Clarity of the solution

Take 5 parts of this product and add water to make a solution containing 10mg per 1ml. The solution should be clear; if it is turbid, it should not be more concentrated than the turbidity standard solution No. 2 (Appendix B of Part II of the Pharmacopoeia of the 2010 edition).

Absorbance

Take 5 parts of this product, dissolve them with water and dilute them quantitatively to make a solution containing 10mg per 1ml. Determine the absorbance at 450nm according to the UV-visible spectrophotometry (Appendix IV A of Pharmacopoeia Part II of the 2010 edition), all of which should not exceed 0.1 .

relative substance

Take this product, weigh it accurately, add 0.1mol / L hydrochloric acid solution to dissolve and quantitatively dilute it to make a solution containing about 1.2mg per 1ml. As a test solution, take a precise amount and quantify with 0.1mol / L hydrochloric acid solution. Dilute to make a solution containing 12 g per 1 ml as a control solution. About 18 mg of impurity A reference is accurately weighed, placed in a 100 ml measuring bottle, 1 ml of 6 mol / L ammonia solution and water are added to dissolve, diluted with water to the mark, shake well, 2 ml is precisely measured, placed in a 10 ml measuring bottle, and water is added Dilute to the mark, shake well, and use it as impurity A reference solution. As determined by high performance liquid chromatography (Appendix VD of Part Two of the 2010 Pharmacopoeia), octadecylsilane bonded silica gel was used as the filler; ammonium acetate sodium perchlorate solution (take 4.0g of ammonium acetate and 7.0 sodium perchlorate) g, add 1300ml of water to dissolve, adjust the pH value to 2.2 with phosphoric acid-acetonitrile (85:15) is mobile phase A, acetonitrile is mobile phase B; linear gradient elution is performed according to the table below. The column temperature was 40 ° C; the flow rate was 1 ml per minute. Weigh appropriate amounts of levofloxacin reference, ciprofloxacin reference and impurity E reference, add 0.1mol / L hydrochloric acid solution to dissolve and dilute it to contain about 1.2mg of levofloxacin, 6ug each of ciprofloxacin and impurity E in 1ml Measure 10ul of the mixed solution and inject it into the liquid chromatograph, take 294nm as the detection wavelength, and record the chromatogram. The retention time of the levofloxacin peak is about 15 minutes. The resolution of levofloxacin peak and impurity E peak and levofloxacin peak and ciprofloxacin peak should be greater than 2.0 and 2.5, respectively. Measure 10ul of the control solution and inject it into the liquid chromatograph. Take 294nm as the detection wavelength and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full scale. Precisely measure 10ul each of the test solution, the control solution and the impurity A reference solution, and inject them into the liquid chromatograph respectively. Record the chromatograms at 294nm and 238nm. If there is an impurity peak in the chromatogram of the test solution, the impurity A (238nm detection) is calculated by the peak area of the external standard method, which should not exceed 0.3%, and the peak area of other single impurities (294nm detection) should not be larger than the main solution area of the control solution (0.2%). ), The sum of the peak areas of other impurities (detected at 294nm) should not be greater than 2.5 times (0.5%) the main peak area of the control solution. Any peak that is less than 0.1 times the area of the main peak of the control solution in the chromatogram of the test solution can be ignored.

Time (minutes)	Mobile phase A (%)	Mobile phase B (%)
0	100	0
18	100	0
25	70	30
39	70	30
40	100	0
50	100	0

Optical isomers

Take an appropriate amount of this product, add the mobile phase to dissolve and dilute it to make a solution containing about 1.0 mg per 1 ml. As a test solution, take an appropriate amount, and quantitatively dilute with mobile phase to make a solution containing about 10 g per 1 ml. As a control solution. It was determined by high performance liquid chromatography (Appendix D, Part Two of the Pharmacopoeia, 2010 Edition). Use octadecylsilane bonded silica as a filler; use copper sulfate D-phenylalanine solution (take 1.32g of D-phenylalanine and 1g of copper sulfate, dissolve by adding 1000ml of water, and adjust with sodium hydroxide test solution pH value is 3.5)-Methanol (82:18) is the mobile phase; the column temperature is 40 ° C, and the detection wavelength is 294nm. Take an appropriate amount of ofloxacin reference substance, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.2mg per 1ml, take 20l into the liquid chromatograph, record the chromatogram, dexofloxacin and levofloxacin flow out in sequence, The resolution of the right and left isomer peaks should meet the requirements. Take 20l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 25% of the full range, and then accurately measure 20l each of the test solution and the control solution, and inject them into the liquid chromatograph Record the chromatogram. The area of the peak of dexofloxacin in the chromatogram of the test solution must not be greater than the area of the main peak of the control solution (1.0%).

