How does doxycycline compare to other antibiotics for treating ESBL-E cystitis. What are the benefits of using doxycycline for urinary tract infections caused by resistant bacteria. Why should clinicians consider doxycycline as a treatment option for ESBL-E cystitis.

Understanding ESBL-E Cystitis and Treatment Challenges

Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) are increasingly common causes of urinary tract infections (UTIs), presenting significant treatment challenges. These resistant bacteria render many first-line antibiotics ineffective, necessitating alternative therapeutic approaches.

ESBL-E cystitis, an infection of the bladder caused by these resistant bacteria, requires careful antibiotic selection to ensure effective treatment while minimizing the risk of further antimicrobial resistance development. The growing prevalence of ESBL-E infections has prompted researchers and clinicians to explore unconventional treatment options, including the use of older antibiotics like doxycycline.

Doxycycline: A Potential Game-Changer in ESBL-E Cystitis Treatment

Doxycycline, a tetracycline-class antibiotic, has emerged as a promising option for treating ESBL-E cystitis. This long-established antibiotic offers several advantages in the context of resistant urinary tract infections:

• Broad-spectrum activity against many bacterial pathogens
• High urinary concentrations, making it effective for bladder infections
• Lower risk of promoting further resistance compared to newer antibiotics
• Oral administration, allowing for outpatient treatment
• Generally well-tolerated with a known safety profile

These characteristics make doxycycline an attractive alternative to more commonly used antibiotics for ESBL-E cystitis, particularly in cases where standard treatments may be ineffective or contraindicated.

Clinical Evidence Supporting Doxycycline Use in ESBL-E Cystitis

Recent studies have provided encouraging evidence for the efficacy of doxycycline in treating ESBL-E cystitis. A retrospective study by Saini et al. demonstrated that doxycycline achieved clinical cure rates comparable to those of other antibiotics commonly used for ESBL-E UTIs, including nitrofurantoin and fosfomycin.

Additionally, in vitro susceptibility testing has shown that many ESBL-E isolates retain sensitivity to doxycycline, even when resistant to other antibiotic classes. This susceptibility pattern suggests that doxycycline may be effective against a broader range of ESBL-E strains compared to some newer antibiotics.

Comparative Efficacy of Doxycycline

When compared to other treatment options for ESBL-E cystitis, doxycycline has shown promising results:

1. Similar clinical cure rates to nitrofurantoin and fosfomycin
2. Lower risk of Clostridioides difficile infection compared to fluoroquinolones
3. Fewer drug-drug interactions than some newer antibiotics
4. Lower cost compared to many newer antimicrobial agents

These factors contribute to doxycycline’s potential as a valuable treatment option for ESBL-E cystitis, particularly in outpatient settings or for patients with contraindications to other antibiotics.

Dosing and Administration of Doxycycline for ESBL-E Cystitis

The optimal dosing regimen for doxycycline in the treatment of ESBL-E cystitis may vary depending on the specific clinical scenario and patient factors. However, a commonly recommended dosage is:

• 100 mg orally twice daily for 5-7 days

This dosing schedule allows for adequate urinary concentrations of the drug while minimizing the risk of side effects. It’s important to note that doxycycline should be taken with plenty of water and that patients should remain upright for at least 30 minutes after taking the medication to reduce the risk of esophageal irritation.

Patient Considerations for Doxycycline Treatment

When prescribing doxycycline for ESBL-E cystitis, clinicians should consider the following patient factors:

• Allergies to tetracycline antibiotics
• Pregnancy status (doxycycline is contraindicated in pregnancy)
• Renal function (dose adjustment may be necessary in severe renal impairment)
• Potential drug interactions, particularly with antacids, iron supplements, and certain medications
• History of esophageal disorders or difficulty swallowing

Careful consideration of these factors can help ensure safe and effective use of doxycycline for ESBL-E cystitis treatment.

Potential Side Effects and Precautions with Doxycycline Use

While generally well-tolerated, doxycycline can cause certain side effects that patients and clinicians should be aware of:

• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Photosensitivity reactions
• Esophageal irritation or ulceration
• Temporary discoloration of teeth in children (not recommended for use in children under 8 years old)
• Rare cases of intracranial hypertension

To minimize these risks, patients should be advised to:

1. Take doxycycline with food or milk if gastrointestinal upset occurs
2. Avoid prolonged sun exposure and use sun protection
3. Take the medication with a full glass of water and remain upright for at least 30 minutes after
4. Complete the full course of treatment as prescribed

By following these precautions, most patients can successfully complete doxycycline treatment for ESBL-E cystitis with minimal adverse effects.

Antimicrobial Stewardship Considerations for Doxycycline Use

The use of doxycycline for ESBL-E cystitis aligns well with antimicrobial stewardship principles. As an older antibiotic with a well-established safety profile, doxycycline offers several advantages from a stewardship perspective:

• Preservation of newer, broad-spectrum antibiotics for more severe infections
• Lower risk of promoting resistance to critically important antibiotics
• Cost-effectiveness compared to newer antimicrobial agents
• Potential for shorter treatment durations, reducing overall antibiotic exposure

Incorporating doxycycline into treatment algorithms for ESBL-E cystitis can help healthcare systems balance effective patient care with responsible antibiotic use, contributing to long-term efforts to combat antimicrobial resistance.

Implementing Doxycycline in Clinical Practice

To effectively integrate doxycycline into ESBL-E cystitis treatment protocols, healthcare institutions should consider the following steps:

1. Develop clear guidelines for when to consider doxycycline as a treatment option
2. Educate clinicians on the benefits and appropriate use of doxycycline for ESBL-E infections
3. Monitor local resistance patterns to ensure continued effectiveness
4. Implement systems to track outcomes and adverse events associated with doxycycline use
5. Regularly review and update treatment protocols based on emerging evidence and local data

By taking these steps, healthcare systems can optimize the use of doxycycline for ESBL-E cystitis while maintaining high standards of patient care and antimicrobial stewardship.

