{"id":1190,"date":"2021-04-15T23:51:49","date_gmt":"2021-04-15T20:51:49","guid":{"rendered":"http:\/\/eurolifecare.com.ua\/?p=1190"},"modified":"2023-09-28T11:41:01","modified_gmt":"2023-09-28T08:41:01","slug":"mesto-levofloksatsyna-v-profylaktyke-y-lechenyy-ynfektsyj-mochevyvodiashchykh-putej","status":"publish","type":"post","link":"https:\/\/eurolifecare.com.ua\/en\/mesto-levofloksatsyna-v-profylaktyke-y-lechenyy-ynfektsyj-mochevyvodiashchykh-putej\/","title":{"rendered":"The role of levofloxacin in the prevention and treatment of urinary tract infections"},"content":{"rendered":"

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The risk of developing a urinary tract infection (UTI) during life exists in 50% of adult women. In girls up to 6 years of age, the risk of UTI is 3 times higher than in boys. UTI often develops in young, sexually active women aged 18 to 29 years. The selection of virulent strains of microorganisms and the growth of their resistance dictate the need to search for new antimicrobial chemopreparations and develop schemes for the prevention and treatment of UTI.<\/p>\n

There are various types of UTI classification depending on pathogenetic mechanisms, localization of the process and other factors, for example, concomitant diseases. UTIs are often divided into uncomplicated and complicated.<\/p>\n

Uncomplicated UTI occurs more often in women with an anatomically and functionally normal urinary tract.<\/p>\n

Complicated UTI develops against the background of obstructive urodynamic disorders – with stones of various localization, strictures of the upper urinary tract, infravesical obstruction, as well as in persons who have undergone various medical manipulations, which makes diagnosis and treatment more difficult. Patients with complicated UTI need more serious medical supervision before and after treatment. Severe forms of UTI require hospitalization and inpatient treatment.<\/p>\n

UTIs in adults can also be classified according to other clinical categories: acute and chronic, acute kidney infection, catheter-associated, urosepsis.<\/p>\n

The range of antibacterial drugs that can be used in empiric therapy and prevention of UTI should be adapted to the list of the main causative agents. The etiology of uncomplicated UTI is quite well studied: the spectrum of etiological agents is the same in lower and upper urinary tract infections, and in 70-95% of cases Escherichia coli is present and in more than 5% \u2013 Staphylococcus saprophyticus. Sometimes other representatives of Enterobacteriaceae, such as Proteus mirabilis and Klebsiella or enterococci, can be isolated.<\/p>\n

In approximately 10-15% of patients with clinical manifestations of UTI, bacteriuria cannot be detected using routine methods.<\/p>\n

The results of numerous multicenter studies have shown that in outpatient practice, the treatment of UTI is possible on an empirical basis, taking into account data on the sensitivity of E. coli (the main pathogen) to antibacterial drugs. In our country, the high sensitivity of outpatient strains of E. coli to fluorinated quinolones, aminoglycosides is preserved, and it is slightly less (resistance about 15-20%) to co-trimoxazole (trimethoprim-sulfamethoxazole); low – to ampicillin, nitroxoline.<\/p>\n

For a long time, co-trimoxazole was the drug of choice for the treatment of UTI in patients without concomitant diseases (Warren J. et al., 1999). Other drugs, usually fluoroquinolones, were used as backup agents. Recently, this algorithm has been reconsidered due to changes in antibiotic sensitivity in different geographic regions.<\/p>\n

Over the last decade, co-trimoxazole resistance has doubled (statistically significantly). The effectiveness of beta-lactams, such as ampicillin and cephalothin, was low already in 1990 (71% and 80%, respectively) and significantly decreased by 1999 (62% and 72%, respectively). On the contrary, no significant changes in the level of resistance to fluoroquinolones and nitrofurans were noted during this period.<\/p>\n

The emergence of antibiotic-resistant strains is often caused by contact with nosocomial infections, inadequate duration of treatment courses, and incorrect prescription of medicinal products. In light of the recent dramatic changes in antimicrobial resistance, there is a need to review the recommendations for the treatment of UTI. Due to the increasing resistance of the majority of uropathogens to traditional antimicrobial drugs, including the “gold standard” – co-trimoxazole, the role of fluoroquinolones in the treatment of UTIs is increasing in the world today. Drugs of the group of fluoroquinolones, united by a common mechanism of action (inhibit the synthesis of the key enzyme of the bacterial cell – DNA gyrase), have a wide spectrum of antimicrobial activity and favorable pharmacokinetic properties (high bioavailability and high degree of excretion with urine in unchanged form).<\/p>\n

