Ciprofloxacin film-coated tablets 500 mg 10 pcs. in Moscow
Due to a decrease in the activity of microsomal oxidation processes in hepatocytes, it increases the concentration and lengthens the half-life of theophylline (and other xanthines, such as caffeine), oral hypoglycemic drugs, indirect anticoagulants, and helps reduce the prothrombin index.
When combined with other antimicrobial drugs (betalactam antibiotics, aminoglycosides, clindamycin, metronidazole), synergism is usually observed; can be successfully used in combination with azlocillin and ceftazidime for infections caused by Pseudomonas spp.; with mezlocillin, azlocillin and other beta-lactam antibiotics - for streptococcal infections; with isoxazolylpenicillins and vancomycin - for staphylococcal infections; with metronidazole and clindamycin - for anaerobic infections.
It enhances the nephrotoxic effect of cyclosporine, there is an increase in serum creatinine; in such patients it is necessary to monitor this indicator 2 times a week.
When taken simultaneously, it enhances the effect of indirect anticoagulants.
Oral administration together with iron-containing drugs, sucralfate and antacid drugs containing magnesium, calcium and aluminum salts leads to decreased absorption of ciprofloxacin, so it should be prescribed 1-2 hours before or 4 hours after taking the above drugs.
Non-steroidal anti-inflammatory drugs (excluding acetylsalicylic acid) increase the risk of developing seizures.
Fluoroquinolones form chelate compounds with magnesium and aluminum ions of the buffer system of the dosage form of didanosine, which sharply reduces the absorption of antibiotics, so ciprofloxacin is taken 2 hours before taking didanosine or 2 hours after taking this drug
Metoclopramide accelerates absorption, which leads to a decrease in the time to reach its maximum concentration.
The combined use of uricosuric drugs leads to a slower elimination (up to 50%) and an increase in plasma concentrations of ciprofloxacin.
Increases the maximum concentration by 7 times (from 4 to 21 times) and the area under the concentration-time curve by 10 times (from 6 to 24 times) of tizanidine, which increases the risk of a pronounced decrease in blood pressure and drowsiness.
Experience with the use of ophthalmic ointment containing ciprofloxacin after microsurgery
The article, based on literature data and our own experience, analyzes the clinical effectiveness of 0.3% ciprofloxacin ophthalmic ointment in complex therapy in patients with conjunctivitis, blepharitis and keratitis. It has been shown that ciprofloxacin reduces the incidence of complications from the conjunctiva and cornea, stimulates epithelization, accelerates healing, and does not cause pain or burning sensation.
Introduction
At the beginning of the twentieth century. a significant proportion in the structure of all complications belonged to inflammatory diseases of the eye after cataract extraction. In the second half of the twentieth century. After the advent of the operating microscope, high-quality suture material and antibacterial agents, the situation changed radically and the frequency of infectious complications decreased several times. However, the transition to sutureless phacoemulsification, especially using corneal incisions, contributed to a significant increase in inflammatory diseases of the anterior segment of the eye in the postoperative period [1, 2].
Issues of prevention and treatment of infectious bacterial inflammation of the anterior segment of the eye (conjunctivitis, blepharitis, keratitis) after microsurgical interventions remain extremely relevant [3]. The effectiveness of a modern ophthalmic drug, an eye ointment containing ciprofloxacin, for the treatment of this type of pathology of the anterior segment of the eye has been studied [4]. As research results have shown, this eye ointment is the most effective ophthalmic drug compared to traditional methods of treatment [5, 6].
To understand the effect of the drug, it is necessary to consider the chain of the body's immune response to the action of a bacterial agent.
Mechanism of immune response
When an infectious-inflammatory agent enters the anterior segment of the eye, the inflammatory T-cell immune response is activated. This form of the immune response is designed to protect against intracellular pathogens localized in cytoplasmic granules - microorganisms phagocytosed by cells, but not destroyed due to a lack of adequate effector mechanisms or their blockade by pathogens.
There are four known stages of the cellular immune response of the inflammatory type [7]:
- Presentation of antigen by dendritic cells to CD4+T lymphocytes, leading to their activation.
- Development of helper T-lymphocytes type Th1 (T-helpers).
- Presentation of antigen by macrophages to previously formed T helper cells (Th1 type), their mutual activation and release of cytokines.
- Activation of cytolysis in phagosomes of macrophages.
Th1 cells and macrophages are responsible for implementing this form of protection. Th1 cells are formed at the stage of launching the immune response and are responsible for the specific component of the reaction (recognition of the antigen and direction of the reaction to its carrier). Macrophages act as effector cells.