Future Research Directions for Doxycycline in ESBL-E Infections

While current evidence supports the use of doxycycline for ESBL-E cystitis, further research is needed to fully elucidate its role in managing these challenging infections. Future studies should focus on:

• Prospective, randomized controlled trials comparing doxycycline to other treatment options
• Optimal dosing strategies for maximizing efficacy while minimizing resistance development
• Long-term outcomes and recurrence rates following doxycycline treatment
• Potential synergistic combinations of doxycycline with other antibiotics for more severe ESBL-E infections
• Impact of doxycycline use on overall antimicrobial resistance patterns in healthcare settings

These research efforts will help refine treatment guidelines and ensure that doxycycline is used effectively and responsibly in the management of ESBL-E cystitis and potentially other resistant infections.

Emerging Technologies and Doxycycline Treatment

As diagnostic technologies advance, new opportunities may arise to optimize doxycycline use for ESBL-E cystitis:

1. Rapid diagnostic tests for ESBL-E detection could allow for earlier, targeted use of doxycycline
2. Pharmacogenomic testing may help identify patients most likely to respond well to doxycycline therapy
3. Advanced drug delivery systems could potentially enhance doxycycline’s efficacy or reduce side effects
4. Machine learning algorithms may assist in predicting treatment outcomes and guiding antibiotic selection

By leveraging these technologies, clinicians may be able to further personalize and optimize doxycycline treatment for patients with ESBL-E cystitis, potentially improving outcomes and reducing the risk of treatment failure.

Practical Implications for Clinicians Treating ESBL-E Cystitis

For healthcare providers managing patients with ESBL-E cystitis, the potential role of doxycycline presents both opportunities and considerations:

• Doxycycline should be considered as a viable treatment option, especially in cases where first-line agents are ineffective or contraindicated
• Careful patient selection is crucial, taking into account individual risk factors, comorbidities, and potential drug interactions
• Clear patient education on proper medication administration and potential side effects is essential for treatment success
• Regular monitoring of local resistance patterns is necessary to ensure continued doxycycline effectiveness
• Collaboration with infectious disease specialists and clinical pharmacists can help optimize treatment strategies

By incorporating these considerations into clinical practice, healthcare providers can effectively utilize doxycycline as part of a comprehensive approach to managing ESBL-E cystitis.

Case-Based Approach to Doxycycline Use

To illustrate the practical application of doxycycline for ESBL-E cystitis, consider the following clinical scenarios:

1. A young, otherwise healthy woman with recurrent ESBL-E cystitis and previous treatment failures with nitrofurantoin and fosfomycin
2. An elderly man with multiple comorbidities and a history of Clostridioides difficile infection following fluoroquinolone use
3. A middle-aged woman with chronic kidney disease and limited oral antibiotic options due to drug allergies

In each of these cases, doxycycline could potentially offer an effective and well-tolerated treatment option, highlighting its versatility in managing ESBL-E cystitis across diverse patient populations.

Doxycycline for ESBL-E Cystitis | Clinical Infectious Diseases

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Clinical Infectious Diseases, Volume 73, Issue 1, 1 July 2021, Pages e274–e275, https://doi. org/10.1093/cid/ciaa1898

Published:

29 December 2020

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Published:

29 December 2020

Corrected and typeset:

16 February 2021

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To the Editor—With great anticipation we read the recently published ahead-of-print guidance on the treatment of antimicrobial resistant gram-negative infections by Tamma et al [1]. It is a very timely, well written, and useful document. However, we noticed the supporting reference for the statement: “Doxycycline is not recommended for the treatment of extended spectrum beta-lactamase—Enterobacterales (ESBL-E) cystitis due to limited urinary excretion,” on page 6. We do not support this statement as approximately 35%–60% of an oral dose of 100 mg of doxycycline dose is excreted unchanged into the urine [2]. The concentrations of doxycycline following a 100 mg oral dose in the urine can range from 60–300 μg/mL in patients with normal renal function, which is significantly greater than the MIC for the extended spectrum beta-lactamase (ESBL)-E that cause acute cystitis [3, 4].

Clinical data indicate that doxycycline has efficacy against susceptible Gram-positive uropathogens, such as Enterococcus faecalis and E. faecium including vancomycin-resistant E. fecium (VRE) and Gram-negative organisms, including E. coli and K. pneumoniae, that cause urinary cystitis [4–7] Additionally, it was also successful in eradication of VRE in the urine [8].

However, doxycycline is typically not used to treat urinary tract infections. This could be due to the fact that neither doxycycline nor tetracycline are always tested or reported against Gram-negative bacteria. There could also be a lack of knowledge regarding the concentrations reached in the urine that greatly exceed the MIC values for certain uropathogens. Its antimicrobial efficacy is increased in acidic environments, including urine [4]. Given the increased incidence in multidrug-resistant Gram-negative bacterial infections and the favorable pharmacokinetic and safety profile of doxycycline, perhaps its use for treating certain types of acute cystitis should be reconsidered. Following oral administration, 95% of a 100 mg dose of doxycycline is absorbed; doxycycline can be used in patients with renal insufficiency as there is a compensatory increase in nonrenal elimination [9]. Doxycycline is generally well tolerated and the most commonly reported adverse effects include nausea, vomiting, diarrhea, epigastric pain, photosensitivity reactions but the rate of treatment discontinuation is low. It has a low propensity for producing Clostridioides difficile infections [10], meanwhile a normal treatment course is relatively inexpensive. Doxycycline should not be given to pregnant females and children under the age of 8 due to the risk of permanent discoloration of developing teeth [5, 9]. Finally, doxycycline does not inhibit or induce any of the Phase I or II drug metabolizing enzymes, thus decreasing the likelihood of drug–drug interactions,

In conclusion, based on the published pharmacokinetic data and MIC values for uropathogenic ESBL-E, doxycycline reaches levels in the urine that should make it a potential option for the treatment of acute cystitis caused by ESBL-E.

