Recurrent viral infection. Causes of frequent cystitis in women. Treatment of severe VVC
A.V. ZAITSEV, MD, Professor, N.V. TUPIKINA,Moscow State University of Medicine and Dentistry, Department of Urology
Urinary tract infection is one of the most common bacterial infections that occurs predominantly in women. At the same time, the achievement of rapid relief of symptoms by optimal selection of antimicrobial therapy with simultaneous control of the pathogen and preventive measures for the recurrence of the disease is currently a difficult task. In an era of growing microbial resistance to antimicrobials, their careful and balanced use is necessary, taking into account possible risk factors for the development of resistance.
This article provides an overview of the current literature on etiology and pathogenesis, key aspects of the diagnosis and treatment of recurrent urinary tract infections. The presented clinical guidelines should contribute to a more adequate prescription of antibiotics in patients with urinary tract infections. According to them, preference should be given to antibiotics with a lower potential risk of increasing the level of resistance. Fluoroquinolones and other broad-spectrum antibiotics should be reserved for second-line therapy. It is also necessary to minimize the use of prophylactic antibiotics in patients with recurrent urinary tract infections, try to eliminate existing risk factors for recurrence in patients, and continue to search for alternative methods of treatment and prevention of urinary tract infections.
Introduction and epidemiology
Urinary tract infection (UTI) is one of the most common bacterial infections, predominantly in women. According to a number of authors, 50-60% of adult women have a single clinical episode of UTI during their life. As a rule, UTI manifests itself in the form of acute cystitis, with complaints of frequent urination and urgency, dysuria, and in some cases blood in the urine. At the same time, the achievement of rapid relief of symptoms by optimal selection of antimicrobial therapy with simultaneous control of the pathogen and preventive measures for the recurrence of the disease is currently a difficult task.
Recurrent urinary tract infection (UTI) is defined as 2 uncomplicated UTIs in a row within 6 months. or, more traditionally, as obtaining 3 positive cultures in the bacteriological analysis of urine within the previous 12 months. . Most relapses occur within the first 3 months. after primary infection, often accompanied by clustering of infections. Mabeck et al. (1972) it was found that about half of women after spontaneous resolution of uncomplicated UTI develop a relapse of this disease over the next year. Among women aged 17 to 82 years with a history of UTI, recurrence was noted in 44% of cases during 1 year of follow-up (53% in women over 55 and 36% in younger women). Results of a prospective study of 1,140 women by Haylen et al. showed that the overall prevalence of recurrent UTI averaged 19%.
Etiology and pathogenesis
Most UTI recurrences occur as a result of reinfection, although in some cases the process is due to the persistence of microorganisms on the urothelium (formation of intracellular bacterial communities, IBC) or the presence of foci of infection, such as stones, foreign bodies, urethral diverticula, infected kidneys. As a rule, diseases of the upper and lower urinary tract have an ascending type of infection due to the local spread of fecal flora from the perianal region to the genitourinary region, where the organisms spread upward through the urethra. However, in almost 85% of cases Escherichia coli is the causative agent of this disease Staphylococcus saprophyticus occurs in 10-15% of cases and only a small proportion falls on such representatives Enterobacteriaceae, how Proteus and Klebsiella spp..
Escherichia coli is the main causative agent of UTI due to the presence of virulence factors that not only affect the affinity of the pathogen for the urothelium (adhesion to epithelial cells due to the presence of fimbriae and villi), but also prevent the development of the patient's immune response. Of course, in addition to the virulence and concentration of the pathogen, the so-called. risk factors for the development of an exacerbation of UTI, which include:
1) anatomical and physiological features of the female body (short and wide urethra, proximity to natural reservoirs of infection - anus, vagina; clitoro-urethral distance, hypermobility of the urethra, urethro-hymenal adhesions; congenital anomalies of development - ectopia of the bladder, ureters; dystopia of the external opening of the urethra, ischial hypoplasia, including neurological conditions in elderly patients associated with spinal cord injury or diabetic neuropathy). Also in this group can be attributed such pathological conditions as relaxation and pronounced prolapse of the pelvic floor, which leads to an increase in the volume of residual urine, which is also a risk of developing recurrent UTI;
2) frequent concomitant gynecological diseases - inflammatory processes in the vagina, hormonal disorders (including hypoestrogenemia - alkalization of the pH of the vagina and a decrease in the number of Lactobacillus), leading to vaginal dysbiosis and the reproduction of pathogenic microflora in it, as well as cervical-vaginal antibodies;
3) behavioral aspects - the frequency of sexual intercourse (presence of STIs) and the nature of the contraceptives used (spermicides), which can increase the rate of vaginal and periurethral colonization of Escherichia coli.
The presence of hematuria and urgent urination, according to some researchers, indicates the presence of a highly virulent microflora. Risk factors for developing RITI include previous sexual intercourse, a new sexual partner, and the use of spermicides. Nonoxynol-9, the most commonly used spermicide, is toxic to lactobacilli, especially those producing H2O2, including Lactobacillus crispatus. The toxic effect of spermicides is less pronounced in relation to E. coli, while its adhesive properties can even be enhanced. There is more frequent colonization of the vagina E. coli in women using spermicides.
In addition, the risk is increased in patients younger than 15 years of age and in the presence of a UTI in the mother's history. Research continues on individual genetic characteristics in patients with RITI, including the Lewis blood type, based on the parameters of 4 antigens encoded by the Le gene (located on chromosome 19) and toll-like receptor polymorphism.
Because the E. coli remains the most common uropathogen, accounting for 65–95% of microorganisms isolated from the urinary tract, many epidemiological studies focus on the study of resistance E. coli. Today, much attention is paid to the relationship between the prescription of antibiotics, their collateral damaging effect and the development of resistance to uropathogens. In regions with a high level of prescription of fluoroquinolones, according to various indications, there is also a high level of resistance to them compared to regions where drugs of this group are prescribed less frequently. Despite existing approved guidelines for the treatment of UTIs, studies conducted in different countries indicate the misuse of antibiotics in both hospital and outpatient practice.
Microorganisms have different mechanisms for developing resistance to antibiotics. Acquired resistance is characterized by the ability of individual strains of bacteria to remain viable at those concentrations of antibiotics that suppress the bulk of the microbial population. Situations are possible when a large part of the microbial population exhibits acquired resistance. The emergence of acquired resistance in bacteria is not necessarily accompanied by a decrease in the clinical effectiveness of the antibiotic. The formation of resistance in all cases is genetically determined: the acquisition of new genetic information or a change in the level of expression of one's own genes. The following biochemical mechanisms of bacterial resistance to antibiotics are known: modification of the target of action, inactivation of the antibiotic, active removal of the antibiotic from the microbial cell (efflux), violation of the permeability of the external structures of the microbial cell, and the formation of a metabolic "shunt". An important element of resistance is the localization of coding genes: plasmid or chromosomal. This characteristic defines the epidemiology of resistance. With plasmid localization of genes, a rapid intra- and interspecies spread of resistance occurs, with chromosomal localization, the spread of a resistant clone is observed.
An example of the development of plasmid resistance is resistance to carbapenems. Klebsiella pneumoniae and resistance to fluoroquinolones Enterobacteriaceae. Plasmids often contain genes encoding resistance to various drugs, so microorganisms that are resistant to one antimicrobial drug may be resistant to others.
The most common mechanism of resistance of microorganisms to β-lactams is their enzymatic inactivation as a result of hydrolysis by β-lactamase enzymes. To date, about 200 such enzymes have been described, among which special attention is paid to extended-spectrum β-lactamases (ESBLs), which occur in E. coli and Klebsiella pneumoniae. The frequency of ESBL expression varies by region, but it is not always possible to obtain accurate national and international data. It is known that plasmids are now being detected in regions where they were not previously detected.
Carbapenems remain effective against ESBL-producing organisms in most cases. At the same time, there is an increase in the incidence of carbapenem-resistant Enterobacteriaceae due to the expression of carbapenemase enzymes. Clinically, the most significant carbapenemases are Klebsiella pneumoniae carbapenemase (KPC); and New Delhi metallo-β-lactamase-1 (NDM-1).
KPC expression has been found in many Enterobacteriaceae, including E. coli and Proteus, as well as in microorganisms not belonging to this class Pseudomonas aeruginosa. In addition to β-lactams (cephalosporins and carbapenems), these strains of microorganisms are usually resistant to quinolones and aminoglycosides. For a long time it was believed that KPC resistance occurs only in the USA, where it was first identified in 2001, but in 2005 KPC was discovered in France in a patient recently hospitalized in the USA. This enzyme is a chromosomal segment capable of inserting into various plasmids, which facilitates rapid and interspecific transmission. Another problem is the unreliability of the determination of resistance using standard methods. It is not always possible to detect in vitro resistance to carbapenems by testing susceptibility to meropenem and imipenem because some carriers remain in the susceptibility zone. Ertapenem susceptibility testing gives better results than other carbapenems. With an increase in the minimum inhibitory concentration (MIC) to carbapenems, a modified Hodge test should be used to further identify resistance. Admittedly, this ad hoc technique is difficult to apply and it is possible that many laboratories fail to detect KPC expression.
Carbapenemase NDM-1 was first identified in a patient hospitalized in New Delhi, India in 2007. Its prevalence in this region is currently estimated at 5% to 18%. In 2010, resistance due to the presence of NDM-1 was observed worldwide, with the exception of Central and South America. In 2012, 13 such cases were reported in the US. Microorganisms expressing NDM-1 are usually sensitive to colistin and may be sensitive to tigecycline and fosfomycin. The NDM-1 gene is transferred with various plasmids, often highly mobile, between Gram-negative microorganisms. They can colonize humans and contaminate water and the environment.
Determination of local resistance is a difficult task. Many hospitals monitor resistance in their microbiology laboratories. These data may reflect more of the spectrum of nosocomial infection than that found in outpatients. Therefore, hospital antibiograms indicate a higher level of resistance in this region. However, IDSA recommends avoiding the use of antimicrobials when local resistance to them is 20%, recognizing that outpatient clinicians may not always follow these recommendations. The study of the resistance of microorganisms in outpatient practice is of great practical importance.