The initial stage of the reaction against intracellular pathogens localized in phagolysosomes is carried out as follows. Dendritic cells that have captured the pathogen or its fragment present the antigenic peptide to CD4+ T cells, which are activated, proliferate, and differentiate into helper T lymphocytes. Already at the stage of antigen recognition, the differentiation of CD4+ T lymphocytes into Th1-type helpers occurs, which is then supported by cytokines produced by dendritic cells - interleukin 12, interferon gamma (IFN-gamma).
The stage of activating interaction between Th1 cells and macrophages is characteristic of the inflammatory immune response. It consists of the interaction of specific Th1 cells with macrophages, which contain on their surface MHC (major histocompatibility complex) class II molecules carrying a peptide fragment of the antigen. Upon interaction, an immune synapse is formed. Activating signals are generated directed both to the Th1 cell and to the macrophage. Signals enter the Th1 lymphocyte through the TCR/CD4 and CD28 molecules. As a result of this repeated stimulation of the T cell (the first stimulation is caused by the presentation of antigen by a dendritic cell), cytokine production increases.
Stimulation of a macrophage during interaction with a Th1 cell is realized by two mechanisms. One of them is contact. The costimulatory molecule CD40 is bound by its ligand CD154. CD40 is spontaneously expressed by macrophages, while its ligand appears on the surface of Th1 cells due to activation during the formation of the immune synapse. The second activation mechanism is mediated by IFN-gamma. When this cytokine binds to the receptor, a signaling pathway involving the kinases Jakl and Jak2, the transcription factor STAT1, as well as additional pathways involving the MAP kinase cascade is activated. The result of activation of macrophages is the expression of numerous genes, leading to an increase in the content of MHCI molecules on the cell surface, especially MHCII, the assembly of NADPH oxidase, and the activation of enzymes of oxidative metabolism. The most specific manifestation of the macrophage response to the stimulating effect of IFN-gamma is the expression of the inducible NO synthase gene. It is NO and its derivatives, such as peroxynitrite (OONO), that cause the death of mycobacteria and other intracellular pathogens that persist and even multiply in phagosomes. All effects of IFN-gamma, including the ability to induce the formation of NO synthase, are enhanced by tumor necrosis factor alpha, produced by both Th1 cells and macrophages themselves. The effectiveness of cytokines produced by Th1 cells increases significantly due to the concentration of their secretion in the area of contact with macrophages. In addition, activation of extraneous cells and their damage are reduced. To ensure this oriented secretion, cell polarization is necessary during the formation of the immune synapse.
Thus, a unified functional system is formed, which plays a key role in the implementation of the inflammatory form of the cellular immune response. Defects in any part of this system lead to the development of immunodeficiencies, accompanied by increased sensitivity to mycobacteria and other pathogens, in response to which Th1 cells and macrophages are involved [8].
Fluoroquinolones
Fluoroquinolones have been known since the 1990s. Their effectiveness in the treatment and prevention of eye infections has been clinically proven. As a result of various modifications, broad-spectrum drugs have been developed that are effective against both gram-negative and gram-positive bacteria. There are monofluorinated (norfloxacin, ciprofloxacin, ofloxacin, levofloxacin) and difluorinated (lomefloxacin) fluoroquinolones [5, 9].
The targets of fluoroquinolones are the bacterial enzymes DNA gyrase, a tetramer consisting of two A and two B polypeptide subunits, and topoisomerase IV, a tetramer consisting of two C and two E subunits. They are type 2 topoisomerases. These enzymes are responsible for replication, genetic recombination and DNA repair, so blocking them leads to impaired division, bacteriostasis and rapid cell death. Fluoroquinolones block these enzymes and thereby disrupt the reproduction of bacterial DNA. Topoisomerase is found in the cells of both prokaryotes (bacteria) and eukaryotes (mammals), but this enzyme differs in structure and function between prokaryotes and eukaryotes. Thus, DNA gyrase is the main enzyme responsible for preparing DNA replication in the bacterial chromosome. This function of DNA gyrase is unique to bacteria. In mammals, a similar enzyme, topoisomerase II, does not catalyze DNA folding and is characterized by low sensitivity to fluoroquinolones, which explains the absence of toxic effects associated with impaired DNA biosynthesis.
In gram-negative bacteria such as Pseudomonas aeruginosa
and
Escherichia coli
, the first target is DNA gyrase, the second is topoisomerase IV.
In gram-positives, such as Staphylococcus aureus
and
Streptococcus pneumoniae
, the first target is topoisomerase IV, the second is DNA gyrase. Fluoroquinolones not only kill bacteria, but also inhibit their growth within two to six hours after exposure [9, 10]. The death of bacteria as a result of exposure to fluoroquinolones directly depends on the concentration of the drug. It follows from this that high intracellular concentrations and inhibition of target enzymes determine the high bactericidal activity of fluoroquinolones.