Nonstandard Abbreviations

Nonstandard Abbreviations

 

• ESBL-E

  extended spectrum beta-lactamase Enterobacterales

 

• VRE

  vancomycin-resistant E. fecium

Note

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

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Oral doxycycline for non-systemic urinary tract infections (UTIs) due to P.

aeruginosa and other Gram negative uropathogens

Oral doxycycline for non-systemic urinary tract infections (UTIs) due to P. aeruginosa and other Gram negative uropathogens

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Stamey was the first to introduce the concept of “urinary spectrum” of orally administered antibiotics to treat non-systemic urinary tract infections (UTIs), i. e., cystitis or catheter associated bacteriuria (CAB). His concept was based on the principle that renally eliminated antibiotics are concentrated to high levels, i.e., supra-serum in urine in patients with intact renal function. Since antimicrobial susceptibility is in large part “concentration dependent,” Stamey reasoned it would be possible to eradicate aerobic Gram negative uropathogens from urine if achievable urinary concentrations exceeded the minimal inhibitory concentration (MIC) of the uropathogen [1]. Clinicians have long pondered why some Gram negative uropathogens are eradicated from urine even when reported as “resistant.” Stamey stressed that serum bases susceptibility testing is relevant only for pathogens in the blood. He and subsequently others showed that it was easy to eradicate “resistant” E. coli from the urine using oral penicillin based on this pharmacokinetic principle [2–4]. Oral antibiotics in particular should be viewed as having a urinary spectrum which may be different from its serum spectrum (Table 1).

Table 1 Urinary spectrum of oral penicillins^a [5–8]

Full size table

Mukerji et al. and Musher et al. showed that oral tetracyclines eliminated Pseudomonas aeruginosa from the urine in most patients, i.e., 85 % with intact renal function [9, 10]. Interestingly, in the Musher study, tetracycline was compared to doxycycline and minocycline. The use of doxycycline and minocycline yielded similar results to conventional tetracycline with a slightly lower rate of eradication [10]. Their study was done in humans as opposed to an in vitro or animal study and remains the largest published study of treating Gram negative aerobic uropathogens in non-systemic UTIs orally with tetracycline, doxycycline or minocycline. Interestingly, clinical effectiveness of tetracyclines was highest with P. aeruginosa but was somewhat less effective against E. coli [10]. At the present time, the clinical significance of these findings is more important than ever due to the limited number of oral anti-P. aeruginosa antibiotics available for the treatment of Gram negative nosocomial cystitis/CAB (Table 2) [5, 14–16].

Table 2 Urinary spectrum of oral tetracyclines^a [5, 6, 11–13]

Full size table

Treating nosocomial non-systemic UTIs due to aerobic Gram negative uropathogens is a common therapeutic challenge. If treatment of nosocomial cystitis/CAB due to non-fermentative Gram negative uropathogens, e.g., P. aeruginosa is desired, most clinicians resort to parenteral therapy [5, 16]. Clinicians base antibiotic selection on serum-based susceptibility reports [17, 18]. Few physicians would consider using oral doxycycline to treat non-systemic P. aeruginosa UTIs. Clinicians often forget that in vitro susceptibility testing is based on achievable serum concentrations for rapidly growing aerobic organisms and primarily pertains to bloodstream infections. In vitro susceptibility testing, by definition, is at best an extrapolation of conditions at the site of infection, i. e., with lower UTIs since susceptibility testing is performed in broth (not serum), at serum pH = 7.4 (not urinary pH) and at 35 °C (not body temperature) [19, 20]. For lower tract UTIs, some have tried to more closely predict in vivo effectiveness by performing susceptibility tests on Gram negative uropathogens in human urine, at urinary pH, and at achievable urinary concentrations (Table 3) [21]. Performed in this manner, in vitro susceptibility results differ markedly from serum based in vitro susceptibility testing [22–24]. This best explains the frequent clinical observation that often Gram negative uropathogens are eliminated from the urine in lower tract UTIs when serum-based susceptibility testing indicated the isolate was resistant [6, 25]. It has been shown in vitro that 64 % of ampicillin resistant E. coli strains were susceptible when tested in human urine, at urinary pH and urinary concentrations (Table 4) [26].

Table 3 The effect of urinary pH on antibiotic activity [6]

Full size table

Table 4 Ampicillin resistant E. coli tested in human urine at urinary pH and at urinary concentrations

Full size table

The implications of these findings are clearly clinically important. Until susceptibility testing is based on factors relevant to the site of infection, e.g., UTIs with susceptibility performed in human urine, at urinary pH, and at achievable urinary concentrations, infectious disease clinicians will continue to try to predict urinary susceptibilities based on the site of infection and pharmacokinetic principles, i.e., tissue concentration, pH, etc. [6, 17, 19, 26–28]. Clinically, this problem most frequently is encountered in treating non-systemic UTIs. As a general rule, if a Gram negative uropathogen is reported as susceptible, one may be assured the antibiotic will be effective against the organism if renal function is intact, i.e., if therapeutic urinary concentrations can be achieved. Conversely, if serum-based susceptibility of a Gram negative uropathogen is reported as resistant, the clinician needs to estimate achievable urinary concentrations taking into account renal function, the MIC of the uropathogen and the effect of urine pH on the activity of the antibiotic since the isolate may in fact be susceptible under these conditions [6, 22–27].

The therapeutic efficacy of an antibiotic to treat non-systemic UTIs due to aerobic Gram negative uropathogens is dependent on intact renal function to assure therapeutic urinary concentrations > MIC of the uropathogen. Further consideration is needed if the patient has renal insufficiency. For mild-moderate renal insufficiency, i.e., CrCl > 50 ml/min, urinary antibiotic concentrations are likely to be effective [10, 13]. However, if renal function is decreased by more than half, i.e., CrCl < 50 ml/min, then estimated achievable urinary concentrations must be halved. If the halved concentration is still > MIC of the organism, then eradication of the uropathogen from the lower urinary tract is still possible [7, 8, 11, 12, 29]. Depending upon the MIC of the aerobic Gram negative uropathogen, even with a creatinine clearance of 30–50 ml/min, many isolates will still be eradicated by oral doxycycline therapy [5, 10, 12]. If an oral tetracycline is being used to treat P. aeruginosa cystitis/CAB with renal insufficiency, i.e., CrCl < 50 ml/min, then doxycycline is preferred. If an oral penicillin or ampicillin is being used to treat “resistant” E. coli cystitis/CAB in a patient with renal insufficiency, i.e., CrCl < 50 ml/min, then amoxicillin is preferred. At any given dose, oral amoxicillin achieves much higher urinary concentrations than with oral ampicillin [5, 7, 8]. Clinicians have no readily available way to approximate the urinary spectrum of orally administered (non-cephalosporin, non-quinolone) antibiotics. This information is presented in Tables 1, 2, 3, and 4.

