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 a previous 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 However, the data to support this statement are limited to 1 case report (see Table 1) and 2 outdated studies.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]
According to a 2012 editorial, oral doxycycline is an underutilized but pharmacokinetically rational option for treating non-systemic urinary tract infections (UTIs) caused by aerobic Gram-negative uropathogens, including Pseudomonas aeruginosa. The central principle is that renally excreted antibiotics achieve urinary concentrations that greatly exceed serum levels, and because antimicrobial efficacy is concentration-dependent, organisms labeled “resistant” by serum-based susceptibility testing may still be eradicated in the bladder if urinary concentrations exceed the organism’s minimal inhibitory concentration (MIC). [10]
For doxycycline, a standard oral dose of 100 mg produces serum levels of approximately 4 mcg/mL but urinary concentrations exceeding 150 mcg/mL in patients with normal renal function. These urinary levels are sufficient to cover many Gram-negative uropathogens, including E. coli, Klebsiella, Enterobacter, indole-positive Proteus, and P. aeruginosa, when MICs are ≤150 mcg/mL. Clinical data has demonstrated that tetracyclines (including doxycycline and minocycline) eradicated P. aeruginosa from urine in approximately 75–85% of patients with intact renal function. Although doxycycline’s eradication rate was slightly lower than tetracycline in that study, results were broadly comparable. Data also reflects approximately 75% success in long-term clinical use of oral doxycycline for P. aeruginosa cystitis/CAB.A key argument is that conventional in vitro susceptibility testing, performed in broth at serum pH (7.4) and interpreted using serum-achievable concentrations, does not reflect in vivo conditions in the urinary tract. When organisms are tested in human urine at urinary pH and achievable urinary drug concentrations, susceptibility rates increase substantially. For example, doxycycline susceptibility among ampicillin-resistant E. coli improved from 40% in standard broth testing to 76% when tested in human urine at urinary pH and concentrations. This discrepancy explains why “resistant” Gram-negative uropathogens may still be eradicated clinically with oral doxycycline in lower UTIs. [10]
Renal function is critical to doxycycline efficacy. With creatinine clearance (CrCl) >50 mL/min, urinary concentrations are typically sufficient to exceed MICs for susceptible strains. If CrCl falls below 50 mL/min, urinary concentrations are estimated to decrease by approximately 50%. If the reduced concentration remains above the MIC, eradication is still possible. Among tetracyclines, doxycycline is preferred in renal insufficiency for treatment of non-MDR P. aeruginosaUTIs. However, doxycycline may fail in approximately 25% of P. aeruginosa strains if urinary levels do not exceed the MIC or if the organism is multidrug-resistant (MDR). Urinary pH also influences activity: tetracycline activity increases in acidic urine (pH <6), which may enhance in vivo efficacy. Early clinical response can be monitored by urinalysis; a rapid decrease in pyuria predicts eventual culture negativity, whereas persistent pyuria suggests failure, potentially due to high MICs or MDR strains. In cases of doxycycline failure, fosfomycin is suggested as a likely effective alternative. [10]
Overall, the article concludes that oral doxycycline—based on achievable urinary concentrations, pharmacodynamic principles, and clinical data—represents a cost-effective and clinically viable alternative to parenteral therapy for many non-systemic Gram-negative UTIs, including a substantial proportion of P. aeruginosa cystitis/CAB, particularly when renal function is preserved and MIC considerations are favorable. [10]
A 2016 in vitro study assessed antibacterial activity of combinations of amikacin and doxycycline against multidrug-resistant 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. [11]
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. [12]