remaining solvent

Take an appropriate amount of methanol and ethanol, accurately weigh it, use an internal standard solution (weigh an appropriate amount of acetone, and dilute with 0.5mol / L hydrochloric acid solution to make a solution containing 0.01mg per 1ml) and dissolve and quantitatively dilute it to make 1ml. A solution containing 100mg, 5ml is accurately measured, placed in a headspace bottle, sealed, and used as a test solution; another methanol and ethanol are accurately weighed and quantitatively diluted with an internal standard solution to make methanol and ethanol in 1ml. For 300g and 500g solutions, accurately measure 5ml, place it in a headspace bottle, seal, and use it as a reference solution; measure according to the residual solvent method (Appendix P, the first method of the Pharmacopoeia, Part II of the 2010 edition). Capillary column with polyethylene glycol (PEG-20M) (or similar polarity) as the fixing solution; column temperature: 40 ° C; inlet temperature: 150 ° C; detector temperature: 180 ° C; headspace bottle Equilibrium temperature is 85 ° C; equilibration time is 30 minutes; take the reference solution headspace sample and record the chromatogram. The resolution between the acetone peak, the methanol peak and the ethanol peak should meet the requirements. Take the test solution and the reference solution for headspace injection and record the chromatogram. The peak area ratio calculated according to the internal standard method should all meet the requirements.

Moisture

Take this product and measure it according to the Moisture Determination Method (Appendix M, Method 1 of Pharmacopoeia, 2010 Edition). The moisture content should be 2.0% to 3.0%.

Residue on ignition

Take 1g of this product, place it in a platinum crucible, and inspect it according to law (Appendix N of Part Two of the Pharmacopoeia 2010 Edition). The residual residue shall not exceed 0.1%.

Heavy metal

Take the remaining residue under the burning residue and inspect it according to law (Appendix H of the 2010 edition of the Pharmacopoeia, the second method). The heavy metal must not exceed 10 parts per million.

Determination of Levofloxacin

It was determined by high performance liquid chromatography (Appendix D, Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Use octadecylsilane bonded silica as a filler; use ammonium acetate sodium perchlorate solution (take 4.0g of ammonium acetate and 7.0g of sodium perchlorate, add 1300ml of water to dissolve, adjust the pH to 2.2 with phosphoric acid)-acetonitrile (85:15) is the mobile phase; the detection wavelength is 294nm. Weigh the appropriate amount of levofloxacin reference, ciprofloxacin reference and impurity E reference, add 0.1mol / L hydrochloric acid solution to dissolve and dilute it to contain about 0.12mg of levofloxacin, 6g each of ciprofloxacin and impurity E in 1ml 10 l of the mixed solution was injected into the liquid chromatograph, and the chromatogram was recorded. The retention time of the levofloxacin peak was about 15 minutes. The resolution of the levofloxacin peak and the impurity E peak and the levofloxacin peak and the ciprofloxacin peak should be greater than 2.0 and 2.5, respectively. .

Assay

Take about 60mg of this product, weigh it accurately, place it in a 50ml measuring bottle, add 0.1mol / L hydrochloric acid solution to dissolve and quantitatively dilute to the mark, shake well, take 5ml precisely, place it in a 50ml measuring bottle, and use 0.1mol / L hydrochloric acid Dilute the solution to the scale, shake well, and accurately measure 10 l into the liquid chromatograph and record the chromatogram. Also take an appropriate amount of levofloxacin reference substance, measure it in the same way, and calculate the peak area according to the external standard method.

Levofloxacin Category

Quinolones.

Levofloxacin storage

Shaded and sealed.