My infectious disease training heavily emphasized the pharmacokinetic aspects of antimicrobial therapy. Based on Stamey’s work, as an infectious disease fellow I began treating non-systemic UTIs due to aerobic Gram negative uropathogens with oral antibiotics. My first experiences were treating “resistant” E. coli cystitis/CAB with oral penicillin V. However, because many oral antibiotics were available to treat “resistant” E. coli cystitis/CAB, the real clinical challenge was in orally treating more problematic aerobic Gram negative uropathogens, e.g., Pseudomonas aeruginosa. I began using oral doxycycline to treat P. aeruginosa cystitis/CAB with good results, i.e., oral doxycycline eliminated P. aeruginosa from the urine in ~75 % of cases. During the past 35 years in infectious disease, I have continued to utilize this approach for P. aeruginosa cystitis/CAB as well as other aerobic Gram negative uropathogens causing nosocomial cystitis/CAB. In infectious disease consultation, many practitioners feel they have few therapeutic options unless an intravenous antibiotic is used. However, clinicians still ponder in disbelief when an oral antibiotic, e.g., doxycycline is used for formidable uropathogen, e.g., P. aeruginosa. Because tetracyclines are not routinely tested against Gram negative uropathogens many physicians do not even consider doxycycline a therapeutic option [11, 12, 17, 18, 20]. I continue to use oral antibiotics successfully based on the estimated urinary concentrations to eliminate a variety of aerobic Gram negative uropathogens from bladder urine.

Excluding cephalosporin and quinolones, currently there are few oral therapeutic alternatives to treat aerobic Gram negative uropathogens causing nosocomial cystitis/CAB [5, 11, 15, 16, 30]. Some oral antibiotics offer an effective alternative to parenteral antibiotics. In this era of limited healthcare resources, carefully selected oral antimicrobial therapy offers a cost effective alternative to intravenous (IV) therapy. Oral antibiotic therapy is less expensive in terms of acquisition and administration costs than comparable IV antibiotic therapy and patients generally prefer oral to IV antibiotics. Obviously, the use of oral antimicrobial therapy virtually eliminates the complications of phlebitis and IV line infections associated with IV antimicrobial therapy. Oral antimicrobial therapy for aerobic Gram negative uropathogens with its many advantages has some limitations [5]. First, oral antibiotic therapy is most likely efficacious using renally eliminated antibiotics in patients with intact renal function to assure high urinary concentrations > the MIC of aerobic Gram negative uropathogens [6, 19]. Second, oral antimicrobial therapy will not be effective against all strains anymore than IV antibiotic therapy will always be effective [5, 16]. Against multi-drug resistance (MDR) Gram negative uropathogens there are few oral antimicrobial options, e.g., methenamine salts for CAB, nitrofurantoin for nosocomial cystitis/CAB or fosfomycin for nosocomial cystitis/CAB (Table 5) [5, 30–33]. Third, oral antimicrobial therapy will be less effective in renal insufficiency and may be ineffective in some patients if renal function is < 50 ml/min. Tetracycline or doxycycline may be used in patients without renal insufficiency. Doxycycline is the preferred tetracycline for treating non-systemic UTIs due to non-MDR strains of P. aeruginosa patients with renal insufficiency. Although doxycycline is effective against most strains of P. aeruginosa (~75 %) in urine, doxycycline may be ineffective in ~25 % of strains if the MIC cannot be achieved when doxycycline levels in the urine are not > MIC or if the Gram negative uropathogen is a MDR strain [1, 14].

Table 5 Oral antibiotic therapy of non-systemic urinary tract infections (UTIs) due to MDR Gram negative uropathogens^a

Full size table

Since urine cultures often take days to be reported, clinical effectiveness may be rapidly predicted by urinalysis (UA). If antibiotic therapy will be effective, the intensity of pyuria in the UA will decrease rapidly. Decreased pyuria is predictive of subsequent urine culture negativity before urine cultures are reported negative later. Persistent pyuria predicts therapeutic failure. If doxycycline fails, the uropathogen is a strain with a MIC > than achievable urinary concentrations or is an MDR strain and fosfomycin is most likely to be effective [32, 33]. The great majority of aerobic Gram negative uropathogens, e.g., P. aeruginosa causing non-systemic UTIs, i.e., cystitis/CAB, can be effectively treated simply and inexpensively with oral doxycycline.

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Actual problems of treatment of urinary tract infections. XIV Congress of the Russian Society of Urology uMEDp

As part of the symposium, held with the support of Astellas, the principles of antimicrobial therapy for acute and chronic lower urinary tract infections, the possibilities of alternative methods for the treatment of recurrent episodes of urinary tract infections, as well as the prospects for the use of macrolides and tetracyclines in treatment of chronic bacterial prostatitis. Particular attention was paid to the choice of antimicrobial drugs against the background of increasing resistance of pathogens, taking into account European standards and Russian recommendations, as well as the role of immunotherapy in the prevention of relapses of lower urinary tract infections.

One of the main problems in the treatment of urinary tract infections (UTIs) at the present stage is associated with a high level of resistance of pathogens to antibacterial drugs. Professor of the Department of Urology and Surgical Andrology of the Russian Medical Academy of Postgraduate Education, MD Lyubov Alexandrovna SINYAKOVA emphasized that the incorrect prescription of antibiotics, their uncontrolled use contribute to the growth of resistance of pathogens and lead to the development of recurrent UTIs.

According to the European Antimicrobial Resistance Surveillance System in European countries from 2001 to 2009A sharp increase in the resistance of the main causative agent of UTI – Escherichia coli to penicillins and third-generation cephalosporins was recorded, critical values ​​​​of 15–25% were reached ¹ . According to Russian data, sensitivity to third-fourth generation cephalosporins also decreased in enterobacteria isolated from patients in intensive care units. Thus, the resistance of enterobacteria to cefepime reached 67%, to ceftazidime – 68.4%, cefotaxime – 82.7% ² . Consequently, the use of these drugs in intensive care units and intensive care units, and even more so as empirical therapy, becomes inappropriate.