Uroculture remains the gold standard for confirming UTIs, but results take more than 24 hours to obtain. In most cases, the diagnosis is based on clinical history, physical findings, and urinalysis. The use of test strips for this is a quick and cost-effective method that allows you to determine the esterase of leukocytes and the presence of nitrite in the urine. This method has low sensitivity, not all uropathogens can convert nitrates to nitrites. Even with negative indicators, it is not always possible to exclude a UTI. The likelihood of UTI increases in the presence of hematuria and the content of nitrites in the urine. The presence of symptoms characteristic of UTI remains decisive, although in women with urinary disorders, bacteriuria may be absent in 30-50% of cases. At the same time, low bacteriuria of 102 CFU against the background of UTI symptoms has a certain diagnostic value.
When the diagnosis is not entirely clear, delayed administration of antibiotics is allowed. In these cases, urine culture is performed, with a positive result, antimicrobial therapy is prescribed after 48 hours. In a randomized controlled trial of this approach, it was found that patients in the group of delayed antibiotics received the drug less often, although in the case of a confirmed UTI, their symptoms persisted 37% longer compared to the group of patients who received immediate antimicrobial therapy. The severity of symptoms in both groups did not differ significantly, and the progression of UTI and the development of pyelonephritis in patients receiving delayed therapy was not observed.
Because of the difficulty in determining the exact level of geographic resistance, many studies have examined individual risk factors for developing resistant UTIs. These factors include age >60 years, recent international travel, history of UTI, chronic disease, recent hospitalization, and prior antibiotic therapy. These risk factors should be considered when prescribing empiric treatment and, if present, a culture study should be considered prior to antibiotic selection.
Diagnostics
Patients with recurrent UTIs should have a thorough history taken, including the possible relationship of UTI episodes to sexual intercourse and contraception. It is necessary to conduct a gynecological examination to exclude inflammatory diseases of the reproductive system, diseases of the urethra, to assess the topographic and anatomical relationships of the lower urinary tract and genital organs, the presence of vaginal atrophy or severe prolapse of the pelvic organs (cystocele or uterine prolapse). The possible presence of residual urine is excluded by ultrasound or bladder catheterization. Ultrasound of the urinary tract and urethrocystoscopy are performed to exclude anatomical abnormalities and neoplasms of the genitourinary system. Screening for the presence of diabetes mellitus, followed by consultation with an endocrinologist, is indicated in the presence of concomitant risk factors. Laboratory studies for complicated or recurrent cystitis, in addition to a general urinalysis (with the determination of nitrites and leukocytes), include:
Bacteriological examination of urine, which is carried out to accurately identify the pathogen and its sensitivity to antibacterial drugs; as well as examination for sexually transmitted infections (PCR from two loci - urethra, cervical canal);
examination for viral infections (ELISA for the determination of immunoglobulins for herpes, cytomegalovirus), a smear and culture of vaginal discharge with a quantitative determination of lactobacilli) to exclude dysbiosis.
Treatment
The choice of antimicrobial drugs for the treatment of uncomplicated cystitis is carried out taking into account the existing recommendations for the treatment of UTIs (EAU, AUA, IDSA, Russian National Guidelines 2014), which are based on the principles of evidence-based medicine and the results of studies. Currently, several drugs have proven efficacy in the treatment of patients with NSP infection.
Nitrofurantoin. Nitrofurantoin is an inactive antiseptic that is activated in the urine by microorganisms.
The microcrystalline form of nitrofurantoin (Furadantin) is rapidly absorbed and causes gastrointestinal disturbances, so it is rarely used. Macrocrystalline nitrofurantoin (Macrodantin) has a larger molecule and is absorbed more slowly. The third form of nitrofurantoin, monohydrate macrocrystals or modified release nitrofurantoin (Macrobid), consists of 75% nitrofurantoin monohydrate and 25% macrocrystals, while a gel-like matrix is formed in the stomach and the drug is released slowly. Bioequivalence increases when the drug is taken with food. Due to rapid renal excretion, the therapeutic concentration in the blood rarely reaches optimal values, and the drug is not used in the treatment of pyelonephritis or prostatitis. The clearance of the drug is proportional to the clearance of creatinine, therefore, in the presence of renal failure, adjustment of the daily dose is necessary.
Comparative studies of the effectiveness of nitrofurantoin showed that a 3-day course of treatment with ciprofloxacin leads to a higher level of eradication of microorganisms than with nitrofurantoin treatment, but the clinical efficacy was the same. A five-day course of treatment with nitrofurantoin is comparable in results to a 7-day course of treatment with trimethoprim-sulfamethoxazole. Uropathogens rarely acquire resistance to nitrofurantoin again, so the drug is prescribed in cases of a probable risk of being resistant to other microbial antimicrobial drugs. However, Proteus, Pseudomonas, Enterobacter, and Klebsiella, which are less common in lower urinary tract infections, are usually inherently resistant to nitrofurantoin.
The most frequently observed adverse events (AE) when taking the drug are associated with the gastrointestinal tract: nausea, vomiting and diarrhea. Less commonly observed hypersensitivity reaction: chills, fever, changes in the cellular composition of the blood and hepatitis. Macrocrystalline nitrofurantoin is better tolerated by patients. Antacids containing magnesium may interfere with the absorption of nitrofurantoin and reduce its concentration in the urine. There are reports of development against the background of treatment of neuropathies and pulmonitis. Chronic pulmonary reactions when taking nitrofurantoin in the UK, Sweden and the Netherlands over the past 30 years amounted to 2.0%, 5.3% and 3.4%. It is not recommended to prescribe nitrofurantoin together with fluconazole due to increased toxic effects on the liver and lungs. Recently, the French Agency for the Safety of Medicines (AFSAPPS) recommended that nitrofurantoin should not be used for the long-term prevention of URTI due to AEs in the liver and lungs, so patients taking this drug should be monitored and informed of possible complications.
In Russia, furazidin potassium salt with basic magnesium bicarbonate (Furamag) is widely used, which is due to the high sensitivity of the main uropathogens (E. Coli - 96.8%; Enterococcus spp. - 100%; Staphylococcus spp. - 100%, Darmis, 2011 ). Unlike other nitrofurans, the drug creates higher concentrations of the active substance in the urine.
Trimethoprim-sulfamethoxazole. A combination drug that appeared in clinical practice in the 1970s. It has a bacteriostatic effect, is rapidly absorbed in the gastrointestinal tract, has a half-life of about 10 hours, and renal excretion is 25-60% during the first 24 hours. This drug is traditionally used for first-line treatment in the United States. Since then, there has been a significant increase in resistance to this drug. In Canada, the resistance rate is currently around 16%, reaching 21.4% in women ≤50 years of age. In Europe, the ECO-SENS study showed that resistance E. coli to trimethoprim-sulfamethoxazole in uncomplicated UTI in Portugal was 26.7%, while in Austria it was only 9.5%. In Spain in 2004, among 3,013 uropathogens, resistance to the drug was observed in 33.8% of cases. According to the Darmis study, in Russia the level of resistance E. coli to trimethoprim-sulfamethoxazole exceeds 20%. According to the recommendations of the European Association of Urology and the Russian National Guidelines, trimethoprim-sulfamethoxazole is not considered as a first-line drug in the treatment of uncomplicated cystitis.
Fosfomycin. Fosfomycin is an inhibitor of the synthesis of the cell wall of microorganisms, structurally different from other antibiotics and showing activity against many uropathogens. The bioequivalence of the drug is about 40%, and the half-life is 4 hours. Due to active renal excretion, a high concentration of fosfomycin in the urine is created, exceeding the MIC for most uropathogens.
For the treatment of uncomplicated LUTI, a single dose of fosfomycin 3.0 g is recommended. Fosfomycin does not bind to plasma proteins, therefore, on the first day of treatment, it appears in the urine, exceeding 440 times the MIC E. coli. This concentration is maintained for 80 hours. Dose changes in case of impaired renal or hepatic function are not required. Adverse events include nausea, vomiting, diarrhea, headache and abdominal pain, vaginitis. When observing more than 800 patients, moderate AEs were noted only in 6.1% of cases. Patients should be warned that after a single dose of the drug, the symptoms regress slowly over 2-3 days, and this does not indicate its ineffectiveness. The use of balsalazide and metoclopramide may lead to a decrease in serum and urinary concentrations of fosfomycin. Fosfomycin is safe in pregnancy.
Fosfomycin resistance is rare and is due to impaired transport of the drug into the bacterial cell or enzymatic modification of the drug. However, many microorganisms resistant to other antibiotics, including those producing ESBL E. Coli, remain sensitive to fosfomycin. When testing 47 strains Klebsiella pneumonia producing ESBL (in 79% of cases KPC and/or CTX-M β-lactamases), which were isolated from the urinary tract in outpatients, it was found that about 90% of microorganisms were resistant to trimethoprim-sulfamethoxazole and levofloxacin, and 40% were resistant to carbapenems. At the same time, in 92% of cases, the sensitivity of these microorganisms to polymyxin B was observed, in 87% to tigecycline and in 79% to fosfomycin.
Comparative studies of the efficacy of fosfomycin in the treatment of uncomplicated LUTI have shown that a single dose of the drug has the same clinical efficacy compared with a 5-day course of trimethoprim-sulfamethoxazole. The clinical efficacy of fosfomycin was comparable to a 7-day course of treatment with nitrofurantoin, eradication of the pathogen was 78% and 86% in the early stages, and after 4-6 weeks. after the end of therapy - 96% and 91%, respectively.
Fluoroquinolones. Ciprofloxacin and levofloxacin are widely (and often inappropriately) used in the treatment of UTIs. The bactericidal effect of these drugs is associated with an effect on DNA gyrase and topoisomerase IV. Fluoroquinolones are well absorbed when taken orally, have a half-life of about 4 hours, and are time- and dose-dependent drugs. The intake of fluoroquinolones causes AEs mainly from the gastrointestinal tract, their level reaches 17%. Among the fluoroquinolones, ciprofloxacin is more likely to cause the development of colitis due to Clostridium difficile. Sometimes there are symptoms from the central nervous system (moderate headache, rarely - epileptic seizures, especially when used together with NSAIDs and theophylline) and allergic reactions (rash). There are known cases of tendon rupture (especially the Achilles tendon) during treatment with fluoroquinolones, the frequency of these complications was 3.2 cases per 1,000 patients, mostly older than 60 years.