Levofloxacin preparation

Levofloxacin tablets

Levofloxacin

Impurity A:

(-) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -1,4-benzoxazine- 6-carboxylic acid

Impurity E:

(-) 9-fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [1,2,3-de] -1, 4-benzoxazine-6-carboxylic acid ^[2-3]

Levofloxacin Drug Description

Pharmacological effects of levofloxacin

This product is the L-body of ofloxacin, and its antibacterial activity in vitro is about twice that of ofloxacin. Its mechanism of action is to inhibit bacterial DNA helicase activity, prevent the synthesis and replication of bacterial DNA and cause bacterial death.

Levofloxacin and Shuanghuanglian injection have serious adverse reactions

The National Adverse Drug Reaction Monitoring Center released the latest issue of "Adverse Drug Reaction Information Notification" to remind medical staff and drug manufacturers in medical institutions to be alert to the serious adverse reactions of levofloxacin injection and Shuanghuanglian injection. According to reports, severe adverse reactions / events of levofloxacin injection are mainly systemic damage, central and peripheral nervous system damage, skin and accessory damage, respiratory system damage, and gastrointestinal system damage. Among them, allergic reactions are more typical and clinical manifestations are as follows: Anaphylactic shock, allergic reactions, dyspnea, erythema multiforme drug rash, laryngeal edema, etc. In the database of the National Center for Adverse Drug Reaction Monitoring, analysis of severe case reports of levofloxacin injection shows that the product has clinically unreasonable use, and some of the problems of unreasonable drug use have become the main factors causing serious adverse events. As clearly indicated in the instructions of levofloxacin injection, patients under 18 years of age are prohibited

There are no shortage of case reports in the database of patients under the age of 18 using the drug and causing serious adverse events.

The National Center for Adverse Drug Reaction Monitoring recommends that clinicians should use drugs in strict accordance with the "Guidelines for the Clinical Application of Antibacterial Drugs" and drug instructions when using levofloxacin injections. Avoid contraindications and use them reasonably when other antibacterials are needed. Renal insufficiency, elderly patients, patients with neurological diseases, etc. should be used with caution or under strict supervision. During the medication, the medical staff should carefully observe the patient's symptoms and signs. Once abnormalities are found, the drug should be stopped immediately, and the diagnosis should be confirmed as soon as possible and symptomatic treatment should be given in time. ^[4]

Pharmacokinetics of Levofloxacin

Absorption is complete after oral administration and the relative bioavailability is close to 100%. After a single oral fasting of 0.1g and 0.2g, the peak plasma concentration (Cmax) reached 1.36mg / L and 3.06mg / L, respectively, and the peak time (Tmax) was about 1 hour. The blood elimination half-life (t1 / 2) is about 5.1 to 7.1 hours. The protein binding rate is about 30% to 40%. This product is widely distributed to various tissues and body fluids after absorption. The ratio of the concentration in the tonsils, prostate tissues, sputum, tears, women's reproductive tract tissues, skin and saliva to the blood concentration is about 1.1 to 2.1. between. This product is mainly excreted from the kidneys in its original form and has little metabolism in the body. Within 48 hours of oral administration, the urine output is about 80% to 90% of the dose. This product excreted a small amount from the feces in its original form, and the accumulated excretion within 72 hours after administration was less than 4% of the administration amount.

Healthy volunteers took 50-200 mg of this product orally, the average peak drug concentration was 0.57-2.04 mg / L, and reached 0.8-2.4 h after the administration. The oral bioavailability is close to 100%. After oral administration, the drug is quickly absorbed and distributed throughout the body, reaching an effective concentration in various tissues and body fluids. Serum elimination half-life was 4-7 hours. It is mainly excreted by the kidneys. About 80% to 85% of healthy adults can be excreted within 24 hours after a single administration. After a single oral administration, the serum concentration varies with the dosage, Tmax is about 0.92 to 1.48h, Cmax And AUC was also significantly dose dependent. No accumulation of serum concentrations was observed due to continuous administration. This product has almost no metabolism in the body. Up to 48 hours after administration, about 85% of the unchanged body in the dosage is excreted from the urine. After a single oral administration in healthy adults, the urine concentration varies with the dose. The concentration of body fluids and tissues is related to the serum concentration, showing good distribution. It showed a rapid and high concentration distribution after oral administration, exceeding the MIC90 of almost all pathogenic bacteria. At the same time, this product can also be well distributed in neutrophils.