There is a significant increase in resistance Escherichia coli and fluoroquinolones ¹ . If in Spain and Italy this indicator reaches the level of 25-50%, then in Turkey it already exceeds the 50% mark. “The reason for the current situation is the same as in our country – the over-the-counter sale of these drugs,” explained Professor L.A. Sinyakov.

The GPIU study, covering about 20,000 patients in 56 countries, also confirmed a very high level of E. coli resistance to fluoroquinolones and co-trimoxazole ³ .

There are some regional differences in antibacterial resistance. Thus, the Russian Federation is characterized by a high frequency of isolation of ESBL-producing enterobacteria, which, according to the ReVANSH study, is 70. 1% (moreover, this phenomenon was detected in 90% of strains Klebsiella pneumoniae and 67.4% strains Escherichia coli ) ² . Professor L.A. Sinyakova recalled that the risk factor for the development of infections caused by ESBL-producing Klebsiella pneumoniae and Escherichia coli is the use of fluoroquinolones (and aminoglycosides) ⁴ . The uncontrolled use of antibiotics has caused “parallel damage” ⁵ – the selection of multi-resistant microorganisms, not only and not so much among strains of pathogens to which antimicrobial therapy was directed, but among microorganisms that were not even included in the spectrum of activity of the drug.

What antimicrobials can be successfully used to treat episodes of acute UTI? According to the ARESC study, the most effective drugs in relation to uncomplicated UTIs in all ten countries where the study was conducted were fosfomycin, macrocrystalline nitrofurantoin and mecillinam (the last two drugs are not registered in Russia) ⁶ . The same drugs are recommended for the treatment of acute uncomplicated cystitis by the American and European Urological Associations. Fluoroquinolones are classified as alternative drugs.

Based on the results of domestic and international studies, the Russian recommendations of 2014 indicate fosfomycin trometamol and nitrofurantoin ⁷ as the drugs of choice for uncomplicated UTIs. This is due to the persistence of the sensitivity of Escherichia coli to these antibiotics over many years of use.

As for the treatment of recurrent UTIs, it should be combined and personalized. First of all, it is necessary to eliminate the risk factors or causes of UTI development, including anatomical features (ectopia of the external opening of the urethra or pelvic organ prolapse). In patients of the older age group, it is necessary to take into account the factor of hypoestrogenemia. Topical estrogens have been reported to reduce the incidence of UTIs (from 23.7% to 6%), as well as the incidence of symptoms of bladder sensation disorders (frequent urination, urge to urinate, nocturia) from 47. 4 to 9.4% reduce urinary pain from 42.2% to 10.7% ^8–10 .

Another important area of ​​therapy is the restoration of the glycosaminoglycan layer. With a long course of infection, the intact glycosaminoglycan layer is destroyed, which protects the epithelial cells of the bladder from the pathogenic effects of urine. Destruction of the glycosaminoglycan layer promotes the adhesion of pathogens and triggers the mechanism of inflammation. Thus, in case of recurrent UTI, the introduction of hyaluronic acid or heparin preparations into the bladder is indicated.

The choice of antibiotic therapy should be based on the results of bacteriological examination, the results of previous antibiotic therapy and allergic history. The Russian guidelines for the treatment of exacerbations of UTI recommend taking full course doses of the following antimicrobials (2014)7:

• fosfomycin trometamol 3 g, one dose every ten days for three months;
• furazidin potassium salt
  
  in combination with basic magnesium carbonate 100 mg twice for seven days;
• norfloxacin 400 mg twice for five days;
• levofloxacin 500 mg once for five days;
• ciprofloxacin 500 mg twice for five days;
• cefixime 400 mg once
  
  within seven days.

Why, in addition to the fosfomycin and fluoroquinolones mentioned above, are third-generation cephalosporins also included in the list of recommended drugs? First of all, due to the high natural activity of these drugs against UTI pathogens – community-acquired strains of Escherichia coli and the low potential for selection of resistant strains. In a domestic multicenter comparative study, the efficacy and safety of cefixime and ciprofloxacin were compared in patients with cystitis. Significant advantages of cefixime in terms of eradication of the pathogen and clinical improvement have been identified ¹¹ . In addition, third-generation cephalosporins, in particular cefixime, create a high concentration not only in the urine, but also in the kidney parenchyma ¹² , which makes it possible to use them in cases where prevention of ascending pyelonephritis is required. It should also be noted the prolonged effect of cefixime (Suprax Solutab is taken once a day) and the possibility of its use from the second trimester of pregnancy.

It is important that in certain cases, third-generation cephalosporins can be the drugs of choice (if sensitive pathogens are detected, if there are a history of risk factors such as recurrent UTIs, chronic pyelonephritis or vesicoureteral reflux with the threat of ascending pyelonephritis).

In conclusion, Professor L.A. Sinyakova once again emphasized that the reduction of resistance is impossible without the rational use of antimicrobials, including the cyclic use of antibiotics, the exclusion of drugs with resistance to which reaches 15% or more, as well as compliance with hospital protocols and formularies for the clinical use of antibiotics.

The problem of treatment and prevention of recurrent infections of the lower urinary tract. The role of immunization

According to modern concepts, the pathogenesis of UTI is based on the interaction of innate mucosal immunity, adaptive immunity with virulent uropathogens. As noted by the head of the department of infectious and inflammatory diseases with groups of clinical pharmacology and efferent methods of treatment of the Research Institute of Urology, Doctor of Medical Sciences, Professor Tamara Sergeevna PEREPANOVA, the first line of defense against pathogenic microorganisms, for which the mucous membranes are the entrance gates of infection, are congenital factors local immunity. A patient’s susceptibility to UTIs is controlled by genetic mechanisms that control the innate immune response.

It is known that not all types of microbes in the urinary tract are equally virulent. The most important factor in the virulence of uropathogenic strains Escherichia coli , 98% of which is present in the feces, and other microorganisms of the Enterobacteriaceae family is their ability to adhere to the urothelium.

