Is there any evidence to support the use of doxycycline in the treatment of ESBL E. coli urinary tract infections?

Comment by InpharmD Researcher

There is a lack of data to support the use of doxycycline for the treatment of ESBL-positive E. coli urinary tract infections (UTIs). The Infectious Diseases Society of America (IDSA) recommends against the use of doxycycline for the treatment of ESBL Enterobacterales (ESBL-E) cystitis or pyelonephritis. In objection to these recommendations, a letter to the editor suggests doxycycline should be considered as a potential treatment option for the treatment of acute cystitis caused by ESBL-E. Two case reports have described the successful use of doxycycline to treat ESBL-E UTIs. However, in one case (Table 1), the patient had ESBL-positive K. pneumoniae and pansensitive E. coli, and in the other case, the patient had prostatitis, limiting any applicability to ESBL-positive E. coli UTIs. In vitro data show doxycycline may have synergistic efficacy with amikacin against ESBL E. coli isolates.

  

PubMed: doxycycline ESBL UTI= 1 result (1 relevant) PubMed: doxycycline ESBL cystitis= 1 result (1 relevant) PubMed: doxycycline ESBL pyelonephritis= 0 results PubMed: doxycycline ESBL= 56 results (5 relevant)

Background

According to the Infectious Diseases Society of America (IDSA) Antimicrobial-Resistant Treatment Guidance for gram-negative bacterial infections, doxycycline is not recommended for the treatment of extended-spectrum beta-lactamase Enterobacterales (ESBL-E) cystitis. Despite the fact that oral tetracyclines have demonstrated effectiveness for the treatment of urinary tract infections (UTIs) in two older clinical outcome studies, the rationale for this recommendation is that both studies primarily focused on the treatment of P. aeruginosa, an organism that is not susceptible to oral tetracyclines. Additionally, doxycycline is primarily eliminated through the intestinal tract and has limited urinary excretion. The panel recommends against the use of doxycycline for treatment of ESBL-E cystitis until more robust data are available demonstrating clinical effectiveness of oral doxycycline for this indication. The panel also recommends against using doxycycline for the treatment of ESBL-E pyelonephritis or complicated UTIs due to its limited urinary excretion and lack of comparative efficacy data to other standard treatments. [1], [2], [3], [4]

In response to the recommendation against doxycycline for the treatment of ESBL-E cystitis due to limited urinary excretion by the IDSA, a 2021 letter to the editor states the authors are not in support of this as approximately 35% to 60% of an oral dose of 100 mg of doxycycline is excreted unchanged in the urine. The concentrations of doxycycline following a 100 mg oral dose in the urine can range from 60 to 300 mcg/mL in patients with normal renal function, which is significantly greater than the mean inhibitory concentration (MIC) for the ESBL-E that can cause acute cystitis. The authors also state that clinical data indicate doxycycline has efficacy against gram-negative organisms, including E. coli, that cause urinary cystitis. However, the data to support this statement are limited to 1 case report (see Table 1) and 2 outdated studies. A 2016 review is also cited in support of this statement which states doxycycline can be used to treat E. coli including ESBL-positive strains, but the data to support this statement are not referenced. The authors also believe that given the increased incidence of multidrug-resistant gram-negative bacterial infections and favorable pharmacokinetics and safety profile of doxycycline, its use for treating certain types of acute cystitis should be reconsidered. It is suggested that based on 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. [5], [6], [7], [8], [9]

A 2016 in vitro study assessed antibacterial activity of combinations of amikacin and doxycycline against multidrug-resistant Escherichia coli (E. coli) isolates. Twenty-four different pulsotypes, including 10 ESBL isolates were collected. Doxycycline alone was found to be effective against only 30% of ESBL E. coli isolates. However, the synergistic effects of amikacin/doxycycline were found to be effective against 80% of ESBL E. coli isolates. Based on these results, it was suggested that the antibacterial activity of doxycycline can be enhanced by the addition of amikacin and is observed against most multidrug-resistant E. coli isolates. These results may not be generalizable to the treatment of UTIs caused by ESBL E. coli. [10]

A 2021 cross-sectional study conducted between March and November 2020 aimed to determine the antimicrobial resistance of ESBL-E isolated from hospital and community settings in Malawi. A total of 101 mid-stream urine samples from patients with clinically suspected UTIs and a total of 195 rectal swabs were randomly collected. Of 73 ESBL-E isolates, E. coli was the most predominant ESBL-E isolated in community settings (70%). Additionally, E. coli accounted for 74% and 50% of isolates from rectal swab and urine, respectively. The highest resistance rates were observed for trimethoprim-sulfamethoxazole (92%), amoxicillin and ceftriaxone (79%), doxycycline (75%), and gentamicin (72%). E. coli isolates specifically were 79% resistant to doxycycline. Despite the high rates of resistance found to doxycycline, these results may not be generalizable to the United States due to the variability in local bacterial pathogens cultured and antimicrobial susceptibility rates. [11]