Levofloxacin indications

For sensitive bacteria:

1. Genitourinary system infections, including simple, complex urinary tract infections, bacterial prostatitis, Neisseria gonorrhoeae urethritis.

2. Respiratory tract infections, including acute attacks of bronchial infections and lung infections caused by sensitive Gram-negative bacilli.

3 Gastrointestinal infections are caused by Shigella, Salmonella, Enterotoxigenic E. coli, Aeromonas hydrophila, Vibrio parahaemolyticus, and the like.

4 Typhoid fever.

5. Bone and joint infections.

6. Skin and soft tissue infections.

7. Systemic infections such as sepsis.

8. Chronic bronchitis.

Levofloxacin was launched in Japan in 1993. The drug has achieved good results in the treatment of respiratory infections, urogenital infections and skin and soft tissue infections. Among them, the effective rate and bacterial clearance rate for treating acute and chronic lower respiratory tract infections reach 80% to 100%. The clearance rate for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and pneumococcus is high, but for pus aeruginosa The removal of bacilli is poor. The effective rate and bacterial clearance rate for complex and simple urinary tract infections are also 80% to 100%. The effective rate for treating skin and soft tissue infections is 80% to 91%, and the clearance rate of methicillin-sensitive staphylococci is close to 90%. The effective rate for treating obstetrics and gynecology, ear, nose, and throat infections is also about 90%.

Staphylococcus, Pneumococcus, Streptococcus pyogenes, Hemolytic Streptococcus, Enterococcus, Digestive Streptococcus, Neisseria gonorrhoeae, Klebsiella Brahimae, Propionibacterium acnes, E. coli, Citric acid , Salmonella (except typhoid and paratyphoid), Shigella, Klebsiella, Enterobacter, Serratia, Proteus, Solitary Cholera, Pseudomonas aeruginosa, Influenza Among Haemophilus, Acinetobacter, Campylobacter, and Chlamydia trachomatis, the following infections caused by bacteria sensitive to this agent are described below.

-Pneumonia, chronic bronchitis, diffuse bronchiolitis, bronchiectasis (when infected), secondary infections of chronic respiratory diseases.

-Laryngitis, tonsillitis (peritonsilitis, peritonsillar abscess) acute bronchitis-pyelonephritis, cystitis, prostatitis, paratestitis, gonococcal urethritis, non-gonococcal urethritis.

-Intrauterine infections, cervicitis, appendicitis, and vestibular glandular inflammation.

-Folliculitis (including pustular acne), rickets, edema, infectious impetigo, erysipelas, cellulitis, lymphangiitis (nodule) inflammation, suppurative paronychia (including ulcer), subcutaneous abscess , Sweat glanditis, cluster acne, infectious pediculoma, abscess around the anus.

-Mastitis, trauma, burns and surgical wounds (superficial) secondary infections.

-Cholecystitis, cholangitis.

-External otitis, otitis media, parasinusitis, suppurative, salivary glanditis.

-Blepharitis, stye, dacryocystitis, conjunctivitis, meibomian glanditis.

-Bacterial hemorrhage, infectious enteritis, salmonella enteritis, cholera.

-Periodontal tissue inflammation, peri Crownitis, jawitis.

Levofloxacin dosage

oral. Usual Adult:

1. Bronchial infection, pulmonary infection: 0.2g once, twice a day, or 0.1g once, three times a day, the course of treatment is 7 to 14 days.

2. Acute simple lower urinary tract infection: 0.1g once, 2 times a day, 5 to 7 days of treatment; Complex urinary tract infection: 0.2g once, 2 times a day, or 0.1g, 3 times a day, 10 courses ~ 14th.

3 Bacterial prostatitis: 0.2g once, 2 times a day, 6 weeks of treatment.

The usual dosage for adults is 0.3 to 0.4 g per day, divided into 2 to 3 times. If the infection is serious or the pathogen is less sensitive, the therapeutic dose of Pseudomonas bacterial infections such as Pseudomonas aeruginosa can also be treated. Increase to 0.6g a day and take 3 servings.