The inflammatory response is triggered by uropathogenic Escherichia coli through virulence factors including P and type 1 pili that mediate adhesion to the urothelium. Chemokine receptors are involved in recognition of bacterial virulence factors, TLR receptors are involved in signaling. Infection-fighting neutrophils Escherichia coli are attracted and activated by chemokines and their receptors. It is the dysfunction of chemokine receptors that has a great influence on individual sensitivity to urinary infection. It should be noted that TLR receptors (TLR-2, TLR-4) also control the severity and activity of the inflammatory response ¹³ .

With persistent infection, the complex defense of the host organism is activated with a gradual transition from nonspecific to specific immunity. The leading role in the activation of the innate and adaptive immune response belongs to antimicrobial peptides, which are produced by leukocytes, epithelial cells of the urogenital, respiratory, and gastrointestinal tracts.

In recurrent UTIs, both types of immune response are important to recognize structures present on the bacterial surface and to initiate an appropriate immune response, but often in recurrent UTIs, the immune response is insufficient. In a study conducted in 2013 by specialists from the Research Institute of Urology to assess the state of innate mucosal immunity in recurrent UTIs, 38 women participated – 28 patients with recurrent UTIs and 10 healthy women. Examination data showed the presence in patients with recurrent UTIs of increased expression of TLR-2 receptors (by 1. 85 times) and TLR-4 receptors (by 22 times), as well as a decrease in the concentration of antimicrobial peptide by 9.78 times. Thus, in patients with recurrent UTIs, the failure of the innate immune response was revealed.

Reinfection with uropathogenic Escherichia coli has been shown to be the cause of recurrent UTIs in 68–72% of cases. For example, in bacterial cystitis, strains of uropathogenic Escherichia coli penetrate into the epithelial cells of the bladder wall and form intracellular bacterial communities inside them. Growing colonies of bacteria, surrounded by a biofilm matrix, form clusters in the wall of the bladder in the form of “cocoons” protruding into its lumen. From time to time, the “cocoons” break, and bacteria, getting into the urine, cause repeated UTIs ¹⁴ .

According to Professor T.S. Perepanova, the difficulties of treating recurrent UTIs are also associated with an increase in the resistance of uropathogens, which constantly change their properties, virulence, actively protecting themselves from antibiotics and antiseptics. One of the reasons for antimicrobial resistance is the uncontrolled use of antibiotics not only in medicine, but also in agriculture and animal husbandry. In this regard, it is necessary to strictly observe the recommended administration regimens and avoid excessive use of antimicrobial drugs, do not use antibiotics without indications (with asymptomatic bacteriuria, bacteriuria against the background of catheters and drains). In addition, it must be understood that the goal of treating recurrent UTIs is not to eradicate the pathogen, but to improve the quality of life of patients by lengthening the relapse-free period. For this reason, the management strategy for patients with recurrent UTIs involves not so much the use of antimicrobials as lifestyle changes and non-antimicrobial prophylaxis. Among the alternative methods of treatment are the use of herbal remedies, probiotics, cranberry preparations, topical application of estrogen, immunotherapy.

The most proven effect on immunoprophylaxis of recurrent UTIs is Uro-Vaxom, a lyophilisate of 18 strains Escherichia coli . The drug is taken according to the scheme: one capsule in the morning on an empty stomach for three months, then a break for three months, after which it is repeated for ten days for at least three months.

Uro-Vaxom stimulates innate and acquired immunity of both cellular and humoral levels. The drug triggers processes that lead to the activation of TLR-2 and TLR-4 receptors in the small intestine, recognizing PAMP (danger signal), stimulation of antigen-presenting cells in Peyer’s patches, increased maturation of dendritic cells, increased phagocytosis of macrophages, neutrophils, and increased production of already anti-inflammatory cytokines and secretory immunoglobulin in the target organ – in the bladder. This is how the innate immune system is activated.

In the intestinal epithelium, PAMPs in Uro-Vaxom are recognized by dendritic cells and initiate various specific immune responses. Through one of these reactions, activated dendritic cells interact with native T-lymphocytes, which leads to the activation of T- and B-lymphocytes. The migration of the latter into the urinary tract stimulates the production of secretory immunoglobulin in the bladder mucosa. This activates acquired immunity. As a result, a large amount of secretory immunoglobulin A accumulates in the epithelium of the urinary tract, which is an important factor in protecting against the introduction of the pathogen and, accordingly, preventing UTIs and their relapses.

Uro-Vaxom has a strong evidence base and is the only drug recommended by the European Urological Association guidelines for immunoprophylaxis in women with uncomplicated recurrent UTIs.

All major randomized, placebo-controlled clinical trials conducted in patients with recurrent UTIs demonstrated a statistically significant superiority of Uro-Vaxom and a significant reduction in the frequency of relapses within six months or one year compared with placebo. According to a meta-analysis, while taking the drug, the frequency of recurrent UTIs decreases by an average of 40% ¹⁵ . In addition, after six months, Uro-Vaxom contributed to a significant reduction in dysuria by 52%, leukocyturia by 47%, bacteriuria by 33% and was well tolerated – all side effects against the background of the drug were comparable to placebo.

The PIREUS multicentre study examined the benefits of Uro-Vaxom for recurrent UTIs compared with placebo for 12 months ¹⁶ . 231 patients received Uro-Vaxom according to the so-called booster scheme: one capsule per day for three months, then a break for three months, after which the second dose was one capsule per day for ten days in the seventh, eighth, ninth month, followed by three months of follow-up. 220 patients entered the placebo group. There was a significant 34% reduction in mean UTI frequency in the Uro-Vaxom group compared with the placebo group. In addition, in the Uro-Vaxom group, a significant decrease in the number of antibiotics consumed was noted (2.4 drugs compared to 2.8 drugs per patient per year, p

An open-label, multicentre, pilot study evaluated the efficacy and safety of Uro-Vaxom in pregnant women with recurrent UTIs ¹⁷ . Uro-Vaxom reduced recurrent UTIs (from 53% to 19%) and antibiotic consumption during pregnancy (from 56% to 13%), was well tolerated with few side effects (nausea and heartburn were reported in 3.2% of cases), and was safe as both for the mother and for the fetus (all children were born healthy with a normal Apgar score).

