In the present study, therapeutic responses of febrile UTIs to antibiotic therapy were compared between UTIs caused by ESBL-producing strains and non-ESBL-producing strains. Prescribing carbapenems has been restricted and allowed only with the permission of the infectious disease (ID) physicians in our hospital. Because attending physicians discussed with ID physicians whether to administer carbapenems or not to their patients, and ID physicians decide based on the patient’s response to empirically administered antibiotics, no children received carbapenems in our study. There were no significant differences in the clinical and microbiological responses of febrile UTIs to non-carbapenem antibiotic therapy between the ESBL and non-ESBL groups. There was also no significant difference in the frequency of APN or VUR between the two groups.
ESBLs are resistant to aminopenicillins and ureidopenicillins as well as extended-spectrum β-lactam agents; ESBLs also usually present resistance to other classes of antibiotics, such as quinolones and trimethoprim/sulfamethoxazole [8, 13, 14]. Therefore, the broadest-spectrum antibiotic agents, carbapenems, are recommended to treat infections caused by ESBL-producing bacteria [7, 8]. Risk factors for UTIs due to ESBL-producing strains in children, including being less than 1 year old, having a recent history of hospitalisation and antibiotic therapy with BLs, the presence of underlying disease, and K. pneumoniae infection, have been reported [1, 4–6, 15, 16]. Given that carbapenem use should be restricted and most cases of UTIs are not life-threatening, previous studies have focused on non-carbapenem antibiotics in UTIs due to ESBL-producing strains [11, 12, 17–19]. However, few studies have examined the therapeutic efficacy of non-carbapenem antibiotics in childhood UTIs caused by ESBL-producing strains [11, 12]. Cephamycins, which are stable against ESBL, as well as fosfomycin and nitrofurantoin showed therapeutic effects for UTIs caused by ESBL-producing strains [18, 20, 21]. However, data concerning their efficacy and safety in children were insufficient for these antibiotics. In addition, cephamycin therapy tends to provoke inducible resistance to itself and occasionally to carbapenems; therefore, cephamycin monotherapy for infections due to ESBL-producing strains has not been accepted [7, 22].
In the present study, clinical and microbiological responses to non-carbapenem antibiotic therapy were not significantly different between the ESBL and non-ESBL groups, even though inappropriate empirical antibiotics were administered in significantly more episodes in the ESBL group than in the non-ESBL group. Previous studies reported favourable outcomes of cephalosporin therapy in UTIs caused by ESBL-producing strains despite the weakness of cephalosporins against ESBL. This phenomenon may have been due to higher antibiotic concentrations in urine compared with serum [1, 12, 19]. Cefotaxime monotherapy in the ESBL group helped achieve defervescence and urinary sterilisation in the present study, but there were only two such cases. Although 50.0 % of the ESBL group received third-generation oral cephalosporins after discharge from hospital and there was no re-emergence of fever or urological symptoms during oral antibiotic therapy, most children of the ESBL group had received a median of 6.0 days of aminoglycoside therapy during their hospitalisation. Prolonged antibiotic effect of aminoglycosides should be considered. In addition, no controlled studies on the clinical efficacy of third-generation cephalosporins in UTIs caused by ESBL-producing strains have been conducted and the use of third-generation cephalosporins is significantly associated with the development of ESBL-producing strains [13, 16, 23]. Furthermore, a recent study reported that ceftriaxone therapy in murine pyelonephritis caused by ESBL-producing E. coli reduced the renal bacterial burden but did not alter renal inflammation . This suggests that in vivo clinical efficacy and long-term outcomes of third-generation cephalosporin therapy in UTIs due to ESBL-producing strains should be further evaluated.
Because clavulanate, a BLI, can inhibit ESBL activity, BL/BLIs were considered an alternative to carbapenems in treating infections due to ESBL-producing strains [25, 26]. In the present study, the susceptibility rates to amoxicillin/clavulanate and piperacillin/tazobactam in the ESBL group (66.7 % and 85.7 %, respectively) were higher than those to cefotaxime, ceftazidime, and cefepime. In the present study, aminoglycosides were empirically administered for 79.1 % of the total episodes and 81.8 % of episodes in the ESBL group. Only 23.8 % of the ESBL-producing isolates in the present study were susceptible to empirically administered BLs and BL/BLIs; however, all of the ESBL-producing isolates were susceptible to empirically administered aminoglycosides. Therefore, empirically administered aminoglycosides in the ESBL group may have contributed to the non-significant findings in the clinical and microbiological responses between the ESBL and non-ESBL groups. Park et al. reported on the clinical and microbiological effects of aminoglycosides in adults and children with UTIs caused by ESBL-producing strains , and the efficacy of aminoglycoside combination therapy has also been demonstrated in bacteraemia caused by ESBL-producing strains . In the present study, tobramycin and gentamicin, which have been used for several decades, were susceptible against > 70 % of the ESBL-producing isolates, and amikacin and isepamicin were susceptible against all of the identified ESBL-producing isolates. Therefore, empirical antibiotics for children presumably having UTIs should include aminoglycosides considering that UTIs caused by ESBL-producing strains have been increasing. Considering the possibility of having reactive pyuria due to a bacterial infection other than a UTI and urosepsis in febrile children with abnormal urinalysis and urinary microscopic examination results, empirical administration of BLs or BL/BLIs in combination with aminoglycosides and adjustment of antibiotics based on the results of urine culture and antibiotic susceptibility of the identified pathogens seem to be more reasonable than empirical aminoglycoside monotherapy.
Given the retrospective nature of the present study, the long-term outcomes of UTIs caused by ESBL-producing strains could not be determined. Because we could not control the administered antibiotics and none received carbapenem therapy, treatment outcomes between carbapenems and non-carbapenems could not be compared. Risk factors for UTIs due to ESBL-producing strains could not be appropriately evaluated in the present study because of the small number of cases in the ESBL group. Although therapeutic effect of non-carbapenems in UTIs due to ESBL-producing strains may change as the number of these cases is increasing, other recent studies also showed a favourable therapeutic effect of non-carbapenems in UTIs caused by ESBL-producing strains [11, 12, 17–21]. However, further studies including a large number of cases should be necessary to exactly define the effectiveness of non-carbapenems in UTIs due to ESBL-producing strains. The frequencies of APN and VUR may be inaccurate because the DMSA scan and VCUG were not performed universally, but in accordance with the attending physicians’ decisions. In addition, UTIs may be over-diagnosed because most urine samples in the present study were collected using a urine bag. However, the present study examined the data from febrile children with abnormal results on urine dipstick tests or flow cytometric analyses in addition to positive urine cultures. APN based on the results of a DMSA scan was diagnosed in 80.4 % of the total 211 episodes. This rate is higher than rates reported in previous studies [2, 12]; therefore, the number of over-diagnosed UTI episodes in the present study might be small. Furthermore, although childhood UTIs need antibiotic therapy for 7 to 14 days , aminoglycosides can cause treatment duration-related nephrotoxicity and ototoxicity . Although definite nephrotoxicity was not observed in the present study, ototoxicity was not evaluated and serum creatinine levels were not repeatedly tested during aminoglycoside therapy in half of the episodes. Therefore, further studies determining the appropriate duration of aminoglycoside therapy, which guarantees both efficacy and safety should be performed. In the ESBL group, rates of susceptibility to oral amoxicillin/clavulanate and trimethoprim/sulfamethoxazole were 66.7 % and 59.1 %, respectively, while 81.8 % (18/22) of ESBL-producing isolates were susceptible to at least one of these two antibiotics. Therefore, the selection of oral antibiotics for UTIs due to ESBL-producing strains should also be further evaluated.