Unlike their non-fluorinated predecessors (nalidixic acid, pipemidiic acid, cinoxacin, etc.), fluorinated quinolones have higher in vitro activity, a wider antimicrobial spectrum, and better pharmacokinetics. Microbial resistance develops less often to them.<\/p>\n

According to the latest recommendations of the American Association of Infectious Diseases, fluoroquinolones can be considered as “first-line” drugs in regions with a high probability of resistant strains. In the recommendations of the European Association of Urologists (2001), it is noted that due to the rather high cost of fluoroquinolones, drugs of this group cannot be recommended as “first-line agents” for empiric therapy, with the exception of regions where the resistance of uropathogens to co-trimoxazole >10 %. Due to the growth of resistance (including resistance to fluoroquinolones in some regions), it is extremely important to further study the structure of secreted uropathogens and their sensitivity to antimicrobial agents, especially in patients with recurrent and complicated UTI (Blazquez R et al., 1999; Guyot A. and et al., 1999).<\/p>\n

In vitro studies have shown that approximately 10-20% of E. coli strains isolated from women with UTIs in the United States are resistant to co-trimoxazole. Alternative drugs for the treatment of uncomplicated UTI are fluoroquinolones and nitrofurantoin, however, reports of their activity against co-trimoxazole-resistant strains are rare. Testing conducted in US laboratories in 1998-2001 showed that 9.5% of such E. coli strains were resistant to ciprofloxacin and 1.9% to nitrofurantoin, and 10.4% of bacteria resistant to ciprofloxacin were resistant and to nitrofurantoin.<\/p>\n

As part of the ECO.SENS international project, 4,734 women with acute uncomplicated UTI were examined in 252 medical centers in 17 countries. E. coli was detected in 77% of cases. It is noted that 42% of E. coli strains are resistant to at least one of 12 antimicrobial drugs. Resistance to ampicillin was 29.8%, sulfamethoxazole \u2013 29.1%, trimethoprim \u2013 14.8%, co-trimoxazole \u2013 14.1% and nalidixic acid \u2013 5.4%. Klebsiella spp. were resistant to ampicillin in 83.5% of cases and to fosfomycin in 56.7%. Other representatives of Enterobacteriaceae, according to Kahlmeter G., 2003, were quite resistant to beta-lactams (ampicillin \u2013 45.9%, amoxicillin\/clavulanate \u2013 21.3% and cefadroxil \u2013 24.6%), nitrofurantoin (40.2 %) and fosfomycin (15.6%).<\/p>\n

The results of studying the sensitivity of E. coli to antibacterial drugs in 15 laboratories in France also showed that only 58.7% of microorganisms are sensitive to amoxicillin, 63.3% to amoxicillin\/clavulanate, 78.2% to co-trimaxozol, 66% to cephalotin, 8%, cefuroxime \u2013 77.6%, cefixime \u2013 83.6%, while for fluoroquinolones these indicators were: norfloxacin \u2013 96.6%, ofloxacin 96.3%, ciprofloxacin 98.3% (Goldstein FW, 2000 ).<\/p>\n

New trends in the development of quinolones are associated with the appearance of fluorinated derivatives that have much higher activity against a wide range of microorganisms, including gram-positive and intracellular pathogens, as well as anaerobes. The emergence of dosage forms for parenteral administration allows the use of “modern” fluoroquinolones for stepwise antimicrobial therapy. The first drug of this group was levofloxacin. Currently, comparative studies of the clinical and bacteriological effectiveness of the so-called “classic” and “new” fluoroquinolones with different dosage regimens in patients with UTI are ongoing.<\/p>\n