Ciprofloxacin, as a representative of the fluoroquinolone series, has very high solubility in water at a neutral pH level. The penetration of ciprofloxacin into the anterior chamber of the eye is facilitated by the mechanism of its active transport. This provides a higher concentration of ciprofloxacin in a humid environment, which, combined with a broad spectrum of action, gives a lasting antibacterial effect. This is very important in the treatment and prevention of infectious bacterial inflammation of the anterior segment of the eye after microsurgical interventions [11, 12].
Ciprofloxacin has a bactericidal effect on gram-negative organisms during the period of rest and division, and on gram-positive microorganisms only during the period of division [13]. Gram-negative aerobic bacteria are sensitive to ciprofloxacin:
- enterobacteria ( Escherichia
coli
,
Salmonella
spp.,
Shigella
spp.,
Citrobacter
spp.,
Klebsiella
spp.,
Enterobacter
spp.,
Proteus mirabilis
,
Proteus vulgaris
); - other gram-negative bacteria (Haemophilus
spp.,
Pseudomonas aeruginosa
,
Moraxella catarrhalis
,
Aeromonas
spp.,
Pasteurella multocida
,
Plesiomonas shigelloides
,
Campylobacter jejuni
,
Neisseria
spp.); - some intracellular pathogens: Legionella
pneumophila
,
Brucella
spp.,
Chlamydia trachomatis
,
Listeria monocytogenes
,
Mycobacterium tuberculosis
,
Mycobacterium kansasii
,
Corynebacterium diphtheriae
; - gram-positive aerobic bacteria: Staphylococcus
spp.
( S. aureus
,
S. haemolyticus
,
S. hominis
,
S. saprophyticus
),
Streptococcus
spp.
( St. pyogenes
,
St. agalactiae
).
D.Yu. Maichuk identifies the main groups of recommended drugs for the treatment of infectious lesions of the ocular surface, among which fluoroquinolones occupy a special place [1, 2, 14].
Spectrum of action and clinical effectiveness of ciprofloxacin (0.3% ophthalmic ointment)
The first place in the frequency of occurrence in the postoperative period is occupied by the main clinical forms of ocular infections of the anterior segment of the eye: conjunctivitis, keratitis and blepharitis. There are many reasons for their occurrence, but the main one is a weakening of the body’s specific immune response. Patients are concerned about lacrimation, pain in the eyes, burning sensation, photophobia, swelling, and severe redness of the eyes. This reduces the quality of life and significantly slows down recovery in the postoperative period.
Recently, many ophthalmologists have noted an increase in the number of resistant forms of eye infections, so a properly selected antimicrobial drug and its timely administration are the key to a good and quick result.
A number of studies have been conducted confirming the clinical effectiveness of ciprofloxacin hydrochloride [14–16] in the treatment and prevention of infectious and inflammatory diseases of the anterior segment of the eyes after microsurgical interventions.
In a study conducted by E.A. Abdulaeva, A.N. Amirov, F.R. Saifullin (Kazan State Medical Academy), 60 patients (76 eyes) aged from 18 to 56 years participated. The study participants were divided into three groups: the first included 16 patients (32 eyes) with blepharoconjunctivitis, the second included 34 patients (34 eyes) with superficial traumatic keratitis, and the third included 10 patients (10 eyes) with deep traumatic keratitis [17]. .
The examination of patients included collection of complaints and anamnesis, visometry, biomicroscopy of the anterior segment of the eye, as well as bacteriological examination of a smear from the conjunctiva and culture of the discharge to determine sensitivity to antibiotics. In addition, the dynamics of patient complaints of discomfort, foreign body sensation, lacrimation, and redness of the eyes were assessed.
Treatment was carried out according to the following scheme. A strip of ointment 1–1.5 cm long was placed behind the lower eyelid of the affected eye, first three times a day for two days, then twice a day for two days, then twice a day for five days. The effectiveness of treatment was determined by the percentage of recovery, the time of disappearance of inflammatory phenomena and the average duration of treatment.
The duration of observation was 30 days. Results were assessed three, seven, 14, 30 days after therapy. A positive therapeutic effect was observed in 96.05% of patients (73 eyes) with infectious and inflammatory diseases of the anterior segment of the eyes. Recovery occurred in 68.4% of patients (52 eyes), improvement – in 27.6% (21 eyes). There was no effect in only 3.9% of patients (three eyes).
