Letters to the Editor
To the Editors:
We read with great interest the report by Poey et al1 regarding amikacin monotherapy as first-line treatment for febrile urinary tract infection (FUTI) in children. In this report, amikacin monotherapy was found to be effective for the empiric treatment of FUTIs mostly caused by non–extended-spectrum β-lactamase (ESBL)–producing bacteria. Although they used amikacin with the aim of targeting a spectrum that also included ESBL-producing strains, only 2 patients had ESBL infection in the cohort.
Amikacin monotherapy is known to be effective for the treatment of urinary tract infection (UTI) because of its high urinary excretion.2 It is approved by the US Food and Drug Administration and is recommended for the treatment of FUTI in children.3 , 4 Despite its promising in vitro activity against ESBL-producing urinary isolates of Escherichia coli,5 there is limited clinical evidence supporting its use for the treatment of FUTIs caused by ESBL-producing E. coli in children.
In our experience with 28 (68% girls) children between 6 and 48 months of age (median age, 13 months), amikacin monotherapy also seemed to be effective for the treatment of FUTIs caused by ESBL-producing E. coli. The diagnosis of UTI was made based on the presence of both pyuria and a positive monomicrobial urine culture [≥100,000 colony-forming units/mL for midstream urine and ≥50,000 colony-forming units/mL for urine obtained by a catheter] for ESBL-producing E. coli. Urine bags were not used for specimen collection for urine culture in our patients. Antibiotic susceptibility and the presence of the ESBL phenotype were determined using the BD Phoenix automated system (Becton Dickinson Diagnostic Systems, Sparks, MD) according to the European Committee on Antimicrobial Susceptibility Testing guidelines.6 Treatment failure was defined as the need for an additional antimicrobial agent for any of the following conditions after treatment initiation: persistence of fever (≥72 hours) or other clinical symptoms of UTI (≥48 hours) or deterioration of patient’s clinical condition within 48 hours or reappearance of fever or other clinical symptoms of UTI following their initial resolution. Amikacin monotherapy was initiated as definitive treatment (after urine culture susceptibility results were available) of FUTIs in pediatric patients ≥3 months of age who failed to respond to the initial empiric treatment, and whose admission urine cultures (obtained at the time of UTI diagnosis) yielded positive results for ESBL-producing E. coli which were resistant to empiric treatment but susceptible to amikacin. Patients were excluded if they had impaired renal function at the baseline, signs of sepsis or septic shock, a history of hearing or vestibular dysfunction or hypersensitivity to aminoglycosides. Based on the susceptibility test results, all the patients had received inappropriate empiric therapy, including third-generation cephalosporins (n = 24), and trimethoprim-sulfamethoxazole (n = 4). All E. coli isolates were susceptible to amikacin with minimum inhibitory concentrations of ≤4 mg/L. Amikacin was given at a dose of 7.5 mg/kg intravenously twice daily.3 , 4 The median duration of treatment was 8 days (range, 3–10 days). Of the 28 patients, 27 (96%) improved clinically without requiring any additional antibiotics; repeat urine cultures on day 3 of amikacin treatment yielded negative results. The median time to resolution of fever was 2 days (range, 1–3 days). Treatment failure was only seen in 1 patient with concomitant bacteremia and persistent fever, who was then treated with intravenous ertapenem. All patients had normal baseline serum creatinine values, and there were no significant changes in serum creatinine levels that were obtained twice weekly. Although we did not routinely perform pre- and posttreatment audiometry, clinically detectable ototoxicity was not observed.
We should emphasize that our patient population is different from that presented by Poey et al.1 Although their cohort mostly consisted of patients with non-ESBL FUTI, all the patients in our cohort had ESBL FUTI. Therefore, we believe that our results could yield more evidence on the clinical effectiveness of amikacin in the treatment of FUTI caused by ESBL-producing E. coli. Furthermore, Poey et al1 used amikacin monotherapy for the empiric treatment of UTI at a dose of 25 mg/kg once daily for a median duration of 3 days according to the French guidelines.7 However, we used amikacin monotherapy for the definitive treatment of UTI caused by ESBL-producing E. coli at the Food and Drug Administration–approved dose of 7.5 mg/kg twice daily.3 The French guidelines recommend using the highest doses of aminoglycosides in the empiric antibiotic therapy of patients with severe sepsis or septic shock, or patients who have a risk of infection with a strain characterized by an increased minimum inhibitory concentration; this corresponds to 25–30 mg/kg for amikacin.7 However, such patients did not exist in the cohort of Poey et al,1 making it difficult to understand whether their patients really need such higher doses. More importantly, the impact of such doses on renal and auditory functions needs to be investigated in children.
In this era of increasing antibiotic resistance, it is obligatory to investigate alternative carbapenem-sparing agents for the treatment of UTIs caused by ESBL-producing Enterobacteriaceae. To prevent the development of resistance, carbapenems should only be used in patients with severe infections with ESBL-producing Enterobacteriaceae other than UTIs. Our results suggest that amikacin might be a reasonable alternative to carbapenems for treating nonbacteremic FUTIs caused by ESBL-producing E. coli in children with normal renal function, if the isolate is susceptible. More prospective controlled trials are warranted to objectively evaluate the optimal dosing, side effects and efficacy of amikacin for the treatment of FUTIs caused by ESBL-producing E. coli strains in children.
Meltem Polat, MD
Department of Pediatric Infectious Diseases
Pamukkale University School of Medicine
Anil Tapisiz, MD
Department of Pediatric Infectious Diseases
Gazi University School of Medicine
1. Poey N, Madhi F, Biscardi S, et alAminoglycosides monotherapy as first-line treatment for febrile urinary tract infection in children. Pediatr Infect Dis J. 2017;36:1104–1107.
2. Vidal L, Gafter-Gvili A, Borok S, et alEfficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2007;60:247–257.
4. Montini G, Tullus K, Hewitt IFebrile urinary tract infections in children. N Engl J Med. 2011;365:239–250.
5. Bouchillon SK, Badal RE, Hoban DJ, et alAntimicrobial susceptibility of inpatient urinary tract isolates of gram-negative bacilli in the United States: results from the study for monitoring antimicrobial resistance trends (SMART) program: 2009-2011. Clin Ther. 2013;35:872–877.
7. French Health Products Safety Agency. Update on good use of injectable aminoglycosides, gentamycin, tobramycin, netilmycin, amikacin. Pharmacological properties, indications, dosage, and mode of administration, treatment monitoring. Med Mal Infect. 2012;42:301–308.