A study of the effectiveness of levofloxacin, ciprofloxacin and gatifloxacin in 26 US hospitals in 2000 (TRUST) showed that P. mirabilis was more sensitive to levofloxacin (94%) than to ciprofloxacin (87.7%) and gatifloxacin (87.7%) . The sensitivity of Pseudomonas aeruginosa to levofloxacin and ciprofloxacin was slightly higher (73-73.5%) than to gatifloxacin (71%). S. maltophilia was also more sensitive to levofloxacin and gatifloxacin (77.7-79.8%) than to ciprofloxacin (29.7-33.0%). The sensitivity of the isolated strains of E. coli to the 3 investigated fluoroquinolones turned out to be almost equal.<\/p>\n

When comparing the effectiveness of a single dose of levofloxacin (200 mg) and a 3-day course of therapy with this drug (100 mg 2 times a day) in 56 women with acute uncomplicated cystitis, no significant differences were revealed. The effectiveness was 96.9% in the first group and 95.8% in the second, and recurrence of UTI 3 months after the end of treatment was observed in 17.4% and 5.6% of cases, respectively (Koyama Y. et al., 2000).<\/p>\n

Data published by Italian authors indicate high clinical and microbiological effectiveness of levofloxacin in a dose of 250 mg for 3 days in uncomplicated UTI, and in a dose of 250 mg for 7-10 days in acute pyelonephritis and complicated UTI (Trinchiere A., 2001 ).<\/p>\n

With complicated UTI, the effectiveness of levofloxacin on bacteriuria reaches 90%, and ofloxacin – 88.5% (Peng MY, 1999). The good effectiveness of levofloxacin is noted in the treatment of complicated UTI in spinal patients (MacMillan R.D., 2001).<\/p>\n

Comparison of antimicrobial activity, pharmacokinetic and pharmacodynamic properties, as well as the results of clinical studies indicate that in the treatment of severe complicated UTI, a dose of levofloxacin 500 mg once a day is comparable to a dose of ciprofloxacin 500 mg twice a day.<\/p>\n

With complicated UTI, levofloxacin at a dose of 250 mg\/day for 7-10 days was more effective and better tolerated by patients than lomefloxacin at a dose of 400 mg\/day for 14 days. Complete microbiological eradication of the pathogen occurred in 95.5% (168\/176) of cases in the levofloxacin group and in 91.7% (154\/168) in the lomefloxacin group (Klimberg I.W. et al., 1998).<\/p>\n

According to a number of authors, levofloxacin is a good alternative for empiric therapy of complicated UTI, as well as a reserve drug for recurrent infection and infection resistant to beta-lactams (Martin S.J. et al., 2001).<\/p>\n

The risk of UTI development after bladder catheterization in hospital conditions is 5% in men and 10-20% in women, after cystoscopy – 4.7%, after transurethral resection (TUR) of the bladder – 39%, after TUR of the prostate – 6 – 49 %, after transrectal prostate biopsy – 6.2-87%, and after remote lithotripsy (DLT) – 5.7%. The choice of a drug for antibiotic prophylaxis of UTI largely depends on its pharmacokinetics and ability to create high concentrations in tissues during the procedure. Levofloxacin meets these requirements and allows to reduce the number of complications after prostate biopsy and endoscopic studies (Trinchieri A., 2002).<\/p>\n

The use of levofloxacin in a single dose of 500 mg led to a decrease in the frequency of UTI in 400 patients who underwent transrectal prostate biopsy to 0.25% (Griffith B.C., 2002).<\/p>\n

Levofloxacin in subsuppressive concentrations may be more effective than ciprofloxacin and ofloxacin in the long-term (anti-recurrence) treatment of UTI (Baskin H., 2002).<\/p>\n

In a comparative study with a single intramuscular administration of netilmycin or dibecaine, conducted at the Tokyo Medical University, the sufficient effectiveness of one-day use of levofloxacin (100 mg 3 times) for the prevention of UTI after urogynecological examinations was shown (Hayashi, 2001).<\/p>\n

The second study, performed by Japanese scientists in 2001, showed that, with an average concentration of levofloxacin in the blood plasma of 2.4 \u03bcg\/ml, its level in the mucous membrane of the bladder is 5.7 \u03bcg\/ml. The obtained data make it possible to recommend levofloxacin for the prevention of UTIs during TUR of the bladder (Hattori T. et al., 2001).<\/p>\n