Resistance to fluoroquinolones is growing rapidly and is dependent on the frequency of their use. Resistance can be transferred to microorganisms with genes through plasmids. When switching due to increased resistance from trimethoprim-sulfamethoxazole to levofloxacin in the treatment of UTI, the level of resistance to the latter in the United States increased from 1% to 9% within 6 years.
Analysis of 11,799 antibiotic prescriptions for UTIs in Swiss outpatients in 2006-2008. showed that the reason for the appointment of treatment in 10,674 (90%) patients was bacterial cystitis. TMP-SMX was prescribed in 2537 (22%) patients, and quinolones were chosen for treatment in 78% of cases.
The frequency of resistance to fluoroquinolones in Russia exceeds 15%, so they are not recommended as first choice drugs. Fluoroquinolones, as drugs with good tissue penetration, are reserved for the treatment of more serious parenchymal organ infections.
other antibiotics. A study of the third-generation cephalosporin cefpodoxime for the treatment of UTIs found it to be less effective than ciprofloxacin and equally effective than trimethoprim-sulfamethoxazole. When comparing amoxicillin/clavulanate with ciprofloxacin, it was found that its effectiveness was lower even in the presence of sensitivity of uropathogens to amoxicillin/clavulanate. In the IDSA recommendations, the use of β-lactam antibiotics is limited due to the risk of increasing resistance due to the selection of strains of microorganisms that produce ESBL and the collateral damaging effect of these drugs. At the same time, studies of microorganism resistance in Spain in 2002-2004. showed that the sensitivity of the main uropathogens (E. Coli, Proteus mirabilis, Klebsiella pneumoniae) to cefixime was 95.8–98.6%. According to the Darmis study, the sensitivity of E. coli to cefikism in the Russian Federation remains at a relatively high level (87.5%), exceeding the level of sensitivity to ciprofloxacin (70.9%). Thus, it can be concluded that, if it is impossible to use the recommended drugs, β-lactam antibiotics: 2-3rd generation cephalosporins or inhibitor-protected aminopenicillins are the drugs of choice for the treatment of LUTI.
The duration of treatment with these drugs should be at least 5 days. Recommended: cefixime 400 mg orally once daily, cefuroxime 250 mg orally bid, ceftibuten 400 mg orally once or amoxicillin/clavulanate 500 mg/125 mg bid.
Treatment of recurrent uncomplicated UTI is similar to that of acute episodes. With frequent relapses, a long-term use of antimicrobial drugs in low doses is recommended for prophylactic purposes. At present, the effectiveness of such long-term courses has been proven, which for trimethoprim-cotrimoxazole is 2-5 years, for other drugs - up to 6-12 months. At the same time, long-term use of antimicrobial drugs in subinhibitory doses leads to the selection of resistant strains of uropathogens, the development of AE, and dysbiosis. Unfortunately, after the cessation of maintenance treatment in 30-50% of cases within 3-6 months. there is a recurrence of UTI. The Russian National Guidelines state that women who clearly associate recurrent UTIs with sexual intercourse should receive postcoital antimicrobial prophylaxis or treatment of recurrent UTIs with full course doses of antimicrobials.
Oral contraceptives and antibiotics. Since UTI patients are often women of childbearing age, many of whom take oral contraceptives (OCPs), the question of their interaction with antibiotics remains open. Despite the publication of more than 200 articles on this topic, in many cases it is difficult to establish their exact interaction. Some antibiotics (particularly rifampicin), which significantly inhibit cytochrome 3A4, can increase the metabolism of OCPs, but they are not used to treat uncomplicated UTI. However, given the serious nature of these effects, it is recommended that alternative methods of contraception be used in addition to OCPs until the first menstrual cycle after antibiotic treatment.
Intravesical pharmacotherapy. A number of studies have been conducted to study the effectiveness of various drugs for intravesical administration, which have a protective effect on the urothelium and prevent the adhesion of uropathogens. Torella et al. (2013) compared the number of RIMP episodes over 6-12 months. in 69 patients divided into three groups, depending on the type of prophylaxis. Group 1 received intravesical administration of 1.6% hyaluronic acid and 2% chondroitin sulfate (Ialuril 1; IBSA). The solution was instilled into the bladder once a week for 4 weeks, then once every 15 days for 2 months, then once every 30 days for 2 months. In the second group of patients, the administration of the drug according to this scheme was combined with the appointment of fosfomycin at 3.0 g. every 10 days for 6 months, and in the third group, patients received only fosfomycin. During the observation period, RIMP episodes were absent in 72.7% of patients in group 1, in 75% of patients in group 2, and in 30.4% of patients in group 3. The authors consider intravesical pharmacotherapy with a solution of hyaluronic acid and chondroitin sulfate an effective method for the treatment and prevention of RITI. However, the need for regular bladder catheterization and the cost of this group of drugs limit the wide clinical application of this method.
Alternative methods of treatment and prevention of RIMP. Due to the slowdown in the creation of new antibiotics and the growth of antibiotic resistance in microorganisms, the need for their more rational use is now obvious. The European Association of Urology (EAU, 2012) guidelines for the management of recurrent uncomplicated lower urinary tract infection (UTI) in women suggest that non-antibiotic prophylaxis should be considered first and antibiotic prophylaxis should only be considered if non-antibiotic prophylaxis has failed (LE:1a , GR: A).
The results of a randomized controlled trial of the efficacy of an antibiotic (ciprofloxacin) and symptomatic treatment (ibuprofen) in 79 patients with NSP infection showed that the timing of regression of symptoms of the disease was almost the same in both groups. On the 4th day of treatment, 58.3% of patients treated with ciprofloxacin and 51.5% of patients treated with ibuprofen noted a complete regression of symptoms (sum of symptom scores = 0), and on the 7th day of treatment their number was 75 % and 60.6% respectively (P-value 0.306). On the 7th day of treatment, negative uroculture (bacteriuria<102 КОЕ) выявлена у 71,9% больных в группе ципрофлоксацина и у 48,5% больных в группе ибупрофена. Лишь 33% больных, получавшим ибупрофен, в дальнейшем была назначена антимикробная терапия в связи с рецидивом заболевания. В остальных случаях наблюдалась асимптоматическая бактериурия, не требовавшая применения антибиотиков .
The most studied option for non-antibacterial UTI prophylaxis is immunoactive prophylaxis, in which antigens of pathogenic microorganisms are applied orally or topically and stimulate an increase in the immune response at sites of infection, such as the urinary tract. Lyophilisate of bacterial lysate 18 strains E. coli(Uro-Vaxom) activates non-specific immunity of the mucous membranes and the specific immune response of the body. The dosage form is presented in capsules of 6 mg for oral administration. Evidence-based clinical trials have shown a 35% to 65% reduction in cystitis recurrence with Uro-Vaxom compared to placebo, as well as a reduction in antibiotic consumption. In a meta-analysis of 11 blinded controlled trials, the drug showed a significant reduction in the incidence of RIMP. For five years of clinical use, more than a million patients have received treatment with this drug. The use of the drug Uro-Vaxom has been included in the recommendations of the European Association of Urology since 2011 for the treatment and prevention of recurrence of UTI, regardless of the type of pathogen (grade of recommendations - B, level of evidence - 1A).
There are reports of the use of immunoactive drugs such as longidase, galavit in the complex treatment of patients with RIMP with a positive clinical effect.
Natural interest is the use of phytopreparations in the treatment and prevention of RIMP. A recently published analysis of studies conducted in Eastern Europe (including Russia) and Central Asia on the effectiveness of the combined drug Canephron (consisting of centaury grass, lovage root and rosemary leaves) confirmed that due to its diuretic, antispasmodic, anti-inflammatory, antioxidant, antimicrobial and nephroprotective effects the drug has a positive clinical value in RIMP. Further study of its action is needed in well-designed, prospective, randomized clinical trials.
An alternative method of preventing RIMP is also the use of cranberry preparations (the active substance is proanthocyanidin A). The mechanism of action is to suppress the synthesis of fimbriae, with prolonged exposure to E. Coli, its adhesive ability decreases. Daily intake of cranberry products containing at least 36 mg proanthocyanidin A may be recommended for the prevention of RITI.
The use of probiotics to prevent RUTIs is a popular and long-standing topic. Suspensions of non-pathogenic strains of Lactobacillus, Bifidobacteria, or Saccharomyces are injected into the vagina to colonize the epithelium, prevent adhesion, and expel pathogens. The vagina in patients with RITI contains less H2O2-producing lactobacilli and is more often colonized by E. coli. In a recent Seattle study, 48 women with a history of UTI received intravaginal Lactobacillus crispatus (Lactin-V) for 10 weeks. This treatment significantly reduced the rate of UTI recurrence compared to placebo controls (p<0, 01) . В другом рандомизированном исследовании эффективность H2O2-продуцирующих лактобактерий оказалась ниже, чем эффективность антимикробной профилактики триметоприм-сульфаметаксозолом . Необходимо проведение дальнейших, более крупных рандомизированных исследований. В руководстве Европейской ассоциации урологов отмечено, что регулярное интравагинальное применение пробиотиков, содержащих лактобактерии, может быть рекомендовано для профилактики РИМП (степень рекомендаций – С) .
Another approach for RUTI without antibiotics is to use low-virulence strains of microorganisms to colonize the MEPs and suppress their infection with pathogenic strains, which has been shown in some clinical studies.
Bacteriophage preparations have good prospects for use as antimicrobial therapy for RIMP. These therapeutic and prophylactic agents contain broad-spectrum polyclonal phages, whose activity extends, in particular, to bacteria resistant to antibiotics. The main advantages of bacteriophages are: high sensitivity of opportunistic microflora to bacteriophages, compatibility with all types of traditional antibiotic therapy, absence of contraindications.
