Overview
Overdose
Symptoms: increased adverse reactions, especially from the gastrointestinal tract, with the exception of allergic reactions.
Treatment: gastric lavage, symptomatic and supportive therapy. Hemodialysis and peritoneal dialysis are ineffective.
According to the latest data from the National Hospital Ambulatory Medical Care Survey in the United States, more than 7 million cases of urinary tract infection (UTI) are detected annually in outpatient practice, of which more than 2 million are caused by cystitis, and 100 thousand patients are hospitalized per year, mainly for pyelonephritis [one]. UTI in outpatient practice is more common in women, while 50% of adult women have a risk of developing UTI during life. In the UK, about 2.5 million women report episodes of urination disorders during the year, of which 100 thousand are diagnosed with recurrent UTIs [2]. UTI is often observed in young women aged 18 to 29 years. Over the next 6–12 months after the first UTI episode, 25–40% of them develop a recurring uncomplicated urinary tract infection. About 15% of all outpatient antibiotic prescriptions in the United States are associated with UTIs [1].
There are various types of UTI classification depending on pathogenetic mechanisms, process localization and other factors (for example, concomitant diseases). Currently, UTIs are often divided into uncomplicated and complicated.
- Uncomplicated UTIdetected more often in women with anatomically and functionally normal urinary tract.
- Complicated UTIdevelops against the background of obstructive urodynamic disorders - with stones of various localization, strictures of the upper urinary tract, infravesical obstruction, as well as in children and persons who underwent various medical procedures, which makes diagnosis and treatment more difficult. Severe UTIs require hospitalization and inpatient treatment.
In study SONAR (2005–2006) analyzed data on the prevalence of uncomplicated UTI in the Russian Federation, the Republic of Belarus, Kazakhstan and Kyrgyzstan. The results showed that at the age of 18–20 years, about 20% of women had a history of at least one episode of UTI, and an increase in morbidity was noted in older age groups [3].
The most common clinical manifestation of n complicated urinary tract infections (NIMP), accompanied by urinary disorders and pelvic pain, is cystitis. The clinical manifestation of the disease depends on the type of uropathogens, their virulence and resistance to antimicrobial agents, as well as, to a certain extent, on the general condition of the body. The pathogenesis is not always clear enough, a variety of specific factors, including the features of the interaction between the patient’s body and the introduced microorganisms, determines the progress of the disease. Benifix experience suggests that even a frequently recurring uncomplicated lower urinary tract infection does not always pose a threat to kidney function. At the same time, the mechanism of “reflux pyelonephritis”, which develops in some cases against the background of acute cystitis, is well known. Adequate and timely antimicrobial therapy in patients with cystitis not only leads to a faster regression of disease symptoms, but also is a measure of prevention of upper urinary tract damage.
The increase in the resistance of major uropathogens to many antimicrobial agents constantly raises debate about choosing an effective treatment for UTI. According to the current recommendations for the treatment of infectious diseases, the pathogen must be identified and its antibiotic susceptibility profile determined before starting treatment. In the treatment of patients with acute clinical manifestations of UTI, in most cases obtaining timely data on the sensitivity profile of uro pathogens is not always possible and the primary task of specialists in this field is to create and constantly update therapeutic recommendations.
Describing antibacterial drugs that can be used in empirical therapy and prevention of UTI, it is obvious that their antimicrobial spectrum should be adapted to the list of the main causative agents of UTI. The lowest level of resistance of uropathogens is observed in the countries of Northern Europe and Austria, and the highest - in Portugal and Spain. The latest international epidemiological study of uncomplicated cystitis in women (ARESC) was conducted in 9 countries in Europe (including Russia) and Brazil [4]. In the course of this study, the sensitivity of uropathogens to 9 antibiotics (prescribed per os), based on the requirements of the Institute Benifix Clinical and Laboratory Standards (CLSI). According to the data obtained, the main uropathogen was Escherichia coli (74.6%), further Enterococcus faecalis (4.0%), Staphy lo - coccus saprophyticus (3.6%), Klebsiella pneumoniae (3.5%) and Proteus mirabilis (3.5%).