References:

[1] Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Antimicrobial-Resistant Treatment Guidance: Gram-Negative Bacterial Infections. Infectious Diseases Society of America 2022; Version 1.1. Accessed August 6, 2022. https://www.idsociety.org/practice-guideline/amr-guidance/
[2] Mukerji AC, Sharma MM, Taneja OP, Saxena SN, Bhatnagar RK, Ghosh-Ray B. A clinical trial of alpha-6-deoxyoxytetracycline (doxycycline) in the treatment of urinary tract infections. Chemotherapy. 1969;14(2):77-85. doi:10.1159/000220613
[3] Musher DM, Minuth JN, Thorsteinsson SB, Holmes T. Effectiveness of achievable urinary concentrations of tetracyclines against "tetracycline-resistant" pathogenic bacteria. J Infect Dis. 1975;131 Suppl:S40-S44. doi:10.1093/infdis/131.supplement.s40
[4] Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006;58(2):256-265. doi:10.1093/jac/dkl224
[5] Jodlowski T, Ashby CR, Nath SG. Doxycycline for ESBL-E Cystitis. Clin Infect Dis. 2021;73(1):e274-e275. doi:10.1093/cid/ciaa1898
[6] White CR, Jodlowski TZ, Atkins DT, Holland NG. Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection. J Pharm Pract. 2017;30(4):464-467. doi:10.1177/0897190016642362
[7] Cunha BA. An infectious disease and pharmacokinetic perspective on oral antibiotic treatment of uncomplicated urinary tract infections due to multidrug-resistant Gram-negative uropathogens: the importance of urinary antibiotic concentrations and urinary pH. Eur J Clin Microbiol Infect Dis. 2016;35(4):521-526. doi:10.1007/s10096-016-2577-0
[8] Lockey JE, Williams DN, Raij L, Sabath LD. Comparison of 4 and 10 days of doxycycline treatment for urinary tract infection. J Urol. 1980;124(5):643-645. doi:10.1016/s0022-5347(17)55594-9
[9] Holloway WJ, Furlong JH, Scott EG. Doxycycline in the treatment of infections of the urinary tract. J Urol. 1969;102(2):249-252. doi:10.1016/s0022-5347(17)62124-4
[10] Lai CC, Chen CC, Huang HL, Chuang YC, Tang HJ. The role of doxycycline in the therapy of multidrug-resistant E. coli - an in vitro study. Sci Rep. 2016;6:31964. Published 2016 Aug 18. doi:10.1038/srep31964
[11] Onduru OG, Aboud S, Nyirenda TS, Rumisha SF, Mkakosya RS. Antimicrobial susceptibility testing profiles of ESBL-producing Enterobacterales isolated from hospital and community adult patients in Blantyre, Malawi. IJID Reg. 2021;1:47-52. Published 2021 Sep 6. doi:10.1016/j.ijregi.2021.08.002
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any evidence to support the use of doxycycline in the treatment of ESBL E. coli urinary tract infections?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-2 for your response.

 

Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection

Design

 Case report

Case presentation

A 70-year-old long-term care male patient with a history of recurrent urinary tract infections (UTIs), type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with a suspected UTI after a nurse noted turbid, dark, foul-smelling urine. Two months prior, the patient had a previous UTI with an extended-spectrum β-lactamase (ESBL) Klebsiella pneumoniae (K. pneumoniae) that was susceptible in vitro to amoxicillin/clavulanate. The patient was treated for 10 days and experienced resolution of symptoms.

On day 1, the patient complained of burning while urinating, but no other symptoms were reported, and the patient remained afebrile without signs of systemic infection. Urine was collected via a straight catheter to prevent contamination and sent to the laboratory for urinalysis. Results came back positive for suspected UTI with a pending urine culture. The patient was initiated on oral ciprofloxacin 500 mg immediately followed by 500 mg twice daily.

On day 2 of ciprofloxacin treatment, the patient continued to report pain with urination in addition to cloudy, amber-colored urine. On day 3, the patient experienced increased burning with urination along with pressure in his lower middle abdomen after voiding that lasted approximately 1 hour. Urine remained malodorous while the urine culture from day 1 was still pending. The patient was eventually switched to amoxicillin/clavulanate 875/125 mg by mouth twice daily for 10 days after a review of his culture from 2 months prior that showed resistance to ciprofloxacin. Ciprofloxacin was discontinued.