Alternative treatment for postmenopausal women includes topical estrogen replacement therapy. Topical application of estriol can lead to a significant reduction in the incidence of UTIs and an increase in the level of lactobacilli in the vagina, which helps to improve the vaginal biocenosis.
In patients with frequent postcoital cystitis, the presence of pronounced urethrohymenal adhesions, hypermobility or vaginal ectopia of the distal urethra, pathogenetic treatment, in addition to postcoital antimicrobial prophylaxis (especially in cases of its low efficiency), may include surgical correction of anatomical disorders: transposition of the distal urethra, dissection of urethro-hymenal adhesions without exacerbation of a chronic inflammatory process.
Conclusion
In conclusion, it should be noted that in an era of growing resistance of microorganisms to antimicrobial drugs, their careful and balanced use is necessary, taking into account possible risk factors for the development of resistance. Clinical guidelines should encourage more appropriate antibiotic prescribing in patients with UTIs. Preference should be given to antibiotics with a lower potential risk of increasing resistance levels. Fluoroquinolones and other broad-spectrum antibiotics should be reserved for second-line therapy. It is necessary to minimize the use of prophylactic antibiotics for RUTIs, try to eliminate existing risk factors for recurrence in patients, and continue to search for alternative methods of treatment and prevention of UTIs.
Literature
1. Khunda A, Elneil S. Recurrent Urinary Tract Infections Associated with Gynecological Disorders. Curr Bladder Dysfunct Rep., 2012, 7(2): 131-140.
2. HoodonTM. Recurrent urinary tract infection in women. Int JAntimicrob Agents, 2001, 17(4): 259-68.
3. Mabeck C.E. Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgrad Med J., 1972, 48 (556): 69-75.
4. Ikaheimo R et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis., 1996, 22 (1): 91-9.
5. Haylen BT et al. Recurrent urinary tract infections in women with symptoms of pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct., 2009, 20(7): 837-42.
6. Hooton TM, Stapleton AE, Roberts PL et al. Perineal anatomy and urine-voiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis., 1999, 29: 1600-160.
7. Hernandez-Rey AE, Vitenson J, McGovern PG. Duplicated ectopic hydroureter presenting as a hydrosalpinx, with chronic pelvic pain and recurrent urinary infections. Fertil Steril., 2007, 88 (6): 1677.
8. ZimmerM et al. Pregnancy in a woman with treated bladder extrophy, split pelvis and hypoplasia of ischial bones. case report. Neuro Endocrinol Lett., 2008, 29(3):292-4.
9. Szucs K, O'Neil KM, Faden H. Urinary findings in asymptomatic subjects with spina bifida treated with intermittent catheterization. Pediatr Infect Dis J., 2001, 20 (6): 638-9.
10. Gupta K, Stamm W.E. Pathogenesis and management of recurrent urinary tract infections in women. World J Urol., 1999, 17 (6): 415-20.
11. Stamey TA, Timothy MM. Studies of intraital colonization in women with recurrent urinary infections. III. Vaginal glycogen concentrations. J Urol., 1975, 114 (2): 268-70.
12. Stamey TA et al. The immunological basis of recurrent bacteriuria: role of cervicovaginal antibody in enterobacterial colonization of the intraital mucosa. Medicine (Baltimore), 1978, 57 (1): 47-56.
13. Raz R et al. Recurrent urinary tract infections in postmenopausal women. Clin Infect Dis., 2000, 30 (1): 152-6.
14 Scholes D et al. Risk factors for recurrent urinary tract infection in young women. J Infect Dis., 2000, 182(4): 1177-82.
15. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health, 1990, 80(3): 331-3.
16. Stamm WE, McKevitt M, Roberts PL et al. Natural history of recurrent urinary tract infections in women. Rev Infect Dis, 1991, 13(1): 77-84.
17. Foxman B, Gillespie B, Koopman J et al. Risk factors for second urinary tract infection among college women. Am J Epidemiol, 2000, 151(12): 1194-205.
18. Scholes D, Hooton TM, Roberts PL et al. Risk factors for recurrent urinary tract infection in young women. J Infect Dis, 2000, 182(4): 1177-82.
19 Hooton TM, Scholes D, Hughes JP et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med, 1996, 335(7): 468-74.
20. Fihn SD, Latham RH, Roberts P et al. Association between diaphragm use and urinary tract infection. JAMA, 1985, 254(2): 240-5.
21. Scholes D, Hawn TR, Roberts PL et al. Family history and risk of recurrent cystitis and pyelonephritis in women. J Urol, 2010, 184(2): 564-9.
22. Ikaheimo R, Siitonen A, Heiskanen T et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis, 1996, 22(1): 91-9.
23. McGroarty JA, Tomeczek L, Pond DG et al. Hydrogen peroxide production by Lactobacillus species: correlation with susceptibility to the spermicidal compound nonoxynol-9. J Infect Dis, 1992, 165(6): 1142-4.
24. Klebanoff SJ. Effects of the spermicidal agent nonoxynol-9 on vaginal microbial flora. J Infect Dis, 1992, 165(1): 19-25.
25. Sheinfeld J, Schaeffer AJ, Cordon-Cardo C et al. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Engl J Med, 1989, 320 (12): 773-7.
26. Hawn TR, Scholes D, Li SS et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One, 2009, 4(6): e5990.
27. Naber KG, Schito G, Botto H, Palou J, Mazzei T. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol., 2008, Nov. 54 (5): 1164-75.
28 Kahlmeter G, Poulsen HO. Antimicrobial susceptibility of Escherichia coli from community-acquired urinary tract infections in Europe: the ECO$SENS study revisited. Int J Antimicrob Agents, 2012, 39(1): 45-51.
29 Johnson L, Sabel A, Burman WJ et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med, 2008, 121(10): 876-84.
30. Grover ML, Bracamonte JD, Kanodia AK et al. Assessing adherence to evidence-based guidelines for the diagnosis and management of uncomplicated urinary tract infection. Mayo Clin Proc, 2007, 82(2): 181-5.
31. Shepherd AK, Paul S. Pottinger PS. Management of Urinary Tract Infections in the Era of Increasing Antimicrobial Resistance. Med Clin N Am, 2013, 97: 737-757.
32 Tenover F.C. Mechanisms of antimicrobial resistance in bacteria. Am J Med, 2006, 119 (6 Suppl 1): S3-10.
33 Gupta N, Limbago BM, Patel JB et al. Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis, 2011, 53(1):60-7.
34. Naas T, Nordmann P, Vedel G et al. Plasmid-mediated carbapenemhydrolyzing - lactamase KPC in a Klebsiella pneumoniae isolate from France. Antimicrobial Agents Chemother, 2005, 49(10): 4423-4.
35. Carbapenem-resistant Enterobacteriaceae containing New Delhi metallo-betalactamase in two patients–Rhode Island, March 2012. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6124a3.htm. AccessedDecember 27, 2012.
36. Nordmann P, Poirel L, Walsh TR et al. The emerging NDM carbapenemases. Trends Microbiol, 2011, 19(12): 588-95.
37. Miller LG, Tang AW. Treatment of uncomplicated urinary tract infections in an era of increasing antimicrobial resistance. Mayo Clin Proc, 2004, 79(8): 1048-53.
38. Deville' WL, Yzermans JC, Van Duijn NP et al. The dipstick test useful to rule out urine infections. A meta-analysis of the accuracy. BMC Urol, 2004, 4:4.
39 Little P, Turner S, Rumsby K et al. Validating the prediction of lower urinary tract infection in primary care: sensitivity and specificity of urinary dipsticks and clinical scores in women. Br J Gen Pract, 2010, 60 (576): 495-500.
40. Kunin CM, White LV, Hua TH. A reassessment of the importance of “low-count” bacteriuria in young women with acute urinary symptoms. Ann Intern Med, 1993, 119(6): 454-60.
41. Little P, Moore MV, Turner S, et al. Effectiveness of five different approaches in management of urinary tract infection: randomized controlled trial. BMJ, 2010, 340: c199.
42. Vellinga A, Murphy AW, Hanahoe B et al. A multilevel analysis of trimethoprim and ciprofloxacin prescribing and resistance of uropathogenic Escherichia coli in general practice. J Antimicrob Chemother, 2010, 65(7): 1514-20.
43. Zhanel GG, Hisanaga TL, Laing NM et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents, 2006, 27(6): 468-75.
44. Vellinga A, Tansey S, Hanahoe B et al. Trimethoprim and ciprofloxacin resistance and prescribing in urinary tract infection associated with Escherichia coli: a multilevel model. J Antimicrob Chemother, 2012, 67(10): 2523-30.
45 European Association of Urology Guidelines on Urological Infections 2013 www.uroweb.org
46. Antimicrobial therapy and prevention of infections of the kidneys, urinary tract and male genital organs. Russian national recommendations, M., 2014.
47 Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE. Infectious Diseases Society of America Diagnosis. Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis., 2010, Mar 1, 50(5): 625-63.
48. Iravani A, Klimberg I, Briefer C et al. A trial comparing low-dose, short-course ciprofloxacin and standard 7 day therapy with co-trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract infection. J Antimicrob Chemother, 1999, 43 (Suppl A): 67-75.
49. Gupta K, Hooton TM, Roberts PL, et al. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch Intern Med, 2007, 167(20): 2207-12.
50. Penn RG, Griffin JP. Adverse reactions to nitrofurantoin in the United Kingdom, Sweden, and Holland. Br Med J (Clin Res Ed), 1982, 284 (6327): 1440-2.
51. AFSSAPS (Agence française de securité sanitaire des produits de santé). Restriction d'utilisation de la nitrofurantoïne en raison d'un risque de survenue d'effets indésirables graves hépatiques et pulmonaires - Lettre aux professionnels (12/03/2012).
52. Palagin I.S., Sukhorukova M.V., Dekhnich A.V., Eidelstein M.V., Shevelev A.N., Grinev A.V., Perepanova T.S., Kozlov R.S., research group "DARMIS". The current state of antibiotic resistance in pathogens of community-acquired urinary tract infections in Russia: results of the DARMIS study (2010–2011).
