Cefditoren: Comparative efficacy with other antimicrobials and risk factors for resistance in clinical isolates causing UTIs in outpatients

Urinary tract infections (UTIs) represent the most frequent bacterial infection encountered in the community setting being caused in their vast majority by members of the family of Enterobacteriaceae [1, 2]. Recently, antimicrobial resistance among uropathogens causing uncomplicated cystitis has increased, as well as the recognition of the importance of the ecological adverse effects of antimicrobial therapy (collateral damage) [2‐6]. Effective empirical therapy must be based on susceptibility profiles of the uropathogens, therefore surveillance studies are important tools to guide antibiotic selection [3]. However, in a “real-life” scenario, empirical therapy is most likely to be prescribed either without a urine culture or before the results become available. A recognized drawback of many published studies is the inclusion of strains collected from hospitals, thus limiting surveillance in populations with easy access to tertiary centers even as outpatients. Additionally, in several laboratory-based studies no distinction could be safely made between complicated and uncomplicated UTIs; that same is true for purely “community” infections and nosocomial or healthcare-associated infections that are being treated in the community [3, 6].

Cefditoren is a third generation oral cephalosporin with a broad spectrum of activity comprising Gram-positive and Gram-negative bacterial species [7, 8]. After an oral 400-mg single dose, the mean concentrations in urine are 186.5 mg/L at 2 to 4 h and 12.7 mg/L at 8 to 12 h; available data have shown its potential to be used in the treatment of UTIs [9]. Cefditoren retained activity against some clinically significant pathogens harboring β-lactamase enzymes. In a study by Sevillano et al., cefditoren exhibited bactericidal activity (>4 log10 reduction) against TEM-1 (penicillinase production or hyperproduction) and TEM-34 derivative (IRT-6) isolates from 4 to 24 h. However, against ESBL-producing strains, no sustained bactericidal activity was demonstrated: against strains harboring the SHV determinant bactericidal activity was achieved only in the 6- to 8-h whereas against the TEM-116 strain a 2-log10 regrowth occurred from 12 to 24 h [9].

The present study was conducted in order to investigate a possible role of cefditoren in the treatment of UTIs treated in the outpatient setting. Given the expanded spectrum of cefditoren, strains of uncomplicated as well as complicated UTIs were included.

Cefditoren is a rapidly bactericidal antibiotic as demonstrated by previous in vitro studies [7‐9]. Clinical data on its use in urinary tract infections are currently lacking whereas microbiological data against uropathogens are scarce [13, 14]. Currently there are not established susceptibility breakpoints for cefditoren against Gram-negative rods; for this reason we used as tentative breakpoint of susceptibility the threshold of ≤1 mg/L, according to recently published evidence as well as the most recently proposed clinical breakpoints by EUCAST, setting susceptibility of the 3^rd generation cephalosporins against Enterobacteriaceae at ≤1 mg/L [13‐15].

This is among the first studies which report antimicrobial susceptibility data of cefditoren in comparison to other commonly used antimicrobials from a large population-based surveillance study of outpatients with UTIs. According to the data presented herein, cefditoren had the lowest rate of resistance among the tested orally-available antibiotics after fosfomycin- which is not marketed in our country in the last 10 years. In vitro activity of cefditoren in our population of uropathogens was in accordance with data from Spain [14], whereas a study from Korea reported higher MIC90 (16 mg/L) compared to our data (0.5 mg/L) [13]. As reported previously, cefditoren was not active against ESBL-producing strains [9, 13], however its activity against TEM/hyperproducers was more variable compared to previous reports although the majority of the strains (63.6%) were inhibited in clinically achievable concentrations [9].

Resistance to cefditoren was associated in our study with resistance to nalidixic acid- and resistance to ciprofloxacin. These observations are in accordance with data from Korea, a country with high levels resistance to ciprofloxacin among uropathogens (30.3% in the study by Ko et al.) [13]. On the other hand, no association of resistance to cefditoren was found with mecillinam, fosfomycin, nitrofurantoin and aminoglycosides, indicating that their use as first line treatment options in community acquired UTIs as recommended by local guidelines would not affect the susceptibility of cefditoren. This observation was also confirmed in a recent large European multicenter study [17]. In both ECO⋅SENS studies, resistance to any antimicrobial studied was markedly higher in isolates resistant to any other antimicrobial, irrespective of whether or not the antibiotics belonged to the same class [17, 18]. This has been partially attributed to a pool of resistance in aminopenicillins, folate inhibitors and fluoroquinolones among E.coli in the community and the long established plasmid- mediated resistance to ampicillin and to trimethoprim/ sulfamethoxazole [17].