In the clinic of urology of Moscow State Medical University, a new antimicrobial drug from the fluoroquinolone group – the L-isomer of ofloxacin – levofloxacin is used for severe UTIs in the postoperative period after large-scale interventions. The choice of fluoroquinolones is explained by the proven ability of drugs of this group to penetrate the biofilm better than others [Stratton, 1996]. The antimicrobial activity of levofloxacin in vitro is 2 times higher than that of ofloxacin. The drug has favorable pharmacokinetics: very high bioavailability (99%) and a high degree of excretion with urine in unchanged form (8%) [Davis, 1994]. Despite the presence of cross-resistance between levofloxacin and other fluoroquinolones, some microorganisms resistant to quinolones may show sensitivity to levofloxacin.<\/p>\n

In vitro studies have proven the activity of levofloxacin against E. coli, Enterobacter, Klebsiella, Proteus mirabilis, Pseudomonas aerogenosa, which are the most frequent causative agents of complicated and uncomplicated urogenital infections.<\/p>\n

We conducted a course of treatment with levofloxacin at a dose of 250 mg once a day for 10 days in 20 patients (19 women and 1 man) aged 24 to 56 years (average age 41.3 years) with complicated UTI. In 19 patients there was an exacerbation of chronic pyelonephritis on the background of long-standing chronic cystitis. One patient was prescribed the drug after contact ureterolithotripsy due to the development of infectious-inflammatory complications. The study included patients with complicated UTI in the initial stages of the development of inflammation, who had not previously taken any antibacterial drugs.<\/p>\n

The analysis of the results was carried out taking into account the subjective evaluation of the effectiveness and safety of the treatment by the patients and the doctor, as well as the data of objective studies: monitoring of blood and urine tests, ultrasonographic monitoring, comparative analysis of urine culture data performed before the start of treatment and on the 3rd, 10th and 17th days of therapy. The effectiveness of treatment with levofloxacin was considered very good in 90% of patients, good in 10%. The tolerability of the drug, as well as the effectiveness, were evaluated by the researchers after the last visit. It was considered very good in 55% of patients, good in 40% and average in 5%. By the end of the course of therapy, all patients did not complain of pain of an inflammatory nature, which occurred at the time of the start of treatment. Monitoring of microbiological research of urine during levofloxacin therapy revealed a positive trend, expressed in a progressive decrease in bacteriuria and its complete disappearance after 7-10 days of taking the drug. The normalization of indicators of general analysis of urine and leukocyte blood formula is noted.<\/p>\n

During the course of the study, ultrasound monitoring of kidney size and renal parenchyma thickness also recorded positive changes – regression to the 7-10th day of treatment in the increase in size of the kidney affected by the inflammatory process and local parenchyma thickening.<\/p>\n

After 7-10 days of taking levofloxacin, 6 patients (30%) had side effects in the form of nausea, 3 of them (15%) had episodes of diarrhea. It should be noted that side reactions were mild. By the end of the study, 3 patients with long-term chronic gastritis complained of nausea. None of the patients required special treatment due to the above-mentioned adverse reactions, all of them continued the study.<\/p>\n

Similar results are given in their works by Richard G. et al. (1998), who used the drug according to a similar scheme and obtained a clinical effect in 98.1% of patients. Such high results are explained by the short duration of use of levofloxacin in urological practice, which causes the absence of strains of microorganisms resistant to it. It should be noted that resistance to fluoroquinolones associated with spontaneous mutations in vitro is extremely rare (Stratton, 1996).<\/p>\n

In 12 patients (average age 46.8 years) with neurogenic urinary disorders and persistent UTI (cystitis, urethritis) during the last 2-3 years, we used levofloxacin in a dose of 250 mg once a day according to an alternative scheme, which implied a long (4- 5 weeks) continuous reception of the drug. Analogous design studies were undertaken in 1989 by Hammerberg D. et al. and in 1991 Waites K.V. et al. with the use of the second fluoroquinolone – norfloxacin. After a long course of treatment with levofloxacin and in the following 3 months of observation, clinical and laboratory signs of UTI were absent in 9 patients (75%). Another 2 patients (16.7%) had a recurrence of UTI 2-3 weeks after stopping levofloxacin. One patient (8.6%) had a persistent UTI during observation.<\/p>\n