53. McIsaac WJ, Moineddin R, Meaney C, Mazzulli T. Antibiotic-resistant Escherichia coli in women with acute cystitis in Canada. Can J Infect Dis Med Microbiol., 2013, Fall, 24(3): 143-9.
54. Deck D, Winston L. Beta-Lactam and other cell wall- and membrane-active antibiotics. In: Basic & clinical pharmacology. 12th ed. New York: McGraw-Hill; 2012.
55. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis, 2011, 15(11): e732-9.
56 Naber KG. Fosfomycin trometamol in treatment of uncomplicated lower urinary tract infections in adult women–an overview. Infection, 1992, 20 (Suppl 4): S310-2.
57 Falagas ME, Kastoris AC, Kapaskelis AM et al. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis, 2010, 10(1): 43-50.
58. Minassian MA, Lewis DA, Chattopadhyay D et al. A comparison between single-dose fosfomycin trometamol (Monuril) and a 5-day course of trimethoprim in the treatment of uncomplicated lower urinary tract infection in women. Int J Antimicrob Agents, 1998, 10(1): 39-47.
59. Stein G.E. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection. Clin Ther, 1999, 21(11): 1864-72.
60 Van der Linden PD, Sturkenboom MC, Herings RM et al. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ, 2002, 324 (7349): 1306-7.
61 Johnson L, Sabel A, Burman WJ et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med, 2008, 121(10): 876-84.
62 Stuck A et al. Determinants of Quinolone versus Trimethoprim-Sulfamethoxazole Use for Outpatient Urinary Tract Infection. Antimicrob Agents Chemother., 2012, March, 56 (3): 1359-1363.
63 Hooton TM, Roberts PL, Stapleton AE. Cefpodoxime vs ciprofloxacin for short course treatment of acute uncomplicated cystitis: a randomized trial. JAMA, 2012, 307(6):583-9.
64 Kavatha D, Giamarellou H, Alexiou Z et al. Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of uncomplicated acute cystitis in women. Antimicrobial Agents Chemother, 2003, 47(3): 897-900.
65. Garcia Garcia MI, Munoz Bellido JL, Garcia Rodriguez JA. Spanish Cooperative Group for the Study of Anitimicrobial susceptibiltiy of Community Uropathogens. In vitro susceptibility of community-acquired urinary tract pathogens to commonly used antimicrobial agents in Spain: a comparative multicenter study (2002–2004).
66. Dickinson B, Altman R, Nielsen N et al. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol, 2001, 98(5 Pt 1): 853-60.
67. Damiano R et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomized trial. Eur Urol., 2011, Apr. 59 (4): 645-51.
68 Torella M et al. Intravesical therapy in recurrent cystitis: a multi-center experience. J Infect Chemother, 2013, Oct, 19(5): 920-5.
69. Bleidorn J et al. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? - Results of a randomized controlled pilot trial. BMC Med., 2010, 8:30.
70 Naber KG et al. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. International Journal of Antimicrobial Agents, 2009, 33: 111-119.
71. Pushkar D.Yu., Zaitsev A.V., Matsaev A.B. Efficiency of longidase for injection 3000 IU in the complex treatment of chronic cystitis in women. XII Russian National Congress "Man and Medicine". Abstracts of reports. S. 664.
72. Usovetsky I.A. The use of a new domestic immunomodulator galavit in the treatment of urogenital infections. Consilium Medicum, 2004, 3:25-27.
73. Naber K. Efficacy and safety of the phytotherapeutic drug Canephron® N in prevention and treatment of urogenital and gestational disease: review of clinical experience in Eastern Europe and Central Asia. Research and Reports in Urology, 2013, 5:39-46.
74 Vasileiou I et al. Current clinical status on the preventive effects of cranberry consumption against urinary tract infections. Nutr Res., 2013, 33(8): 595-607.
75. Falagas ME, Betsi GI, Tokas T et al. Probiotics for prevention of recurrent urinary tract infections in women: a review of the evidence from microbiological and clinical studies. Drugs, 2006, 66(9): 1253-61.
76 Karlsson M, Scherbak N, Khalaf H et al. Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-kB activity in Escherichia colistimulated urinary bladder cells. FEMS Immunol Med Microbiol, 2012, 66(2): 147-56.
77. Stapleton AE, Au-Yeung M, Hooton TM et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis, 2011, 52(10): 1212-7.
78 Beerepoot MA, Ter Riet G, Nys S et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med, 2012, 172(9): 704-12.
79. Sundén F, Håkansson L, Ljunggren E, Wullt B. Escherichia coli 83972 bacteriuria protects against recurrent lower urinary tract infections in patients with incomplete bladder emptying. J Urol., 2010, Jul, 184 (1): 179-85.
80 Sillankorva S et al. Efficacy of a broad host range lytic bacteriophage against E. coli adhered to urothelium. Curr Microbiol., 2011, Apr. 62 (4): 1128-32.
81. Zakharova Yu.A. et al. Therapeutic and prophylactic preparations of bacteriophages in the treatment of pregnant women with pyelonephritis: practical experience, long-term results. Medical Council, 2013, 8:58-62.
82. Perrotta C, Aznar M, Mejia R et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev, 2008, 2: CD005131.
83 Ronzoni G et al. Transposing the urethral meatus in the treatment of recurrent and postcoital cystitis in women with hypospadias. BJU Int., 2001, 87(9): 894-6.
84. Gvozdev M, Loran O, Gumin L, D "iakov V. Transposition of the distal urethra in surgical treatment of recurrent lower urinary tract infection in women. Urologiia, 2000, 3: 24-7.
UROLOGY AND GYNECOLOGY
L.A.SINYAKOVA, Doctor of Medical Sciences, Professor, M.L.SHTEINBERG, A.M.PLESOVSKY, RMAPE, Moscow
Recurrent lower urinary tract infections:
DIAGNOSIS AND TREATMENT
The problem of recurrent infections of the lower urinary tract (LUTI) in women, affecting not only the physical health of women, but also the sexual life of a married couple, childbearing, is currently not only acquiring a social character, but is also interdisciplinary. RUTs are common (every 10 women suffer from chronic, often recurrent cystitis), but only 40% of women with dysuria develop chronic cystitis. Insufficient knowledge of the etiology and pathogenesis of RURTI, the lack of an algorithm for diagnosis and treatment and unified approaches to this serious problem among various specialists (urologists, gynecologists, therapists, dermatovenereologists) lead to the ineffectiveness of the therapy
and a high recurrence rate.
Keywords: recurrent infections of the lower urinary tract, dysbacteriosis, dysuria, chronic cystitis
In the vast majority of cases, RUTs are secondary, develop against the background of sexually transmitted infections, anomalies in the location of the external opening of the urethra, hypoestrogenemia, inflammatory diseases of the pelvic organs (PID), endometriosis, pelvic venous plethora. Unfortunately, the treatment most often comes down to the appointment of various antibacterial drugs, and doctors do not take into account the role of endometriosis, salpingo-oophoritis, herpes in the genesis of the patient's complaints. Inadequate examination of RURTI patients (in particular, by therapists who should not be involved in the examination and treatment of these patients) exacerbates the problem, leads to the development of dysbacteriosis, vaginal dysbiosis. Chronic cystitis with frequent relapses can lead to the development of ascending pyelonephritis, disruption of the closing apparatus of the ureter orifices with the occurrence of vesicoureteral refluxes, which is a much more serious problem. Errors in the treatment of these diseases are costly for patients. Often in clinical practice, doctors, not getting the effect of antibiotic therapy, instead of trying to find out the cause of the development and recurrence of the disease, prescribe long-term continuous courses of treatment with drugs of various groups. persists in the face of inadequate treatment.
dyspareunia, forcing women to refuse sexual relations, making it difficult to plan pregnancy. Another problem is the treatment of only the woman and the lack of examination and treatment of the sexual partner.
In 2005, we proposed an algorithm for the diagnosis and treatment of recurrent urinary tract infections, according to which it is necessary to examine patients for the presence of STIs, anomalies in the location of the external opening of the urethra, which necessitates a differentiated approach to the treatment of this category of patients and conducting not only etiological, but also pathogenetic therapy (Table 1).
Recently, we have seen that this algorithm is incomplete. Among 200 patients with dysuria examined in the clinic over the past 3 years, 5 patients were diagnosed with interstitial cystitis, confirmed by cystoscopy and morphologically. At the same time, some of these patients had never completed urination diaries before admission to the clinic, and they were prescribed antibiotic therapy for chronic cystitis. This indicates that doctors do not know the algorithms for examining patients with certain diseases. Another problem is that in the presence of clear clinical signs of interstitial cystitis, cystoscopy is performed without adequate (general) anesthesia due to ignorance of the recommendations of the European Association of Urology, recommendations developed by the US National Institutes of Health, as well as a lack of understanding of the essence of the problem.
■ Chronic cystitis with frequent relapses can lead to the development of ascending pyelonephritis, disruption of the closing apparatus of the mouths of the ureter with the occurrence of vesicoureteral refluxes, which is a problem.
And medical
advice #7-8 2011
Recently, more and more often there are patients with chronic urethritis and recurrent cystitis, which develop against the background of viral infections. Damage to the organs of the urinary system is secondary, and urination disorders in some cases occur against the background of a pronounced violation of the normal microflora of the vagina. Therefore, we believe that the algorithm for examining patients with dysuria should include filling out urination diaries (at least two days in advance), smears from the urethra, vagina, cervical canal, sowing from the vagina for flora and sensitivity to antibiotics with mandatory quantitative determination of lactobacilli, enzyme immunoassay (ELISA) with the determination of immunoglobulins G and M to herpes types 1 and 2 and cytomegalovirus.
A common mistake is that outpatient clinicians perform a cystoscopy and, if leukoplakia is found, do not take a biopsy.