Medication for pregnant women

Drugs for pregnant and lactating women Note that animal experiments have not confirmed teratogenic effects of quinolone drugs, but studies on drug use in pregnant women have not yet reached a clear conclusion. In view of the fact that this drug can cause joint disease in juvenile animals, pregnant women are forbidden. Breastfeeding should be suspended when using this product.

1) Safety has not been established during pregnancy, so medicine is not available for pregnant women or women who may become pregnant.

2) Because ofloxacin will move into breast milk, women should not take medication during breastfeeding. Avoid breastfeeding when medication is necessary.

Medication for children

The safety of this product in infants and young children and adolescents under 18 years has not been determined. However, this product can cause joint disease when used in several young animals. Therefore, it is not suitable for children and adolescents under 18 years of age.

Medication for elderly patients

Elderly patients often have renal dysfunction, because some of this product is excreted through the kidney, it needs to be reduced.

Levofloxacin adverse reactions

1. Gastrointestinal reactions: abdominal discomfort or pain, diarrhea, nausea or vomiting.

2. Central nervous system reactions can include dizziness, headache, drowsiness, or insomnia.

3 Allergic reactions: rash, itching of the skin, occasionally exudative polymorphic erythema and angioedema. Photosensitivity is rare.

4 Occasionally:

(1) Seizures, mental disorders, irritability, confusion, hallucinations, tremors.

(2) manifestations of interstitial nephritis such as hematuria, fever, and rash.

(3) Phlebitis.

(4) Crystalline urine is more common in high-dose applications.

(5) Joint pain.

5. A few patients can have elevated serum aminotransferases, increased blood urea nitrogen, and decreased peripheral blood elephant white blood cells, mostly mild and transient.

The patient is well tolerated. In the observation of 918 patients, 1.2% of the patients experienced gastrointestinal reactions, mainly manifested as abdominal discomfort, subduction and diarrhea; central nervous system reactions such as insomnia, headache, dizziness, etc. accounted for 0.8%; about 2.4% of patients Transient serum aminotransferases are elevated, eosinophils are increased, or white blood cell counts are reduced. The adverse reactions were mild, and compared with ofloxacin, the adverse reactions were rare.

The adverse reactions reported in 3649 cases accounted for 2.77% (101 cases). The main adverse reactions were stomach and abdominal discomfort, diarrhea, soft stools, belching, nausea and other digestive symptoms 2.22% (81 cases), rash, erythema, pruritus and other allergic symptoms 0.47% (17 cases), insomnia, headache, 0.60% (22 cases) of mental symptoms such as head weight and dizziness, 0.14% (5 cases) of systemic symptoms such as general fatigue, chills, heat sensation, and decreased body temperature. Others have shoulder or back pain, dyspnea, palpitations, and taste. Abnormal symptoms were 0.27% (10 cases). The changes in clinical test values were mainly a 1.9% increase in GPT (46/2439 cases), a 1.4% increase in GOT (34/2442 cases), and an increase in eosinophil leukocytes by 1.4% (28/2063 cases). Occasionally shocks, severe toxic epidermal necrosis, cutaneous mucosal eye syndrome, cramps, acute renal insufficiency, jaundice, interstitial pneumonia, severe colitis with bloody stools such as pseudomembranous colitis and rhabdomyolysis, etc. reaction.

Serious side effects occasionally have the following serious side effects. Therefore, the drug should be stopped and the appropriate treatment should be given under full observation and confirmation of abnormalities.

(L) Shock, allergic symptoms (initial symptoms, erythema, chills, dyspnea, etc.).

(2) Toxic epidermal necrosis (Lyell syndrome). Skin and mucous membrane eye syndrome (StevensJohnson syndrome).

(3) Spasm.

(4) Acute renal insufficiency.

(5) Jaundice (initial symptoms: nausea, vomiting, loss of appetite, burnout, itching, etc.).

(6) (Aleucocytosis (initial symptoms: fever, sore throat, burnout, etc.).

(7) Interstitial pneumonia (symptoms: fever, cough, dyspnea, abnormal chest X-rays, eosinophilia, etc.). (Disposal methods: Paracorticosteroids, etc.). Severe colitis with bloody stools such as pseudomembranous colitis. (Symptoms: abdominal pain, frequent diarrhea, etc.).