The accompanying questionnaire enabled us to classify UTIs as “complicated” or “uncomplicated” and to elucidate risk factors for resistance to cefditoren beyond the well-recognized use of an antibiotic of the same class in the previous 15 days-3 months [6, 19, 20]. The presence of fever indicating complicated UTI, previous use of a cephalosporin or a fixed combination of clavulanate or a quinolone for any reason and recent history of UTI in the last two weeks and three months were elucidated in the univariate analysis as risk factors for cefditoren resistance; however only the history of UTI retained statistical significance in the multivariate analysis, with an Odds Ratio of 39.65 for the preceding two weeks and 22.67 for the preceding two months. Cephalosporins are not currently indicated as first line antibiotics in acute uncomplicated cystitis, not only because other classes of antibiotics provide more convenient schemes of treatment, but also for epidemiological reasons [3, 21]. However, an emerging trend of resistance in cotrimoxazole is documented in several regions [2, 6, 13, 14]. IDSA and several other national guidelines advise against the empirical use of cotrimoxazole in settings with known resistance above the threshold of 20% [3, 20, 21]. In our country, data acquired through a big population-based surveillance revealed a resistance rate of 19.2% for AUC E. coli strains [10]. According to these recently published data from our group, the most potent in vitro antibiotics available for oral use in AUC in our community were fosfomycin, mecillinam, cefuroxime axetil, ciprofloxacin and amoxicillin/clavulanic acid with resistance rates of 1.6%, 3.4%,1.7%, 2.2% and 5.2% respectively. Interestingly, in this study cefditoren and oral cefuroxime displayed co-resistance only in isolates harboring ESBL or MBL mechanism of resistance (Table 7), although their overall susceptibility rates in the studied population were comparable (97.1% versus 94.1% respectively). Currently available data do not permit to adopt for cefuroxime the same risk factors elucidated for cefditoren but it is important to note that compared to other countries, cephalosporins of 2nd and 3rd generation and amoxicillin/clavulanic acid retain susceptibility among common uropathogens in UTIs in our community [2, 10, 17, 18]. As mentioned above, fosfomycin trometamol is no longer available in the Greek market. On the other side, collateral damage with the use of quinolones as well an alarming percentage of first step mutants among uropathogens in both uncomplicated (6%) and complicated infections (12.7%) [10] has prompted severe restriction policies against their indiscriminate use in the Greek community; this is also true in many countries [22, 23]. Furthermore the between the ECO⋅SENS I (1999–2000) and ECO⋅SENS II (2007–2008) studies ciprofloxacin resistance almost doubled in Greece [17, 18], mandating quinolone sparing policies in our community.

A certain weakness of this study is the lack of clinical data for almost one third of the studied isolates. However the lack of significant differences in resistance rates against all antibiotics tested between the populations with and without clinical information, as well as the large and representative sample of our study argues in favor of an extended applicability of the conclusions in our community. Furthermore the addition of a pool of isolates without clinical data allowed for a simulation of real life treatment scenario of an outpatient with UTI. Another possible weakness is the lack of clinical therapeutic data, which would enable us to detect therapeutic failure in the community with currently used agents, but this was beyond the design and the scope of the current study.

Certainly no strong argument exists for the use of cefditoren as first line option in acute uncomplicated UTIs since other treatment options mentioned above retain good activity. However many UTIs treated in the community setting are not episodes of acute uncomplicated cystitis mandating concentrations in the upper urinary tract; patients are often pretreated with other first-line classes of antibiotics; apart from recent antibiotic use patients with complicated urinary tract infections treated as outpatients frequently bear risk factors for resistance to multiple classes of antibiotics [3, 20]. Cefditoren could represent a treatment option in several cases among the above-mentioned patient/risk groups. According to our results, cefditoren could also be used in our community as a switch to oral treatment of patients with UTIs and risk factors for resistance to 1^st line options, initially treated with a parenteral antibiotic. A strong argument for the selection of cefditoren could be the lack of cross-resistance with aminoglycosides, mecillinam, nitrofurantoin and fosfomycin.

In summary, cefditoren was the most potent in vitro antibiotic available for oral use in our country, against all three major pathogens causing UTIs in the outpatient setting. A potential was demonstrated for its use as empirical treatment in outpatients with no recent history of UTI, as an alternative to first line antimicrobials or in patients with risk factors for resistance to currently indicated first treatment options. Clinical studies are warranted to clearly define its possible role in the treatment of UTIs in outpatients.