The patient is diagnosed with "leukoplakia of the bladder" and this is limited. However, depending on the results of the morphological study, tactics fundamentally change, because and squamous cell papilloma, requiring transurethral resection of the bladder, and true bladder leukoplakia (squamous cell metaplasia with keratinization - pre-cancer) outwardly look the same. For squamous metaplasia of the epithelium of the bladder without keratinization, which is the result of chronic inflammation, most often against the background of urogenital infections, the destruction of the glycosaminoglycan layer of the bladder mucosa is characteristic. Pathogenetic therapy in this case
tea, as in interstitial cystitis, should be aimed at restoring the mucopolysaccharide layer. Given the above, we propose the following algorithm for diagnosing recurrent cystitis (Table 2).
There are two subjective reasons for the increase in dysbiotic and infectious-inflammatory diseases of the genitals:
1. Irrational, often unreasonable antimicrobial treatment of non-existent diseases, due to incorrect interpretation of the results of laboratory tests by doctors, in particular, high-quality PCR.
2. Self-medication with various over-the-counter and prescription antimicrobial drugs.
The drugs of choice for the treatment of acute cystitis, according to the recommendations of the European Association of Urology in 2010, are fosfomycin trometamol, nirofurantoin, trimethoprim-sulfamethoxazole (only in regions where resistance<20%) (табл.
In these guidelines, fluoroquinolones are classified as alternative drugs; prescription of drugs for acute uncomplicated cystitis is not recommended, because worldwide there is a progressive increase in resistance to fluoroquinolones. Antibacterial therapy for recurrent infections of the lower urinary tract cannot be empirical, therefore, the targeted use of antibiotics is indicated, taking into account the results of bacteriological examination of urine. The appointment of uroantiseptics is not effective, due to low
■ The algorithm for examining patients with dysuria should include filling out urination diaries (at least two days in advance), swabs from the urethra, vagina, cervical canal, culture from the vagina for flora and sensitivity to antibiotics with mandatory quantitative determination of lactobacilli, enzyme immunoassay (ELISA) with determination of immunoglobulins G and M to herpes types 1 and 2 and cytomegalovirus.
Table 1. Algorithm for the diagnosis and treatment of recurrent urinary tract infections
Algorithm for the diagnosis of recurrent cystitis
Algorithm for the diagnosis of non-obstructive pyelonephritis
Careful history taking! Identification of risk factors: early onset of sexual activity, frequent change of sexual partners, the presence of invasive manipulations, concomitant chronic gynecological diseases, vaginal dysbiosis
Vaginal examination
General urine analysis
Urinalysis, complete blood count, biochemical blood test
Urine culture
Testing for STIs
Ultrasound examination of the kidneys, bladder with the determination of residual urine
Ultrasound examination of the kidneys using color doppler, power doppler, bladder
Cystoscopy with biopsy
X-ray studies
Examination by a gynecologist
UROLOGY AND GYNECOLOGY
UROLOGY AND GYNECOLOGY
Table 2. Algorithm for diagnosing recurrent cystitis
Algorithm for diagnosing recurrent cystitis Analysis of patient complaints
Careful history taking! Identification of risk factors: early onset of sexual activity, frequent change of sexual partners, presence of invasive manipulations, concomitant chronic gynecological diseases, viral infections
(herpes, cytomegalovirus), vaginal dysbiosis Completing urination diaries Vaginal examination Complete urinalysis Urine culture for flora and sensitivity to antibiotics Swab: urethra, vagina, cervical canal Examination for the presence of STIs (PCR - urethra, cervical canal)
ELISA with the determination of immunoglobulins G and M for herpes types 1 and 2 and cytomegalovirus Sowing of vaginal discharge for flora and sensitivity to antibiotics with quantitative determination of lactobacilli Ultrasound examination of the kidneys, bladder with determination of residual urine, uterus, appendages, Dopplerography of the pelvic vessels Cystoscopy with biopsy Examination by a gynecologist
Diagnosis Most common causative agent Initial empiric therapy (2003) Initial empiric therapy (2010)
Acute cystitis, uncomplicated E. coli, Klebsiella, Proteus, Staphylococci Fluoroquinolones Trimethoprim-sulfamethoxazole* (only in regions where resistance<20% для E. т1л)
Fosfomycin trometamol Nitrofurantoin
Ampicillin Fosfomycin Trometamol
Nitrofurantoin Fluoroquinolone (alternative) (avoid for uncomplicated cystitis whenever possible)
Table 4. Opportunistic microflora of bladder biopsy specimens
103-105 ROLMP (n=34) Ability to form biofilms (n=12)
Staphylococcus spp. 6 4
Kocuria spp. 5 4
Acinetobacter spp. 4 2
Klebsiella pneumoniae 4
Proteus mirabilis 4
Pseudomonas spp. 3
Burkholderia cepacia 3 2
Flavimonas oryzihabitans 2
Brevundimonas vesicularis 3
tissue concentrations of drugs and high resistance to them of the main causative agents of RUT.
AND THE ROLE OF BIOFILM IN THE ETIOPATOGENESIS OF RUT
Currently, it is recognized throughout the world that the main form of existence of bacteria in natural conditions is a biofilm. They are found in more than 80% of cases of chronic infectious and inflammatory diseases, which allows us to put forward the concept of chronic diseases as biofilm diseases.
Up to 60% of infections (respiratory and urinary tract infections, osteomyelitis, endocarditis, infectious complications in cystic fibrosis, etc.) are caused by sessile for-
mami bacteria. The formation of biofilms in the focus of inflammation leads to a chronic infection process and is accompanied by unsatisfactory results of antibiotic therapy. The most relevant types of bacteria,
And medical
TIP #7-i 2011
that form biofilms during infections are staphylococci, representatives of the Enterobacteriaceae family, Pseudomonas aeruginosa, etc., as well as various types of mycoplasmas.
Another evidence is the observation during bacteriological examination of biopsy specimens of the bladder mucosa obtained in our clinic during cystoscopy in patients with RURTI.
In the study of 38 biopsies of the bladder in 89% of cases (n=34), the growth of opportunistic microflora 103-105 CFU was obtained (Table 4).
A biofilm is a structured community of bacterial cells enclosed in a self-produced polymer matrix and adhered to inert or living surfaces. It contains a large number of bacteria immersed in the intercellular matrix, covered with a membrane consisting of a bi-lipid component, polysaccharides and proteins. The bilipid layer of the surface shell of the communities contains more cardiolipin and less lysophospholipids than the membranes of bacterial cells, which gives this structure increased strength.
The formation of biofilms is a complex complex dynamic process consisting of several stages: the first is the fixation of planktonic bacterial cells to the surface - adhesion, the second is the proliferation of adherent cells with the formation of primary colonies, as well as the absorption of planktonic cells into the film, and the third is the colonization of the biotope and the formation of a matrix with the separation of bacterial cells from the biofilm with their subsequent distribution.
Adhesion to biological surfaces (tissue cells, vessel walls) is due to the specific interaction of adhesin proteins or pili lectins of the exoplasmic compartment of a bacterial cell with receptors or certain domains of the host cell membrane surface.
The biofilm matrix is able to prevent the rate of diffusion of some antibiotics and other biocidal drugs, depending on its biochemical composition and the metabolic activity of the population. For example, aminoglycosides diffuse through the matrix for a rather long time, while fluoroquinolones easily penetrate this barrier. The problem of increased resistance of biofilms to the action of antimicrobial agents has several aspects: diffusion barrier; the ability of bacteria to accumulate in the matrix extracellular enzymes that destroy antibiotics; the aggregative nature of biofilms associated with a decrease in the area of the open surface of cells - the physical inaccessibility of molecules; resistant cell phenotype. Reduced metabolism of microorganisms in the biofilm leads to the emergence of antibiotic tolerance.
The formation, growth, and migration of planktonic cell forms for colonization in biofilms are regulated by
UROLOGY AND GYNECOLOGY
UROLOGY AND GYNECOLOGY
population level through the mechanisms of intercellular communication. "Quorum sensing" (QS) is a process of collective coordination of gene expression in a bacterial population that mediates specific cell behavior. Communicative mechanisms for the transfer of mobile genetic elements in infectious lesions make it possible to distribute genes of antibiotic resistance, virulence, and additional physiological capabilities with maximum speed.
All immune defense factors contribute to the elimination of bacterial cells outside biofilms (planktonic forms), but antibodies, complement proteins and phagocytic cells are not able to penetrate the exopolysaccharide layer. Antibiotics are able to penetrate this barrier and destroy microorganisms within the biofilm itself, but the surviving persister cells, with their high tolerance and ability to survive, remain intact.
Some time after the termination of antibiotic therapy, the synthesis and accumulation of antitoxins in persister cells begins, cytotoxins are neutralized, and all biological processes are activated. For a macroorganism, this process is accompanied by chronic infection, the appearance of manifesting signs of the disease associated with the reactivation of the immune system and the action of virulent factors of bacterial cells.
The data obtained partly explain the reasons for the ineffectiveness of antibiotic therapy, since most antibacterial drugs used to treat RUTs do not penetrate into biofilms, but act
only on planktonic forms of bacteria. Systemic fluoroquinolones and fosfomycin trometamol have proven ability to penetrate biofilms. The growth of resistance of the main RTI pathogens to fluoroquinolones forces them to limit their use, and therefore the indications for the use of fosfomycin trometamol with long courses (1 time in 10 days for 3 months) are expanding.
Treatment of RURTI should be pathogenetically substantiated and include:
■ correction of anatomical disorders;
■ STI treatment;
■ correction of hormonal disorders;
■ postcoital prophylaxis;
■ treatment of inflammatory and dysbiotic gynecological diseases;
■ correction of hygienic and sexual factors;
■ correction of immune disorders;
■ local treatment.
Compliance with the principles of pathogenetic therapy has proven to be effective. However, it is necessary to remember and warn patients that the transposition of the external opening of the urethra in patients with vaginal ectopia of the urethra does not relieve urethritis, but only creates anatomical conditions that contribute to more effective treatment.