On day 4, the patient was reported to be feeling mildly better despite still voiding medium dark yellow urine. The culture returned positive for Escherichia coli (E. coli) and ESBL-positive K. pneumoniae. The K. pneumoniae was multidrug-resistant (MDR) while the E. coli was pansensitive. Since the patient had previously used amoxicillin/clavulanate for UTI treatment and approximately 24 hours had passed without relief of symptoms, it was decided to initiate the patient on a tetracycline antibiotic. Amoxicillin/clavulanate was discontinued, and the patient was initiated on doxycycline hyclate 100 mg twice daily for 14 days.

On day 5, the patient reported improvement in urinary symptoms; however, he was still voiding hazy, light yellow, amber urine. The patient complained of nausea in the evening that was suspected to be due to doxycycline. Ondansetron was prescribed to manage the nausea. On day 6, there was still some burning during urination but no other complaints. The patient continued to show improvement and by day 7, he had no pain or burning with voiding, and his nausea subsided. Complete blood count obtained on day 11 revealed normal white blood cell count of 8,600/cm. No further UTI therapy was necessary after completing the 14-day course of doxycycline. No relapse in UTI was reported to occur in the 90 days following treatment.

Study Author Conclusions

Resistance to E. coli and K. pneumoniae is an emerging concern worldwide. Current standards of care suggest susceptibility testing for complicated UTIs prior to antimicrobial therapy. Provided both isolates are susceptible, doxycycline may be a viable option in the treatment of MDR UTIs with E. coli and K. pneumoniae, as successful treatment was observed. More clinical data regarding doxycycline use in complicated UTIs are necessary before formulating stronger recommendations.

 

References:

White CR, Jodlowski TZ, Atkins DT, Holland NG. Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection. J Pharm Pract. 2017;30(4):464-467. doi:10.1177/0897190016642362

 

Persistent Extended-Spectrum β-Lactamase-Positive Escherichia coli Chronic Prostatitis Successfully Treated With a Combination of Fosfomycin and Doxycycline

Design

 Case report

Case presentation

A 53-year-old male who had been referred for treatment of persistent chronic prostatitis had mild benign prostatic hypertrophy (BPH) and was allergic to penicillin. Over the prior 6 months, urinalyses revealed high-grade pyuria, few red blood cells, and abundant mucous threads. Urine cultures repeatedly grew extended-spectrum β-lactamase (ESBL)-positive Escherichia coli (E. coli) resistant to doxycycline but susceptible to ampicillin/sulbactam, carbapenems, aminoglycosides, and nitrofurantoin. The patient had received treatment for 1 month with oral nitrofurantoin 100 mg every 12 hours; however, after discontinuation, his symptoms of dysuria, frequency, and foul-smelling urine returned. Urine cultures also remained positive for ESBL-positive E. coli. Diagnostic studies were unremarkable. 

The patient did not respond to doxycycline therapy after being referred for oral antibiotic therapy for his recurrent chronic prostatitis. The strain was reportedly susceptible to fosfomycin; therefore, the patient was treated with fosfomycin 3 g PO every 72 hours for 1 month. Within days of discontinuing fosfomycin, the patient relapsed with a return of foul-smelling urine, high-grade pyuria, and positive urine cultures for ESBL-positive E. coli. The patient was then re-treated with 'high-dose' fosfomycin (6 g PO every 72 hours) for 1 month. One week after completing 'high-dose' fosfomycin therapy, his symptoms again returned in addition to his ESBL-positive E. coli bacteriuria.

Repeat susceptibility testing indicated his strain remained susceptible to fosfomycin. Two weeks after transurethral resection of the prostate (TURP) was done to remove prostatic calcifications, his foul-smelling urine, pyuria, and ESBL-positive E. coli bacteriuria recurred. Antibiotic resistance was not the determining explanation for recurrent prostatitis. Post-TURP, the patient no longer had BPH, but prostatic calcifications, not removed by TURP, remained. Despite his ESBL-positive E. coli being doxycycline-resistant, it was decided to retreat him with a combination of fosfomycin 3 g PO every 72 hours plus doxycycline 100 mg PO every 12 hours. The symptoms and pyuria reportedly resolved, and urine cultures became negative in 2 weeks. The patient remained free of infection.

Study Author Conclusions

Remarkably, the patient's infection rapidly cleared with combination therapy with fosfomycin plus doxycycline. After 2 weeks of combination therapy with fosfomycin plus doxycycline, his urine was no longer foul smelling, his urinalysis became normal (no pyuria, red blood cells, or mucus threads) and his urine has since remained culture-negative.

 

References:

Cunha BA, Gran A, Raza M. Persistent extended-spectrum β-lactamase-positive Escherichia coli chronic prostatitis successfully treated with a combination of fosfomycin and doxycycline. Int J Antimicrob Agents. 2015;45(4):427-429. doi:10.1016/j.ijantimicag.2014.12.019