The present single-center study included a large cohort of 233 female patients with AUC and evaluated the clinical efficacy of CCL in the patients. Several results of the present study deserve attention. First, the present study showed the excellent efficacy of CCL in patients with AUC. The overall cure rate was 94%, and from the perspective of gram staining in the present study, each cure rate of gram-negative pathogens, except for E. coli-ESBL, showed approximately >95%, and other five gram-positive pathogens also showed an acceptable efficacy rate, ranging from 75% to 100%. This is in line with the recent multi-institutional study including 155 Japanese patients with AUC . With respect to the adverse events related to CCL, as previous studies described low incidence of side effects [2, 3], only one patient was excluded in this study due to nausea, which disappeared the next day after CCL discontinuation. Therefore, we believe that CCL is thus effective and tolerable in patients with AUC.
Second, CCL for AUC also had an effect even in patients with resistance to CEZ, as shown in the susceptibility test. In the current study, although 15 (6.3%) patients were revealed to be resistant to CEZ, 14 out of the 15 (93.3%) patients were treated by CCL, which may be explained by the striking pharmacokinetics of CCL [10, 11]. CCL was found to be rapidly absorbed in the gastrointestinal system; thus, its plasma concentration usually peaked within one hour after administration with no CCL detected in the serum at six hours. Then, the principal route of excretion of the drug was the urinary tract; thus, 60%–80% of the drug could be found in the urine. Therefore, its urine concentration might be sufficient for treating most of the pathogens resistant to CEZ, as shown in the in vitro test; this bioavailability is higher than that of the third-generation cephalosporin . Moreover, similarly, it is reasonable to speculate that this high bioavailability would contribute to the acceptable cure rate of 53.3% in patients with E. coli-ESBL in the current study. Although E. coli-ESBL is defined by the susceptibility test in vitro as resistant to almost all kinds of cephalosporin , there have been increasing evidence of positive impact of cephalosporin antibiotics on the pathogen, which supports our finding [14-16]. Cefmetazole (CMZ) in particular has been reported to be comparable with carbapenems as the definitive therapy for E. coli-ESBL in patients with nephritis and even those with bacteremia [15, 16]. However, the diversity of E. coli-ESBL including 300 strains in the world would lead to a variety of results in terms of the effect of CMZ, and no consensus has been reached until now .
Referring to the Japanese Association for Infectious Disease/Japanese Society of Chemotherapy (JAID/JSC) guidelines , CCL is recommended as the second-line treatment for premenopausal women with AUC based on two Japanese nationwide studies, which reported that approximately 10% of gram-positive cocci (GPC) were reported to be resistant to cephalosporins [18, 19]. However, the low prevalence of causative GPC in patients with AUC has been reported for decades. The Japanese nationwide studies reported it as 13.4%. A much lower rate was shown in the present study at 5.5%, consistent with the finding of a large randomized control trial reporting that GPC was found in 25 (3.8%) of the 661 female patients with AUC . Therefore, as long as data on urine culture do not exist at the initial treatment of AUC, and resistance rate of cephalosporins for GPC was calculated to be approximately 10%, the introduction of wide-spectrum antibiotics under the assumption that such GPC resistant to narrower antibiotics may be unnecessary for almost all cases, or rather leading to a shortage of appropriate treatment options for serious infections . Therefore, in the present study, the difference in the overall in vitro resistance rate of 13.8% and overall clinical success rate of 94.0% may be because of the high bioavailability of CCL; the gap between the results of the susceptibility test and clinical outcomes highlights the importance of pharmacokinetics and imperfection of susceptibility test in selecting the appropriate antibiotics . Prospective studies are needed to investigate the association among susceptibility test, pharmacokinetics, and clinical outcomes.
For the last decade, the economical approach has also been highlighted in the choice of appropriate treatment for AUC because of rapidly increasing healthcare costs, which has been a significant issue worldwide . The price of a 250-mg CCL capsule at the time of writing this article costs 48.0 Yen in Japan, whereas a 500-mg LVFX tablet costs 135.6 Yen; thus, one-week therapy of 750-mg CCL is 58.8 Yen more costly than that of LVFX. However, there is no doubt that the indiscriminate use of wide-spectrum antibiotics has been accepted as a definitive risk factor for the emergence of MDR pathogens , which have been reported to potentially worsen the severity of UTIs compared with pathogens without the resistance . In other words, MDR would contribute to the high economic burden to the healthcare system due to frequent laboratory examinations, longer length of hospital stay, and administration of broad-spectrum antibiotics for worse infections . A multinational observational study including 20 hospitals in eight countries showed that the presence of MDR was related to a higher cost . In a report by the Canadian Committee on Antibiotic Resistance focusing on hospital-associated infections, especially methicillin resistant Staphylococcus aureus, antimicrobial resistance adds $8.7 to $13.9 million more indirect costs compared to infections without drug resistance . In short, this economical concern supports the introduction of relatively narrow-spectrum antibiotics in patients with AUC in the long run. Additionally, duration of antibiotic treatment may also play an important role in both the economic status and the emergence of MDR pathogens . In fact, studies showing the feasibility of a single three-gram dose of FOM in patients with AUC flourished recently for the reduction of economic burden and the prevention of MDR pathogens [28, 29]. To date, an interventional clinical trial evaluating short-term antibiotic treatment for urinary tract infection is ongoing (NCT03256825) .
Some limitations need to be considered when interpreting the results of our study. First, the study was retrospective in nature and relied on previously collected data. Second, although duration of CCL was not uniform in each case, all patients were treated with CCL for five to seven days. Therefore, the slight difference of two days at most in the duration of the treatment would not significantly affect our result. Third, taking regional differences in antimicrobial resistance into consideration, the results of the present study may not be applicable to all institutions. However, as high bioavailability and narrower spectrum of CCL remain steady worldwide and for all time periods, CCL as the treatment of AUC is worthy of consideration in terms of the striking basic feature and prevention of MDR pathogens. Fourth, in spite of the lack of the data on CCL’s susceptibility due to the guideline of the CLSI Document M100-S22,
CEZ, which had as the same spectrum as CCL mainly except for Haemophilus influenzae, was tested in all patients. Hence, we believe that the current analysis using susceptibility test of CEZ is reliable to investigate the efficacy of CCL in patients with AUC.