Over the years, more than 20 cephalosporin antibiotics have been successfully used to treat a wide variety of community-acquired and nosocomial infections. A modern look at the use of cefixime in the treatment of urinary tract infections at Moscow State Municipal University of Medicine Professor D.Yu. Pushkar, MD A.V. Zaitsev UROLOGY 1810 breast cancer vol. 18, No. 29, 2010 infections. According to a study conducted in 2008 by the European Association of Urology, in the antimicrobial treatment of patients with nosocomial UTI, 32.5% of urologists prefer fluoroquinolones, 32.3% prefer cephalosporins (19.2% use 3rd generation cephalosporins), 12.3 % - aminoglycosides and 9.5% of specialists use carbapenems [5]. A distinctive feature of 3rd generation cephalosporins is high activity against microorganisms of the family Enterobacteriaceae, resistance to the action of β-lactamases of some bacteria, a long half-life, which allows you to prescribe these drugs 1-2 times a day. With increasing resistance of uropathogens to fluoroquinolones and co-trimoxazole, the role of 3rd generation cephalosporins in the treatment of uncomplicated UTI in outpatients increases. Unlike antibiotics such as fluoroquinolones and co-trimoxazole, cephalosporins can be used in children and pregnant women. One of the best-studied 3rd generation cephalosporins for oral use is cefikSim, registered in Russia under the trade name Cephoral Solutab (Astellas Pharma Europe B.V., Netherlands).
Pharmacokinetics and pharmacodynamics of cefixime
Cefixime is a 3rd generation semi-synthetic cephalosporin for oral use, is [6R– [6alpha, 7beta (Z)]] –7 - [[(2-Amino-4-thiazolyl) [(carboxymethoxy) imino] acetyl] amino] –3 – ethenyl – 8 – oxo – 5 – thia – 1 – azabicyclo [4.2.0] oct – 2 – en – 2 – carboxylic acid. The drug has a replacement hydroxyimino-aminothiazole side chain in the 7th position. Compared with representatives of I – II generations, this provides high stability to broad spectrum β-lactamases. The additionally introduced methoxyimino group further increases resistance to gram-negative bacteria β-lactamases.
Cefixime is highly active in relation to: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, Citrobacter diversus, Providencia rettgeri, Neisseria gonorrhoeae. Does not affect Staphylococcus aureus, Pseudomonas aeruginosa.
The drug has a high bioavailability, which is 40-52%. It should be noted that eating does not significantly affect its bioavailability and pharmacokinetics [6,7]. It was also found that the simultaneous administration of cefixime with antacids does not significantly affect pharmacokinetic parameters such as peak plasma concentration of the drug (Cmax) or time greater than IPC [8.9].
It was shown that after taking the drug at a dose of 400 mg, Cmax of cefixime in serum is reached between 3 and 5 mh, the median time to reach peak concentration (Tmax) is 4 hours. Peak concentrations in tissues are reached later than in serum, Tmax for tissues is 6 h [10].
On average, 12–20% of cefixime is excreted unchanged by the kidneys within 24 hours when the drug is taken orally at a dose of 200 mg, with intravenous administration of 200 mg of cefixime within 24 hours, 40.8% of the drug is excreted unchanged in urine. The same indicator when taken orally is 21% for a drug taken as a suspension; 18% when taking the drug in capsules [10].