Thus, according to clinical studies, immunostimulating therapy with the use of Uro-Vaxom can prevent the development of recurrences of cystitis for up to 12 months due to the activation of the body’s own defenses. In addition, Uro-Vaxom is well tolerated and has a positive experience in pregnant women.

Macrolides and tetracyclines in the treatment of chronic prostatitis in routine clinical practice in Russia: preliminary results of the TAURUS 9 observational program0086

Chronic prostatitis is known to be the most common urological disease in young men. There is a group of antibacterial drugs, which, according to the professor of the Department of Urology of the First Moscow State Medical University. THEM. Sechenov, d.m.s. Andrei Zinovievich VINAROV, penetrate well into the prostate gland – these are fluoroquinolones, trimethoprim, macrolides and tetracyclines. Traditionally, fluoroquinolones have been considered the drugs of choice in the treatment of bacterial prostatitis. However, their widespread use has led to an increase in the resistance of the recognized pathogen of chronic bacterial prostatitis Escherichia coli and other representatives of Enterobacteriaceae spp. In addition, more and more often, atypical flora, intracellular bacteria, are found in patients with chronic prostatitis. According to some studies, chlamydia, ureaplasma and mycoplasma, due to the difficulty of their detection in routine clinical practice, can be the true cause of the development of the so-called abacterial prostatitis (chronic pelvic pain syndrome) ¹⁸ . Macrolides and tetracyclines are highly effective against these pathogens, which is confirmed by the recommendations of the European Association of Urology.

In order to evaluate the effectiveness of macrolides and tetracyclines in men with chronic prostatitis in everyday clinical practice in Russia, the observational program TAURUS (2013–2014) was carried out, the first epidemiological results of which were presented to the participants of the symposium.

The primary goal of this program was to evaluate the efficacy of macrolides and tetracyclines in men with chronic prostatitis in daily clinical practice, and the secondary goal was to evaluate their safety. During the first visit after obtaining the consent of the patients for the study, an anamnesis was taken, examination was carried out and treatment was prescribed. The examination included an assessment of the condition in accordance with the Chronic Prostatitis Symptom Index (CPSI), digital rectal examination, ultrasound, urinalysis before and after prostate massage, analysis of prostate secretion. During the second visit, a follow-up examination was conducted to evaluate the effectiveness and safety of therapy.

The TAURUS program covered 23 Russian centers from Moscow, St. Petersburg, Yekaterinburg, Chelyabinsk, Omsk, Nizhny Novgorod, Samara, Penza, Saratov, Perm, Barnaul, Krasnodar, Rostov, Voronezh. In total, more than 30 research doctors took part. The recruitment of patients was carried out from December 2013 to May 2014, as a result of which 1268 patients with chronic prostatitis receiving therapy on an outpatient basis were included in the program, of which 1218 patients were included in the analysis. The average age of the participants was 39.7 ± 12.7 years, the duration of chronic prostatitis in the general population is about 46 months. During the previous three months, 14.6% of patients received therapy for chronic prostatitis, somatic diseases occurred in 28.2% of patients.

The distribution of therapy among 1218 patients was as follows: 304 (24.9%) patients were treated with macrolides, 393 (32.3%) – tetracyclines, 521 (42.8%) patients were on combination therapy. In total, about 51% of program participants received doxycycline monohydrate at a dose of 100 mg twice a day, 64.9% of patients – josamycin at a dose of 500 mg three times a day.

Efficiency was assessed by the clinical conclusion of doctors, positioning the outcome of treatment as recovery, improvement, ineffectiveness of therapy. At the stage of preliminary data analysis before the finalization of the final report, the results of therapy were not announced, however, the expected final figures of effectiveness, according to A.Z. Vinarov, they promise to be high. The final results of the study will be made available to the medical community in early 2015.

The same applies to the safety of macrolide and tetracycline therapy for chronic prostatitis. Before obtaining accurate safety figures, assessed by the clinical opinion of doctors on the tolerability of drugs and by the number of registered side effects, A.Z. Vinarov mentioned that the overall number of adverse events among patients was insignificant and generally consistent with the safety profiles of both groups of drugs.

Thus, for the first time in the Russian Federation, a large-scale non-interventional study of the efficacy and safety of macrolides and tetracyclines in the treatment of chronic prostatitis in routine clinical practice (TAURUS) was conducted with the participation of 1268 patients. The preliminary results of the study made it possible to designate the population of patients who can be indicated for this therapy, as well as the structure of monotherapy and combination therapy with macrolides and tetracyclines. The results of efficacy and safety expected in the near future will make it possible to draw a conclusion on the practical feasibility of using these antibiotics in the treatment of chronic prostatitis and subsequently optimize modern recommendations for the treatment of such a significant pathology as chronic prostatitis.

“Based on the results of the TAURUS program, it will be possible to draw conclusions about the clinical efficacy and safety of macrolides and tetracyclines, in particular josamycin and doxycycline monohydrate. This will allow to designate the place of these drugs in the treatment of chronic prostatitis in routine clinical practice. However, of course, it can already be said now that further in-depth study of the effectiveness and safety of macrolides and tetracyclines in chronic prostatitis will be required, including taking into account data on the etiology and resistance of pathogens, ”stated Professor A.Z. Vinarov, completing the speech.

Mycoplasma infection | Dikul Center

Mycoplasma is a bacterium that can infect various parts of the body. The area of ​​infection depends on the type of mycoplasma – it can be the skin, lungs or urinary tract.

All mycoplasmal bacteria have one thing in common. Unlike other bacteria, mycoplasmas do not have cell walls. In addition, they are much smaller than other bacteria. This structure allows mycoplasmas to be resistant to most antibiotics, since the mechanism of their detrimental effect on microbes is based on damage to the bacterial wall. There are about 200 types of mycoplasma bacteria, but most of them are harmless. The following types have a certain danger:

• Mycoplasma pneumoniae
• Mycoplasma hominis
• Ureaplasma urealyticum
• Ureaplasma parvum
• Mycoplasma genitalium

Mycoplasma pneumonia

This type of mycoplasma can cause lung infection. At least a third of patients suffer from pneumonia in a mild form. Most people, especially children, are diagnosed not with pneumonia, but with tracheobronchitis.

