Single-Dose Aminoglycosides for UTIs

Introduction

UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus spp., Klebsiella spp., etc.) and other Gram-negative organisms. UTIs are classified based on risk factors (uncomplicated vs. complicated) and the area of the urinary tract affected (cystitis vs. pyelonephritis).

Treatment of asymptomatic bacteriuria is often not beneficial and only supported by guidelines in pregnant women and before urological procedures that compromise the mucosa. Inappropriate antibiotic use has led to increased resistance in uropathogenic bacteria. Barriers to traditional oral antibiotic therapy include increasing bacterial resistance, nonadherence rates approaching 60%, and medication access issues.

Key Points

UTIs are most commonly caused by Enterobacteriaceae (E. coli, Proteus, Klebsiella) and other Gram-negative organisms.
Single-dose aminoglycoside therapy may be a plausible option for cystitis and can be given IV or IM (no IV access required); gentamicin is the most-studied agent.
The risk of adverse events with single-dose aminoglycosides is low, though nephrotoxicity and ototoxicity remain concerns.
Single-dose aminoglycosides should NOT be used as first-line therapy.

Clinical Detail

Rationale

Excellent activity against most uropathogens, including drug-resistant Enterobacteriaceae
Eliminated as active drug almost exclusively by the kidneys with concentrations 100-fold greater in the urine than plasma
Post-antibiotic effect of aminoglycosides may persist for up to 72 hours
Toxicities may be limited with one-time administration
Prevents medication access & adherence concerns

Aminoglycoside Dosing & Administration

Property	Gentamicin	Amikacin	Tobramycin
Dose	5 mg/kg IV/IM once Underweight [TBW < IBW]: use TBW Nonobese [TBW 1x to 1.25x IBW]: use IBW or TBW Obese [TBW > 1.25x IBW]: use adjusted body weight	15 mg/kg IV/IM once	5 mg/kg IV/IM once
Administration	IM: undiluted 40 mg/mL vial IV: Dilute in 50 to 200 mL of NS, LR, or D5W and infuse over 30 min to 2 h	IM: use undiluted 500 mg/2 mL vial IV: Dilute in 100 to 200 mL of NS, LR, or D5W and infuse over 30 min to 60 min	IM: use undiluted 80 mL/2 mL vial IV: Dilute in 50 to 100 mL of NS, LR or D5W and infuse over 20 min to 60 min
PK/PD	–IM: rapid & complete absorption –No CYP-mediated metabolism –Urine (70% unchanged drug)	–IM: rapid & complete absorption –No CYP-mediated metabolism –Urine (94–98% unchanged drug)	–IM: rapid & complete absorption –No CYP-mediated metabolism –Urine (90–95% unchanged drug)
Adverse effects	Nephrotoxicity; ototoxicity
Considerations	Caution in renal impairment; large volume for IM administration

Definitions

Uncomplicated — non-pregnant women with no known anatomical and functional abnormalities of the urinary tract or comorbidities
Complicated — all men, pregnant women, anatomical or functional abnormalities of the urinary tract, indwelling urinary catheters, renal diseases, and/or other immunocompromising diseases such as diabetes
Cystitis — infection confined to the bladder; symptoms of increased urinary urgency, frequency & dysuria
Pyelonephritis — infection extends beyond the bladder; cystitis symptoms + fever, chills, flank & pelvic pain

Evidence

Overview of Evidence

Field	Goodlet et al. 2018
Design	Systematic review (n=13,804 patients across 13 studies published from 1978 to 1991)
Included studies	Single-dose aminoglycoside with no concomitant antibiotic therapy Average patient: pediatric female with acute uncomplicated cystitis secondary to E. coli with normal renal function treated in the outpatient setting 7 studies with a comparator arm: Single dose oral fosfomycin Oral trimethoprim-sulfamethoxazole, amoxicillin, or cephalosporin x 5–10 days 72% of isolates were E. coli Netilmicin was the most commonly used aminoglycoside, followed by amikacin and gentamicin
Outcomes	Overall microbiologic cure rate of 94.5% ± 4.3% No differences between pediatric- and adult-only studies No differences between aminoglycosides and comparator arms Patients with anatomical abnormalities were less likely to have initial microbiologic cure Overall 19% (84/443) 30-day recurrence rate in studies that had minimum 30-day follow-up Only 0.5% (64/13,804) reported adverse effects, mainly due to vestibular toxicity (53 patients) and nephrotoxicity (7 patients)
Limitations	Majority of patients (13,258/13,804) were from one study Generalizability is questionable 8 studies (pediatric only) & 3 studies (adults only) Only 1 study included patients with moderate or severe renal impairment (10/44 patients) Only 2 studies included patients with pyelonephritis No cases of sepsis or bacteremia were reported Older studies Did not study against modern uropathogens Did not compare to commonly used agents, such as nitrofurantoin or IV ceftriaxone Did not assess for future uropathogen resistance Symptom data was not reported Patients could have been treated for asymptomatic bacteriuria Lack of assessment of clinical cure rate for majority of studies No studies were blinded Unknown drug dosing of comparator arms

The Bottom Line

Consider use in patients with	AND multiple of the following
Lower urinary tract infection (cystitis) No systemic signs/symptoms Normal renal function, and No urinary tract abnormalities	Medication access issues Known medication nonadherence Multiple antibiotic allergies Known history of resistant organisms Unable to take oral medications

Conclusions

Single-dose aminoglycoside therapy may be a plausible treatment option in patients with cystitis.
Aminoglycosides can be administered either the IV or IM route, and therefore, does not necessarily require IV access. Gentamicin may be considered the preferred aminoglycoside based on frequency of use in studies.
The risk for adverse events with single-dose aminoglycosides is low, however, there are concerns for nephrotoxicity and ototoxicity.
Single-dose aminoglycoside should NOT be recommended as first-line therapy. It can be considered in patients with acute cystitis with normal renal function and multiple barriers to the standard of care.

References

Bonkat G, Bartoletti RR, Bruyere F et al. EAU Guidelines on Urological Infections. Urological Infections. 2019.

Uncomplicated Cystitis and Pyelonephritis (UTI). Clinical Infectious Diseases. 2011;52(5):e103-e120.

Clinical Practice Guideline for the management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

Clinical Infectious Diseases. 2019;68(10):e83-75.

Goodlet KJ, Benhalima FZ, Nailor MD. A Systematic Review of Single-Dose Aminoglycoside Therapy for Urinary Tract Infection: Is It Time To

Resurrect an Old Strategy? Antimicrob Agents Chemother. 2018 Dec 21;63(1):e02165-18.

Tags:aminoglycoside urinary tract infection gentamicin stewardship

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