According to S.L. Rocheva, the use of a group of second-generation fluoroquinolones also demonstrates a good therapeutic effect in infectious and inflammatory diseases of the anterior segment of the eye. 15 patients were observed, of which 12 (24 eyes) with bacterial and three (six eyes) with chlamydial conjunctivitis. In the first three days, the eye ointment was applied three times a day, subsequently twice a day. Therapy continued until complete recovery. The results of treatment were assessed on the third, fifth - seventh, eighth - tenth, 11-14th days, as well as after three to four months of long-term observation period. To monitor the effectiveness, we used a three-point system of symptoms, such as photophobia and lacrimation, blepharospasm, swelling and hyperemia of the conjunctiva, amount of discharge, foreign body sensation (mild signs - 1 point, moderately expressed - 2 points, pronounced - 3 points).
Complete regression of the symptoms of the disease was observed in the range from five to seven to 14–15 days and varied significantly depending on the type of conjunctivitis. The earliest recovery periods were recorded for catarrhal inflammation of the conjunctiva (sixth day), the later for membranous inflammation (ninth day) and the latest for inflammation of the conjunctiva with follicular reaction (12th day).
S.L. Rocheva notes that ciprofloxacin (0.3% ophthalmic ointment) is well tolerated by patients, does not cause allergic or toxic reactions, and ensures recovery in 100% of those studied [18].
We also used ciprofloxacin in the postoperative period after cataract extraction to prevent the occurrence of infectious and inflammatory eye diseases. Nine patients operated on for cataracts (nine eyes) were prescribed ciprofloxacin (0.3% ophthalmic ointment) for prophylactic purposes. In the first two days after surgery, the ointment was applied three times a day, the next five days - twice a day. The duration of observation was 14 days. The results were assessed on the first, third, seventh and 14th days after surgery. A positive effect was observed with the use of eye ointment, since the percentage of infectious and inflammatory diseases was zero. Patients noted the absence of a burning sensation and the rapid restoration of visual functions in the postoperative period.
Conclusion
A review of literature data and our own experience confirm the clinical effectiveness of using 0.3% ophthalmic ointment containing ciprofloxacin in complex therapy of patients with conjunctivitis, blepharitis and keratitis, as well as their prevention in the postoperative period after microsurgical interventions. Eye ointment can be recommended for widespread use for the prevention and treatment of infectious and inflammatory diseases of the anterior segment of the eye.
Ciprofloxacin (for infusion), 1 piece, 100 ml, 2 mg/ml, solution for intravenous administration
Suction
After an intravenous infusion of the drug at a dose of 200 mg or 400 mg, Cmax is reached after 60 minutes and is 2.1 μg/ml and 4.6 μg/ml, respectively.
Distribution
Plasma protein binding - 20-40%. Vd - 2-3 l/kg. Ciprofloxacin is well distributed in body tissues (with the exception of fat-rich tissues, such as nervous tissue). The antibiotic content in tissues is 2-12 times higher than in plasma. Therapeutic concentrations are achieved in saliva, tonsils, liver, gall bladder, bile, intestines, abdominal and pelvic organs, uterus, seminal fluid, prostate tissue, endometrium, fallopian tubes and ovaries, kidneys and urinary organs, lung tissue, bronchial secretions , bone tissue, muscles, synovial fluid and articular cartilage, peritoneal fluid, skin. It penetrates into the cerebrospinal fluid in a small amount, where its concentration in non-inflamed meninges is 6-10% of that in the blood serum, and in inflamed meninges - 14-37%. Ciprofloxacin also penetrates well into the ocular fluid, bronchial secretions, pleura, peritoneum, lymph, and through the placenta. The concentration of ciprofloxacin in blood neutrophils is 2-7 times higher than in serum. The activity of ciprofloxacin is slightly reduced at acidic pH values.
Excreted in breast milk.
Metabolism
Metabolized in the liver (15-30%) with the formation of low-active metabolites (diethylciprofloxacin, sulfociprofloxacin, oxociprofloxacin, formylciprofloxacin).
Removal
With intravenous administration, T1/2 is 5-6 hours. It is excreted mainly by the kidneys by tubular filtration and tubular secretion in unchanged form (with intravenous administration - 50-70%) and in the form of metabolites (with intravenous administration - 10%), the rest - through the gastrointestinal tract. After intravenous administration, the concentration in urine during the first 2 hours after administration is almost 100 times higher than in serum, which significantly exceeds the MIC for most pathogens of urinary tract infections.
Renal clearance - 3-5 ml/min/kg; total clearance - 8-10 ml/min/kg.
Pharmacokinetics in special clinical situations
In chronic renal failure (creatinine clearance>20 ml/min), the percentage of the drug excreted through the kidneys decreases, but accumulation in the body does not occur due to a compensatory increase in drug metabolism and excretion through the gastrointestinal tract. T1/2 in chronic renal failure increases to 12 hours.