A person can get this infection by airborne droplets from an infected person.

If a person is infected with Mycoplasma pneumoniae, there may be symptoms such as:

• Sore throat
• Cough
• Temperature increase
• Feeling tired
• Headache

Your doctor may prescribe one of the following types of antibiotics to treat an infection:

• Macrolides, such as azithromycin (ZIthromax) or erythromycin (Erythrocin)
• Tetracyclines such as doxycycline

Mycoplasma hominis

This type of mycoplasma lives in the urinary tract and genitals in about half of all women and a smaller number of men. But if a person is in good health, then there is nothing to worry about. These mycoplasmas rarely cause infection. Women with a compromised immune system are most at risk.

Sometimes a woman can get this infection during sex. The bacteria can also be passed from mother to child during childbirth.

In women, these bacteria may be associated with inflammatory conditions in the pelvic organs, infection of the reproductive organs. If pregnant, they can lead to problems such as:

• Ectopic pregnancy
• Prematurity
• Miscarriage

Mycoplasma hominis can also cause fever and infection in the newborn.

Diagnosis of this infection requires analysis of a sample of fluid from the vagina or urethra. Once the bacterium is verified, treatment with antibiotics from the tetracycline family, such as doxycycline, will be recommended.

Prevention of infection from this infection is the use of a condom and limiting the number of partners.

Ureaplasma urealyticum and Ureaplasma parvum

Most healthy women have these bacteria in the cervix or vagina, and some men also have them in the urethra. As a rule, they do not cause any health problems.

Ureaplasma can be transmitted during sex. If a woman is infected and is pregnant, then there is a certain risk of infecting the child in the womb or during childbirth.

Women may experience the following symptoms:

• Painful urination
• Abdominal pain
• Pain, odor or vaginal discharge
• Edema at the entrance to the urethra
• Urethral discharge

Infected males may develop urethritis.

During pregnancy, bacteria can cause infections in both mother and baby. Newborn problems may include:

• Low birth weight
• Pneumonia
• Septicemia

To diagnose ureaplasma infection, the doctor may perform a blood test:

• Blood
• Amniotic fluid sample
• Placental tissue sample
• Cervical swab sample
• Urethral swab Urethra

Your doctor may prescribe an antibiotic to treat the infection.

Choices may include:

• Macrolides such as azithromycin
• Tetracyclines such as doxycycline

The second line of treatment would be fluoroquinolones such as moxifloxacin.

If a woman becomes infected during pregnancy, the newborn baby may also need antibiotics.

Mycoplasma genitalium

This is a type of mycoplasma and is a very small prokaryotic organism (bacterium) that can lead to infection of the urethra or genital tract through sexual contact.

Quite often this type of mycoplasma does not cause symptoms, but in certain cases there may be symptoms similar to those that develop with other STIs (such as chlamydia and gonorrhea) – for example, inflammation in the urethra and genital tract. If the infection is left untreated, complications such as swelling of the scrotum in men can develop, and in women, vaginal bleeding and even infertility.

Mycoplasma genitalium is considered a “finicky” bacterium, which means that it requires very specific conditions to study in the laboratory, which makes it much more difficult to choose treatment tactics.

Symptoms

Mycoplasma genitalium is described as a “hidden” pathogen, so most people have no visible symptoms. Studies have shown that MG in 95% of men and almost 60% of women does not show symptoms and the infection is cured without treatment.

If a person develops symptoms, they are similar to other STIs such as chlamydia or gonorrhea, which can sometimes lead to misdiagnosis and delay in adequate treatment.

In men, most often, the infection leads to the development of urethritis or an inflammatory process in the urinary tract of people.

Symptoms may include:

• painful or burning sensation when urinating
• itching in the penis
• discharge from the urethra

In women, the following conditions are most likely to develop:

• cervicitis
• bacterial vaginosis (BV)
• inflammatory processes in the pelvic organs
• premature birth
• spontaneous abortion

Symptoms of these pathologies include:

• vaginal discharge
• vaginal itching
• soreness or burning when urinating
• abdominal pain
• metrorrhagia, more often between periods or after sex
• pain during sex
• fever

If a person has any of these symptoms, a doctor should be consulted.

What causes Mycoplasma genitalium?

Mycoplasma genitalia is a bacterium that is sexually transmitted and can cause infection. A person can become infected through any genital contact. Some studies suggest that Mycoplasma genitalium is as easily transmitted as chlamydia.

Diagnosis

Diagnosis of mycoplasma is difficult due to the lack of available tests. Sometimes a diagnosis of Mycoplasma genitalium is made only after treatment for more common STIs, such as gonorrhea or chlamydia, has failed, or if there are symptoms but tests for other STIs are negative.

Diagnosis of Mycoplasma genitalium, may be made in the presence of persistent symptoms of urethritis or cervicitis.

To confirm the diagnosis, the doctor may order a nucleic acid amplification test, which can detect certain genetic characteristics of the bacterium Mycoplasma genitalium. This test can be done using a urine sample or a vaginal or urethral swab.

Treatment

Many commonly prescribed antibiotics may not be effective in treating this infection.

Antibiotic resistance.

Recent studies have shown that Mycoplasma genitalium may be resistant to first-line antibiotics such as moxifloxacin, azithromycin, and macrolides. And therefore, treatment can be quite difficult.

Due to the resistance of Mycoplasma genitalium to many antibiotics, the following treatment options are recommended:

If susceptibility testing is possible:

• For macrolide sensitivity: doxycycline + azithromycin – according to scheme
• With resistance to macrolides: doxycycline + moxifloxacin – according to the scheme

If susceptibility testing is not available:

• : doxycycline and moxifloxacin.

Any human sexual partners should also be tested for mycoplasma infection, even if they are asymptomatic.

Mycoplasma genitalium risk factors

As with many STIs, there are several risk factors that can increase the risk of MG infection, including:

• having sex without a condom or other barrier method
• recently diagnosed with chlamydia or gonorrhea
• multiple sexual partners in the last 12 months
• HIV or AIDS

Is there a risk of genital mycoplasma infection if a woman is pregnant?

Pregnant women are at risk of contracting Mycoplasma genitalium.