(9) Rhabdomyolysis (may be accompanied by sharp deterioration of renal function). (Symptoms: myalgia, weakness, elevated CPK, elevated myoglobin in blood and urine, etc.).

(10) Hypoglycemia (prone to appear in patients with diabetes and patients with renal dysfunction).

(11) Tendon disorders such as Achilles tendonitis and tendon rupture.

(12) Disorders and other mental symptoms.

Severe side effects that have occurred abroad There have been occasional reports of the following serious side effects of other new quinolone antibacterial agents. Therefore, you should fully observe and confirm that there is an abnormality, stop the medication, and give appropriate treatment.

(L) Hemolytic anemia

(2) Allergic vasculitis

(3) Depression

Other side effects

(L) Allergies are occasionally edema, urticaria, heat sensation, photosensitivity, and sometimes symptoms such as rash, pruritus, or erythema should be discontinued when these symptoms occur.

(2) Occasional tremor, numbness, visual abnormalities, tinnitus, hallucinations, drowsiness, and sometimes insomnia, dizziness, headache and other symptoms.

(3) There is a phenomenon that the blood urea nitrogen (BUN) rises in the kidney.

(4) GOT, GPT, Al-P, -GPT rise may appear in the liver.

(5) Anemia, leukopenia, thrombocytopenia, and eosinophilia increase in blood. Therefore, attention should be paid to observations, and medication should be stopped immediately when abnormalities occur. Digestive organs sometimes show symptoms of nausea, vomiting, abdominal discomfort, diarrhea, loss of appetite, abdominal pain, and indigestion. Occasionally, symptoms such as stomatitis, glossitis, thirst, abdominal distension and constipation appear. Other occasional burnout, fever, arthralgia, irritability, and abnormal taste.

Levofloxacin contraindications

Patients allergic to this product and fluoroquinolones are contraindicated.

See Norfloxacin, because this product is mainly excreted from the kidney, those with reduced renal function should be used in a reduced amount, and elderly patients should also be reduced as appropriate. Those with a history of allergies to quinolone antibacterials are contraindicated.

The mechanism of action of fluoroquinolones such as norfloxacin is to inhibit DNA synthesis. The damage to cartilage was found in young rats. Therefore, this kind of drug should not be used in children and pregnant women. Breastfeeding should be suspended during application. The drug can be secreted into milk.

Patients with central nervous disease such as epilepsy should avoid using fluoroquinolones such as this product, because they are prone to severe central nervous system reactions.

Severe renal dysfunction should also be avoided, as adverse reactions such as convulsions can occur.

Medication for the elderly The drug is mainly excreted from the kidney (refer to "in vivo pharmacokinetics"), but because most elderly patients have low renal function, continuous high blood concentrations may occur. Therefore, attention should be paid to the dosage and interval of medication, taking cautious medication such as 100 mg once, twice a day.

Levofloxacin precautions

1. Because Escherichia coli is more resistant to fluoroquinolone drugs, urine culture specimens should be retained before administration, and the drug should be adjusted with reference to the bacterial drug sensitivity results.

2. Crystallized urine can occur when the product is used in large doses or when the urine pH is above 7. In order to avoid the occurrence of crystallized urine, it is advisable to drink plenty of water and keep the urine output above 1200ml for 24 hours.

3 Those with impaired renal function need to adjust the dosage according to renal function.

4 Avoid excessive exposure to sunlight when using this product. Discontinue medication if a photosensitivity reaction or other allergic symptoms occur.

5. In the case of liver failure, if it is severe (cirrhotic ascites), the drug clearance can be reduced, the blood drug concentration is increased, and the liver and kidney function are reduced. It is necessary to weigh the advantages and disadvantages and adjust the dose.

6. Patients with previous central nervous system diseases, such as those with epilepsy and history of epilepsy, should avoid application. When there are indications, they should be carefully weighed after pros and cons are applied.

7. Reports of follow-up inflammation or rupture of follow-up sacrifice. If any of the above symptoms occur, the drug should be stopped immediately until the symptoms disappear.

Levofloxacin drug interactions

1. Urine alkalizing agent can reduce the solubility of this product in the urine, leading to crystalline urine and renal toxicity.