Considering that in the vast majority of cases in young patients suffering from RURTI for a long time, especially against the background of urogenital infections, squamous cell metaplasia of the epithelium without keratinization is detected during biopsy, it is necessary to include treatment methods aimed at restoring the glycosaminoglycan layer of the bladder mucosa in the pathogenetic therapy algorithm: instillations of heparin into the bladder in long courses (3 months), intravesical administration of Uro-Gial, use of Longidase. It is advisable to perform instillations against the background of patients taking Canephron®N, which, having a multidirectional effect (antibacterial, anti-inflammatory, antispasmodic, diuretic), has proven its effectiveness and good tolerance as a therapeutic and anti-relapse agent. The duration of the use of Kanefron®N for RUTs should be 3 months. One of the important advantages of the drug is its high safety, confirmed by experimental and clinical data, incl. and during pregnancy (Sterner W., Korn W.D., Volkmann P., 1988).
After an adequately performed treatment of RURTI, a long-term, individually selected profile is needed.
■ The formation of biofilms in the focus of inflammation leads to a chronic infection process and is accompanied by unsatisfactory results of antibiotic therapy. The most relevant types of bacteria that form biofilms during infections are staphylococci, representatives of the Enterobacteriaceae family, Pseudomonas aeruginosa, etc., as well as various types of mycoplasmas.
And medical
TIP #7-i 2011
Changing the developed algorithms allows them to be successfully applied in clinical practice, reduces the number of diagnostic errors and improves treatment outcomes.
LITERATURE
1. Kosova I.V. The role of urogenital infections in the etiology of cystitis and non-obstructive pyelonephritis in women: Diss. ... cand. honey. Sciences. - M., 2005.
2. Loran O.B., Sinyakova L.A., Kosova I.V. Recurrent urinary tract infections. Algorithm for diagnosis and treatment. - M., MIA. - 2008, p. 29.
3. Blango M.G. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics / M.G. Blango, M.A. Mulvey // Antimicrob. Agents Chemother. - 2010. - Vol. 54, no. 5. - P. 855-1863.
4. Kirov S.M. Biofilm differentiation and dispersal in mucoid Pseudomonas aeruginosa isolates from patients with cystic fibrosis / S.M. Kirov, // Microbiology. - 2007. - No. 153. - P. 3264-3274.
5. McAuliffe L. Biofilm formation by mycoplasma species and its role in environmental persistence and survival / L. McAuliffe, // Microbiology. - 2006. - No. 152. - P. 913-922.
6. Biofilms, Infection and Antimicrobial Therapy / ed. J.L. Pace, . - Boca Raton: Taylor & Francis Group, 2006. - 495 p.
7. Donlan R.M. Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms / R.M. Donlan, J.W. Costerton // CLIN. MIC. REV. - 2002. - Vol. 15, no. 2. - P. 167-193.
8. Lewis K. Riddle of Biofilm Resistance / K. Lewis // J. Antimicrob. Chemother. - 2001. - Vol. 45, no. 4. - P. 999-1007.
9. H.ibya N. Antibiotic resistance of bacterial biofilms / Niels H.ibya, // Int. J. of Antimic. agents. - 2010. - No. 35. - P. 322-332.
10. Jian L. Bacterial Resistance to Antimicrobials: Mechanisms, Genetics, Medical Practice and Public Healt / L. Jian, // Biot. Let. - 2002. - Vol.24, No. 10. - P. 801-805.
11. Moker N. Pseudomonas aeruginosa Increases Formation of Multidrug-Tolerant Persister Cells in Response to Quorum-Sensing Signaling Molecules / N. Moker, // J. of Bact. - 2010. - Vol. 192, no. 7. - P. 1946-1955.
UROLOGY AND GYNECOLOGY
At least in the first years of life, it is quite normal to carry several respiratory infections. These infections (like other early infections) help structure and train the immune system. Determination of the nature of the pathology can only occur in connection with the severity of the infection and the average frequency established during the observation of the cohort. So six to ten episodes of nasopharyngitis is the rule in the first years of life with a peak frequency occurring between six and 18 months. Also for otitis media, epidemiological studies from Pittsburgh have convincingly shown that more than two-thirds of children who see a doctor in the first three years of life have had at least one episode of otitis media and that a third of children have had three episodes or more.
Respiratory recurrent infections are often poorly received by families and frighten practitioners. For many patients, these recurrent infections are nothing more than a sequence of viral infections largely determined by age, maturation of the immune system, environmental factors (siblings, nursery, iron deficiency, etc.) For others, they are evidence of the first manifestation of atopy. The link between allergies and respiratory infections is very difficult to establish. Both pathologies are frequent, the patient population is both allergic and treated with recurrent infections, and viruses are known to be the most common cause of exacerbation of the disease in respiratory allergies; and, conversely, the atopic region explains the severity of viral infections. In addition, if there is no doubt that iron deficiency increases the susceptibility to infections, then recurrent infections can interfere with iron intake. For some patients, infections may be the first sign of an underlying, more severe disease (local or sometimes immune). It is extremely rare for an immune deficiency to be manifested solely by recurrent respiratory infections without association with other infections of various localizations. At the same time, more subtle immune deficiencies have been described in some patients. Prellner et al. showed that children with recurrent otitis had lower levels of antibodies to certain pneumococcal serotypes than healthy control children of the same age. The same results were obtained by Yamanaka et Faden for the non-typing H. influenzae P6 protein. Environmental factors obviously play a certain larger role than the actual immune deficiency.
The management of such children should never hide the fact that the natural course itself leads to a cure in the vast majority of cases. Also Alho et al. Finland reported a two-year follow-up of a cohort of 222 children meeting the internationally accepted definition of recurrent otitis media and receiving no specific treatment; only 4% of them developed chronic otitis media and 12% continued to develop recurrent acute otitis media. Also in relation to respiratory infections of the lower respiratory tract, it is now known that the vast majority of infants with episodes of recurrent wheezing associated with viruses do not evolve towards asthmatic disease.
Definitions
The most common international definition of recurrent otitis media is three episodes within six months or four episodes per year. For the formation of a group, the definition four times a year is not sufficiently discriminatory, in particular, in relation to small children who are in a group. In fact, these definitions must be interpreted depending on the confidence in the diagnosis of previous episodes, age, context (nursery, presence of brothers and sisters ...), on the local state between episodes.
The internationally accepted definition of recurrent tonsillitis is seven or more episodes within one year or ten within the last two or three years. In addition, matching the diagnosis of previous cases may present a problem. The prevalence in France of rapid diagnostic tests for group A streptococcus (TDR) is likely to be an advance in distinguishing between streptococcal infections and others.
There are no internationally accepted definitions for nasopharyngitis, but "more than six episodes of febrile nasopharyngitis per year starting at the age of three years" seems acceptable for grouping.
Sinusitis creates an even more complex problem. If there is a definition of recurrent sinusitis (recurrence of symptoms after a free interval of two days), then the difficulty of diagnosing each episode is generally recognized and there is no consensus definition of recurrent sinusitis. The only one found in the literature is a derivative of otitis media (three in six or four in a year).
There is no internationally accepted definition for pneumonias; two episodes in a year, or three episodes over an unknown period, should be considered as recurrent pneumonias, provided that radiography was normal between episodes. The recurrence of a parenchymal infection in the same area should definitely force you to search for a local cause.
With respect to bronchiolitis, three episodes in the first two years of life suggest infantile asthma; in fact it must be interpreted depending on the atopic personal and family context. As for laryngitis and bronchitis, there are no internationally accepted definitions.
What about practice?
The outcome expressed in this chapter is a reflection of a consensus group of experts. They will probably be applied in their entirety to all patients, but they should be integrated step by step in addition to treatment delivery.
Almost all examinations should include a general blood count, an allergological examination, that is, the detection of atopy in these diseases:
The essence of the general blood formula is to detect neutropenia or lymphopenia, to determine the lack of iron (hemoglobin level and the average volume of erythrocytes);
Allergological examination is proposed to be carried out depending on the anamnesis, capabilities and habits of various doctors; schematically depending on the age of patients and the context:
· Up to three years: total IgE, specific or targeted IgE distributed in sets (Trophatop, Phadiatop, for example);
· After three years: skin tests (prick test) or search for specific IgE (Phadiatop).
Other examinations are indicated for various recurrent respiratory infections:
· Nasopharyngeal fibroscopy: this is not necessary if there are clinical signs of obstruction or permanent serous otitis media between episodes of acute otitis media (OMA), as adenoidectomy is indicated. If required, then its purpose is to clarify the state of vegetation and identify mediated signs of gastroesophageal reflux;
PH-metry aims to identify gastroesophageal reflux (RGO) that does not appear outwardly;
· The dosage of immunoglobulins (IgG, IgA in particular) is often difficult to interpret in the first year of life;
· Assessment of response to vaccine antigens (tetanus, diphtheria, Hib) may be more useful;
· Dosage of IgG (IgG2) subclasses should not be administered until the age of two years and in the case of normal results of previous studies.
For recurrent otitis, the initial examination includes a complete blood count and an allergological examination. Only then can we discuss the conduct of nasopharyngeal fibroscopy. PH-metry and immunological analysis should only be considered as a third step if previous tests are negative and if infection exists. For recurrent nasopharyngitis, the same type of examination, completed with a chest x-ray, can be performed.
With regard to recurrent tonsillitis, no examinations are useful. In fact, it is exceptionally rare that this situation could lead to the identification of an additional cause.
In rhinosinusitis, an individual examination includes, in addition to the general blood count and allergic examination, a chest x-ray and a sweat test. An immunological examination, pH-metry, and a scan for bone defects or minimal polyposis may then be performed. Finally, negative prior examinations and the persistent nature of rhinosinusitis should lead to brossage or nasal biopsy to rule out primitive ciliary dyskinesia.
For recurrent respiratory infections of the lower respiratory tract, identifying the cause is fundamental. Schemes 1,2 and 3 offer a decision tree for pneumonia, bronchiolitis and recurrent bronchitis, including the management and conduct of various surveys. Often, the examination leads to the identification of multiple causes or various risk factors for recurrent respiratory infections.
What is the treatment?