According to Aron et al. (2000), performing a prostate biopsy without prescribing antibiotics leads to a significant increase in the frequency of bacteriuria and bacteremia. The frequency of UTI development in this case is 8-26% (Kapoor D. et al., 1998; Isen K. et al., 1999). Most authors recognize the need for preventive antibacterial therapy, which includes, at least, a single dose of a broad-spectrum antibiotic (most often – fluoroquinolone) before or during prostate puncture.<\/p>\n

The purpose of the second study, conducted in the urological clinic of the Moscow State Medical University, was to develop an optimal scheme for preparing a patient for a transrectal biopsy of the prostate gland to reduce the frequency of urinary infection. To achieve the specified goal, the authors compared the effectiveness of levofloxacin and a cleansing enema used in various modes and combinations. In the clinic of urology of Moscow State Medical University, 108 patients were randomly selected into 4 groups:<\/p>\n

Levofloxacin in a dose of 500 mg orally 2 hours before biopsy and cleansing enema.
\nOnly a cleansing enema.
\nLevofloxacin in a dose of 250 mg once a day orally for 5 days.
\nLevofloxacin in a dose of 250 mg once a day orally for 48 hours.
\nIndications for biopsy were usual: an increase in the level of prostate-specific antigen (PSA) higher than 4 ng\/ml and\/or changes in the prostate on digital rectal examination. The average age of the examined patients was 64.4 years, the average PSA level was 15.8 ng\/ml. Biopsy was performed from 6-18 points under ultrasound and finger control in outpatient and inpatient conditions. Since, according to our data and the results of foreign authors, the frequency of infectious complications does not depend on the number of biopsy punctures [1], we did not consider the relationship between the specified parameters. However, the number of patients with a different number of biopsy points was approximately the same in all 4 groups.<\/p>\n

Patients who took any antibacterial drugs 2 weeks before the biopsy were excluded from the study; patients with immunosuppressive conditions; those who have recently (within 3 months) had a UTI, as well as patients with an indwelling catheter, heart valve prostheses, etc.<\/p>\n

Reception of levofloxacin began 2 hours before the biopsy, with long-term reception continued at 250 mg every 24 hours. A cleansing enema was performed at 10 p.m. the day before the study and 2 hours before the biopsy.<\/p>\n

Assessment of bacteriuria in the middle portion of urine was carried out before the biopsy, 48 hours and 5 days after the manipulation. Within 3 days after the biopsy, all patients had their body temperature measured 3 times a day (its increase was regarded as a manifestation of bacteremia). Before the biopsy and 5 days after it, bacteriuria was not noted in any of the patients. In all febrile patients, hyperthermia was stopped no later than by 3-4 days (cases of urosepsis, prostate abscesses were not observed).<\/p>\n

The conducted research made it possible to conclude that when performing a transrectal multifocal biopsy of the prostate gland, prophylactic use of antibacterial agents is indicated in all cases, even for patients with no risk factors for urinary tract infection.<\/p>\n

According to earlier studies conducted at the urology clinic of MGMSU, in patients with a history of genitourinary infections (prostatitis, orchitis, epididymitis, urethritis), the risk of developing any complication (hematuria, acute urinary retention) was 1.8 times higher, and the risk of infectious complications increased 8.3 times compared to patients with an unencumbered urological history.<\/p>\n

It is interesting that no significant difference was found when prescribing levofloxacin after biopsy within 48 hours and 5 days, but this fact requires further study. It should be noted that oral intake of levofloxacin in various doses was highly effective for the prevention of infectious complications of such a frequently used procedure as transrectal biopsy of the prostate.<\/p>\n

Thus, levofloxacin can be used in modern urological practice:<\/p>\n

when preparing patients for a complex urodynamic study;
\nwhen preparing patients for transrectal biopsy of the prostate gland;
\nwhen performing TUR of the prostate gland or bladder;
\nwhen performing endovesical iontophoresis;
\nwhen performing endovesical laser ablation;
\nfor the treatment of acute cystitis and non-obstructive pyelonephritis;
\nfor preventive therapy in patients with frequently recurring cystitis;
\nwhen performing minimized operative interventions in patients with stress urinary incontinence
\nThere is no doubt that as pharmacology develops and new drugs appear, the search for new regimens of antibiotic prophylaxis will continue. With UTIs, especially their complicated forms, the use of levofloxacin can provide a more convenient and safe monotherapy and, probably, will reduce the cost of treatment.<\/p>\n

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