2. When quinolone antibacterials are combined with theophylline, it may be due to the competitive inhibition of the binding site with cytochrome P450, which results in a significant decrease in the liver elimination of theophylline, prolonged blood elimination half-life (t1 / 2), increased blood concentration, Symptoms of theophylline poisoning, such as nausea, vomiting, tremor, restlessness, agitation, convulsions, palpitations, etc. Although this product has a small effect on theophylline metabolism, the theophylline blood concentration and dosage should be measured when combined.

3 The combination of this product with cyclosporine can increase the blood concentration of cyclosporine. It is necessary to monitor the blood concentration of cyclosporine and adjust the dose.

4 Although this product is used in combination with the anticoagulant warfarin to enhance the latter's anticoagulant effect, the patient's prothrombin time should also be closely monitored.

5. Probenecid can reduce the secretion of this product from the renal tubules by about 50%. When combined, it can cause toxicity due to the increased blood concentration of this product.

6. This product can interfere with the metabolism of caffeine, leading to reduced caffeine elimination, prolonged blood elimination half-life (t1 / 2), and may produce central nervous system toxicity.

7. Both antacids and irons containing aluminum and magnesium can reduce the oral absorption of this product and should not be combined.

8. When this product is combined with the non-steroidal anti-inflammatory drug fenbufen, occasional seizures occur, so it should not be combined with fenbufen.

9. Combination of this product with oral hypoglycemic drugs may cause blood sugar disorders. Therefore, care should be taken to monitor blood glucose concentration during the medication process. Once hypoglycemia occurs, this product should be discontinued immediately and given appropriate treatment.

Similar to ofloxacin, this product has no significant effect on metabolism of theophylline and other drugs in the body.

The combination of this product with antacids and iron agents containing magnesium and aluminum will reduce the absorption of this product and may reduce its effect, but when used with ranitidine, there is no obstruction to its absorption.

Phenylacetic acid or biphenone acid non-steroidal anti-inflammatory painkillers are used in combination with levofloxacin to cause spasms.

Clinical application of levofloxacin

Clinically increasing the amount of levofloxacin has objective reasons for the general increase in bacteria's resistance to quinolone drugs, as well as factors that blindly use the drug because of its excessive safety. The incidence of adverse effects of the drug increases with increasing dose. The dose of 100ml injection has been increased from 100mg to 200mg and 300mg. However, the safety and rationality of using large-dose levofloxacin injection is worthy of discussion and discussion.

Large-dose levofloxacin injection is not suitable for patients with markedly reduced renal function. The 2000 edition of the Pharmacopoeia 2000 "Clinical Instructions" "Levofloxacin" states that those with reduced renal function should be dosed according to the degree of decline: serum creatinine clearance (ml / min ) Is 40 ~ 70, the dose is 100mg, once every 12 hours; when it is 20 ~ 40, the dose is 100mg, once every 24 hours; <20, the dose is 100mg, once every 48 hours.

In the instructions for use of some levofloxacin injections, the medication regimen for patients with impaired renal function is significantly different from the pharmacopoeia: when the blood creatinine clearance rate is 50 to 80, the adult is 400 mg daily, divided into two drops; 20 to 49 At the time, the first dose was 400 mg, and then 200 mg every 24 hours; at 10 to 19 hours, the first dose was 400 mg, and thereafter, 200 mg every 48 hours. In fact, a single injection of 400 mg of levofloxacin in patients with normal renal function has easily induced adverse reactions. When this dose is given to patients with significantly reduced renal function, it will inevitably form a sustained high blood concentration level, increase the incidence of adverse reactions and increase the patient's kidney burden. It is recommended to use the pharmacopoeia as the primary reference for medication to ensure patient safety.

Older people should not use high-dose levofloxacin injection. Uncle Li, 90 years old, was hospitalized for treatment in a community hospital due to urinary tract infection. The doctor gave 200 mg / 100 ml of levofloxacin injection intravenously. Without waiting for the medication to be finished, the family members found that Uncle Li's eyes remained on the ceiling and he did not wake up. He was stiff and thought he was seriously ill. The patient did not wake up until the doctor was advised to stop the drug immediately and take measures such as diuresis to accelerate the excretion of the drug.