Whenever a therapeutic or surgical cause is established, specific treatment should begin: specific treatment for respiratory allergies, gastroesophageal reflux (RGO), immune deficiency with injection of polyvalent immunoglobulins ... Also, in all cases, parents should be offered control of all factors ok- relapse-friendly environment (tobacco, nursery, allergic environment…). Oligoelements, immunostimulants and other immunomodulators have been proposed for the treatment of upper respiratory tract infections. No controlled trial comparing sufficient numbers of patients has found benefit.
The benefit of en spray administration of beta-hemolytic streptococci to stimulate the training barrier effect between infectious episodes has been confirmed by many clinical studies conducted by Swedish groups in angina and OMA. These products are not available in France and are not currently in the preventive therapeutic arsenal of any of the countries. Also anti-adhesion molecules (drugs) (oligosaccharides such as xylitol) have been proposed with conflicting results.
For recurrent ORL infections, medical or surgical treatment has been suggested, regardless of the cause.
With regard to angina, tests for the diagnosis of group A streptococci (TDR) should in the near future distinguish between recurrent angina, those caused by group A streptococci, and others. For the former, antibiotic treatment in particular has proven effective in favoring better eradication or reduced recurrence (second-generation and third-generation cephalosporins amoxillin-acide clavunique, clindamycin, rifampicin).
Except for children presenting with obstructive phenomena or complications such as adenophlegmon, amygdalectomy should remain an exception, and patience, as the main weapon, should be hammered into the heads of parents. Indeed, a recent study has confirmed that the modest benefit seen after amygdalectomy in moderately affected children does not justify this type of intervention compared to the risk of morbidity caused by the surgery itself.
For recurrent OMA, nonspecific types of treatment have been most widely studied: long-term prophylactic antibiotic therapy, adenoidectomy, transtympanic aeration, and vaccines.
· Prophylactic daily low-dose antibiotic therapy has been shown in double-blind versus placebo (en double insu versus placebo) controlled trials to be effective in preventing recurrence of OMA. The effectiveness is modest (a decrease of 0.12 OMA episodes per month and per child), but significant. The most commonly used drug was amoxicillin. The evolution of bacterial resistance, namely, pneumococci, indicates a lower efficiency and, above all, an adverse environmental impact. Therefore, the proponents of this method have either abandoned or limited indications for the most severe cases.
· Surgery (adenoidectomy with or without aerators) is effective in cases of nasal obstruction or serous permanent otitis media between episodes of OMA. In the absence of severe serous otitis media between OIAs, the benefit of surgery is limited. In fact, neither adenoidectomy/amygdalectomies nor aerators significantly reduced the number of acute episodes in the treated group compared to the control groups. Conversely, aerators reduce the number of days with OMA. The modest benefits must be weighed against the inherent disadvantages of this method: general anesthesia, bleeding (adenoidectomy/amygdalectomies), tympanic scars (aerators) and finally cost.
· Influenza vaccines, such as inactivated injectable vaccines and live attenuated (attenuated) vaccines, can reduce the incidence of OMA. Three studies demonstrated a one-third reduction in the incidence of OMA in vaccinated groups in children with no specific OMA antecedent attending nurseries or other institutions. Conversely, a recent randomized en double insu study of almost 800 patients aged six to 24 months found no reduction in OMA in the vaccinated group. At the same time, it should be noted that during the last two years of the study, the incidence of influenza was especially low in children receiving placebo: 15.9% in the first year and 3.3% in the second. An Italian study using a virosomal (not available in France) vaccine found the same efficacy in children eligible for recurrent otitis media. Although children with recurrent otitis are not included in the population for which influenza vaccination is recommended in France by the vaccination committee, this immunization is probably one of the prophylactic treatments showing the best benefit/risk/cost ratio in preventing OMA.
· Pneumococcal conjugate vaccine is theoretically one of the most promising treatments for children with recurrent otitis media; it is recommended for these patients by the American Academy of Pediatrics USA. Indeed, these children often have anti-pneumococcal antibodies (IgA, IgG2) against serotypes often present in OMA, at lower levels than controls. Moreover, the synthesis of antibodies in them after the introduction of the anti-pneumococcal polysaccharide vaccine is sensitively less good than in normal children of the control group. Many large double-blind controlled studies using conjugate vaccine in healthy infants from two months of age have shown a significant reduction in the number of patients with recurrent OMA in the conjugate vaccine group (10% reduction in recurrent otitis media and more than 20% reduction in transtympanic aerator settings). Also, many studies have shown that in children with recurrent otitis media not responding to polysarade vaccines, conjugate vaccines were immunogenic. Naturally, the immunogenicity was less good than in healthy children without otitis media, but this proved to be sufficient for most patients and serotype population (antibody levels increased by 4 or more from 1 mgr/ml after vaccination).
A recent double-blind controlled study in patients with OMA antecedents vaccinated after a median of 18 months (Prevenar at prime, then polysaccharide vaccine at reminder) showed no reduction in otitis in the pneumococcal vaccine group. Various hypotheses have been put forward in an attempt to explain the misleading results. It is most likely that in these debilitated patients there was a replacement in the nasopharynx of pneumococcal serotypes contained in the vaccine with other bacteria (other pneumococcal serotypes or other species). Even if pneumococcal vaccines did not reduce the frequency of OMA episodes in children meeting the criteria for recurrent OMA, two beneficial effects can nevertheless be identified: a decrease in the risk of systemic infections and a decrease in antibiotic resistance of existing bacteria. In fact, the serotypes contained in the pneumococcal conjugate vaccine in France represent the vast majority of antibiotic-resistant species. By reducing the carriage and involvement of these species in OMA, this reduces the risk of having a resistant species.
The benefit of influenza vaccines and pneumococcal conjugate vaccines should not be limited to recurrent OMA, but should be extended to children with recurrent pneumopathy.
Conclusion
Respiratory non-recurrent infections are a common problem in pediatrics. The challenge is to identify children with comorbidities without multiplying the magnitude and treatment of "normal" children: interviews, clinical examinations, and a few additional examinations are indispensable. Benefit/risk/cost ratios of medical and proposed surgical treatments should be weighed against the prospects of vaccines being provided, namely influenza and conjugated anti-pneumococcal vaccines.
Viral infections are usually divided into anthroponoses (they only infect humans) and zoonoses (animal diseases that are transmitted to humans, such as rabies). The mechanism of virus infection by arthropods is called transmissible. The disease can be transmitted from animal to human through blood-sucking mosquitoes, ticks. It is possible that infection is not with one specific virus, but with several at once, in which case the infection will be mixed.
Viral infections are acute, as well as recurrent (chronic). Let's talk more about the second. Due to their frequent asymptomatic recurrent infections are not recognized by patients at an early stage, they can be latent for a long time and lead to more serious disorders of the internal organs. For example, chronic hepatitis B results in cirrhosis of the liver.
There are several types of recurrent viral infections, including Varicella-Zoster virus (Varicella Zoster), herpes zoster (Herpes zoster), genital herpes (Herpes simplex II), Epstein-Barr virus (EBV). Quite often today in the clinical picture of such diseases there is a general deterioration in the patient's condition, as well as various other complaints. Let's look at some types.
Virus Varicella-Zoster (Virus Varicella Zoster)
Such a polyvalent virus is the cause of chickenpox, as well as herpes zoster. May affect the skin and mucous membranes of humans. Complications usually affect the nervous system. Treatment is carried out strictly according to the doctor's prescription with acyclic nucleosides.
Epstein-Barr virus
This is a fairly common virus that is present (but does not manifest itself in any way) in the body of most of us. It is often asymptomatic. The transmission of the virus occurs by airborne droplets (with a kiss - with saliva). Sometimes a person is infected through a blood transfusion.
Chronic hepatitis (CH)
Many physicians agree that chronic hepatitis should be considered only as a chronic viral infection, which is why the methods of treatment have become mostly antiviral. The main types are hepatitis B and C.
The pathological process develops in the connective tissue (liver). Necrosis of the liver parenchyma occurs. General weakness, heaviness in the right hypochondrium, subfebrile temperature - these are the main signs of chronic hepatitis. Treatment is reduced to the appointment of a special diet, adherence to the daily regimen, as well as the adoption of interferon-α, nucleoside analogs (lamivudine, adefovir, entecavir), as well as pegylated interferon α-2a (pegasis).
Cytomegalovirus (CMV)
Cytomegalovirus is a widespread disease. Transmission occurs in various ways (from a sick person, mainly through sexual contact). If the human immune system is strong enough, then the course of the virus can occur asymptomatically. Otherwise, it takes generalized forms. In pregnant women, such a virus can provoke infection of the placenta, as well as the child in childbirth. Sometimes in severe cases, fetal pathology develops.
Such a virus also affects internal organs - the liver, kidneys, heart. The main treatment is antiviral drugs and immunomodulators prescribed by a doctor.
herpes simplex virus
Almost 90% of the world's population is infected with herpes simplex, but for many it is in a "dormant" state, and for some, the appearance is provoked by some unfavorable factors (hypothermia, colds). Exacerbations in this case, on average, will occur several times a year.
There are herpes simplex virus 1 (localized on the lips, in the face), as well as herpes simplex virus 2 (in the genital area). Although at present such localization by type of virus is not mandatory. Seasonality (autumn-spring period) plays an important role in the picture of relapses.
The main treatment for an exacerbation is antiviral drugs (acyclovir, valaciclovir, famciclovir). In a chronic relapsing course of any localization, first of all, a comprehensive examination is carried out to diagnose and then eliminate all possible causes that may lead to improper functioning of the immune system.
Chronic Fatigue Syndrome (CFS)
Manifested by night sweats, muscle weakness, joint pain, generalized enlargement of the lymph nodes, as well as neurological changes, of which general weakness comes to the fore. To date, the most probable theory of the occurrence of this syndrome was expressed by American scientists (D. Goldstein and J. Salamon). She says that the main cause of CFS is a viral lesion of the central nervous system (dysregulation of the temporo-limbic region occurs) in genetically predisposed individuals, as well as against the background of secondary immunodeficiencies. Moreover, the main importance is given to the neurotropic viruses listed above (HSV-1,2, HSV-6,7,8, EBV, CMV).