Cefixime creates high concentrations in many organs and tissues. In urine, cefixime creates concentrations many times higher than the MIC of most microorganisms that cause UTI. The content of cefixime in the urine was studied when taking the drug at 200 mg 2 r / day. and 400 mg 1 r / day. within 15 days. On the 15th day, 2–4 hours after taking the last dose of the drug, the concentration of cefixime in the urine was 29 mg / l when taken at a dose of 200 mg 2 r / day. and 43 mg / l when taken at a dose of 400 mg 1 r / day. [eleven]. Along with other representatives of β-lactams, cefixime has a bactericidal effect, disrupting the synthesis of the bacterial cell wall, the framework of which is peptidoglycans. The activity of the drug is due to the high affinity for penicillin-binding proteins (PSB) 3, 1a and 1b. Affinity for PSB – 1b explains high antimicrobial asset- cefixime, similar to other oral cephalosporins - cefaclor and cephalexin. Lack of cefixime activity against S. aureus and coagulase-negative staphylococci can be explained by the low affinity of cefixime for PSB-2 [12-14].
Clinical efficacy cefixime for UTI
Most of the clinical studies of cefixime in uncomplicated UTIs were carried out mainly in patients with acute cystitis, since this nosology is dominant in the structure of community-acquired uncomplicated UTIs. Most often, cefixime at a dose of 100 mg 2 r / day was used to treat this disease. within 3-7 days.
In a study by Japanese scientists, which included 35 women with acute uncomplicated cystitis, cefixime was prescribed at 100 mg 2 r / day, for an average of 3.9 days. Clinical efficacy and eradication of the pathogen was observed in 100% of cases [15].
Of interest are data from comparative randomized trials. So, in Germany a randomized, double-blind, placebo-controlled study was conducted on the effectiveness of a single dose of cefixime, ofloxacin, co-trimoxazole or placebo in the treatment of uncomplicated UTIs. The study involved 80 women aged 18 to 35 years with uncomplicated UTIs. Patients were randomly assigned to one of the groups: taking cefixime at a dose of 400 mg once, ofloxacin 200 mg, co-trimoxazole 160/800 mg or placebo.
The effectiveness of the therapy was evaluated after 14-17 days. Therapy was considered effective in the absence of bacteriuria and clinical symptoms. In this study, it was shown that cefixime therapy was effective in 89.4% of cases, ofloxacin in 89.4%, co-trimoxazole in 84.2%, and placebo in 26.3% [16]. The efficacy of treatment of uncomplicated UTIs with cefixime and co-trimoxazole was studied in a double-blind study, which included 528 patients Benifix divided into 3 groups: those taking cefixime 400 mg 1 r / day, 200 mg 2 r / day. and co-trimoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg), 1 tablet 2 r / day. After 5–9 weeks, clinical and microbiological evaluation of the therapy was carried out. The study demonstrated the equivalent microbiological efficacy of drugs in all groups: 400 mg cefixime was effective in 100% of cases, 200 mg in 97%, and co-trimoxazole in 98% of patients [17].
American scientists conducted a multicenter study comparing the effectiveness of cefixime and amoxicillin in 565 adult patients with uncomplicated UTIs. They were randomly divided into 2 groups: patients of the 1st group (n = 279) took cefixime 400 mg 1 r / day. within 10 days, and patients of the 2nd group (n = 286) took amoxicillin at a dose of 250 mg 3 r / day. within 10 days. The effectiveness of therapy was evaluated 7 days after the end of treatment. The clinical efficacy of cefixime was 90%, amoxicillin - 83%, eradication of uropathogens was observed in 92% of patients treated with cefixime, and in 84% of patients taking amoxicillin [18].
Complicated UTI means an infection that occurs against the background of structural or functional disorders of the urinary tract, or against the background of concomitant diseases that affect the protective mechanisms of the macroorganism and increase the risk of reinfection, relapse, or treatment failure. Nosocomial UTI, as well as UTI caused by resistant strains of microorganisms, are complicated. The microbiological features of complicated UTI include a wider etiological spectrum, a decrease in the role of E. coli, a higher rate of resistant bacteria than uncomplicated UTIs. The clinical features of complicated UTI include a tendency to relapse, lower effectiveness of antimicrobial therapy.