The Pharmacopoeia stipulates that the elderly should reduce the dosage of levofloxacin to 100mg once every 12 hours. Some clinicians lack understanding of this regulation, and there is little difference in dosage between the elderly and adults. It should be noted that 200-300 mg of levofloxacin is safer for adults, but it often makes it difficult for the elderly, especially elderly patients, to bear, and even causes adverse consequences. The kidneys, heart, liver, and nervous system of the elderly are declining, and the body's water content is reduced, so it is easy to form high blood drug levels and difficult to excrete. Therefore, the dosage of levofloxacin should be selected according to the specific circumstances of elderly individuals.

Note that the dosage of levofloxacin injection is selected according to the individual differences of women. In patients using levofloxacin injection, it is more common in women who have adverse reactions such as nausea, vomiting, headache, dizziness, palpitations, and insomnia. Among them, women who are thin, with significantly lower body weight, and who implement weight loss are high incidence groups. This is not accidental, but because the usual dosage will make the blood concentration level of the above individuals higher than normal people, and their heart, nervous system and gastrointestinal tract are relatively poorly tolerated. Levofloxacin injections should be different for men and women. For female patients who are weak and underweight, a single dose of levofloxacin should not exceed 200 mg.

Patients with urinary tract infection should not use large-dose levofloxacin injection. Levofloxacin is excreted by the kidney and does not decompose in the body. Therefore, the concentration of urinary medicament is high, which is suitable for the treatment of urinary tract infection. It has been described in the literature that given a conventional amount of levofloxacin, the urine concentration can be as high as 300 mg / L; after 24 hours of administration, it can still reach 60 mg / L, which is 50 times that of the susceptible MIC90. Therefore, a small dose of levofloxacin can be used for urinary tract infections, especially for lower urinary tract infections, and is suitable for oral administration. People with urinary tract infections generally do not need to use large doses of levofloxacin injection. Large doses will adversely affect kidney function.

When using high-dose levofloxacin injection, more attention should be paid to drug interactions. When high-dose levofloxacin injection is combined with certain drugs with a tendency to interact, the potential adverse reactions may become obvious. For example, it can raise the blood concentration level of theophylline, causing symptoms such as tachycardia, arrhythmia, etc .; it is easy to induce epilepsy when combined with non-steroidal anti-inflammatory analgesics such as ibuprofen and indomethacin.

The use of high-dose levofloxacin injection may consider sequential administration. When the dose of levofloxacin is the same, the peak concentration value of injection is significantly higher than that of oral administration, but the difference in bioavailability and half-life is not large. Therefore, sequential administration is recommended. That is, the injection is first administered to rapidly increase the blood concentration level, and then the oral administration is used instead. The characteristics of fast injection, strong effect and simple, safe, economical and long-lasting effect of oral administration can be exerted simultaneously.

Levofloxacin should be used cautiously to rescue alkaloids when overdose of poisoning. It is clearly stated in the "Pharmacological Instructions" of the 1995 edition of "Ofloxacin" that patients with urinary pH above 7 are prone to crystallized urine. With alkalizing agent. It was also explained under "ciprofloxacin hydrochloride" that urinary alkalizing agent can reduce the solubility of the drug in urine, resulting in crystalline urine and renal toxicity. However, the rescue method for levofloxacin overdose given by the drug instruction manual is to alkalize the urine with sodium bicarbonate to accelerate the excretion of the drug. The above seemingly contradictory explanations may be based on different interpretations of the characteristics of levofloxacin being soluble in both acids and bases. However, levofloxacin hydrochloride is more soluble, so the drug can be precipitated in alkaline urine. The author believes that urine basifying agents should be used with caution to rescue the poisoning caused by excessive levofloxacin, and it is safe to use diuretics, urinary catheterization and other methods to promote drug excretion.

Large-dose levofloxacin injection is suitable for medium-to-severe infection with levofloxacin as a concentration-dependent antibiotic. Large-dose can help improve the efficacy and inhibit the generation of drug-resistant bacteria. However, high-dose injections such as 300mg / 100ml should be used in moderate and severely sensitive bacterial infections. It is inappropriate to use it for mild infections. In the absence of clear indications of bacterial infection, it is even more undesirable to use high-dose levofloxacin injections as antipyretic and anti-inflammatory drugs.