Susceptibility testing of extended-spectrum-β-lactamase (ESBL)- producing Enterobacteriaceae against oral antimicrobials, including fosfomycin and mecillinam

Julie A Creighton

Abstract spectrum β-lactamase (ESBL)-producing Enterobacteriaceae Background (3,4). At Canterbury Health Laboratories (CHL) in 2004 there During the last decade in New Zealand there has been a were only 5 patients with ESBL-producing Enterobacteriaceae dramatic increase in the isolation rate of extended spectrum β- isolated, and all strains were E.coli. By 2012 the number of lactamase (ESBL)-producing Enterobacteriaceae, particularly patients with ESBL-producing Enterobacteriaceae had climbed causing urinary tract infections (UTI) from patients residing in to nearly 200 patients, with eleven different species identified. the community. These isolates are frequently co-resistant to This number had already been eclipsed in the first 8 months of many oral antimicrobials. In order to treat the patient in an 2013. Of most concern is the increasing prevalence of ESBL- ambulatory care setting, avoid costly and inconvenient IV producing Escherichia coli, causing urinary tract infections administered antibiotics and limit the use of carbapenems, both (UTIs) in community based patients: a trend which has been the patient and the health system could benefit from more oral recognised globally (5-7). treatment options. ESBL-producing Enterobacteriaceae, particularly E.coli with Aim CTX-M-15 type ESBLs, often associated with sequence type The aim of this study was to gather local data on the in-vitro 131 (ST131), tend to be co-resistant to several antibiotic susceptibilities of ESBL-producing Enterobacteriaceae from our classes in addition to the expanded spectrum β-lactam institution, against two potentially useful oral antibiotics: antibiotics (8,9). The most recent study by the Institute of fosfomycin and mecillinam. Environmental Science and Research showed a predominance Methods of CTX-M-15 in New Zealand (10). Limited treatment options for Routine susceptibilities were performed by BD PhoenixTM, with these multi-resistant isolates have forced the use of fosfomycin and mecillinam performed by the Clinical and carbapenems, particularly for serious infections, often resulting Laboratory Standards Institute (CLSI) disk diffusion methods. A in the emergence of carbapenemase producing isolates – at an total of 109 non-duplicate ESBL-producing Enterobacteriaceae alarming rate in some countries (11). Patients in primary care, isolates, from 102 patients were included in this study. especially those with uncomplicated infections such as simple cystitis, could benefit from the availability of an effective oral Results agent, rather than costly and inconvenient IV administered Fosfomycin was active against 77/78 (98.7%) Escherichia coli antibiotics. In turn, the health system would benefit from and 19/21 (90.5%) Klebsiella pneumoniae, with an overall reduced hospital admissions and other associated health costs. susceptibility of 96.3% against all isolates tested. Mecillinam was also highly active, with 90.8% of all isolates classified as Fosfomycin and mecillinam have been used extensively for the susceptible, being particularly effective against E.coli 74/78 treatment of UTIs, mainly in Scandinavia and Europe, for (94.9%) and K.pneumoniae 20/21 (95.2%). Nitrofurantoin was decades while resistance rates remain low (12). Neither drug is active against 72/78 E.coli (92.3%) but had diminished currently licensed or funded in New Zealand. Fosfomycin susceptibility against the other isolates tested. The remaining tromethamine is the soluble salt form of fosfomycin, suitable for oral agents: augmentin, ciprofloxacin, trimethoprim, and oral administration. High concentrations of fosfomycin are trimethoprim/sulphamethoxazole, performed poorly against the achieved in the urine as the drug is excreted unchanged. isolates tested. Of the parenterally administered antimicrobials, Bactericidal action is achieved by interference of peptidoglycan gentamicin was only active in 50.5% of the isolates studied, but biosynthesis: an early stage of bacterial cell wall development all isolates were susceptible to meropenem. (13). Fosfomycin has broad spectrum activity against a range of Gram positive and Gram negative organisms, although it not as Conclusions useful against Pseudomonas aeruginosa and Acinetobacter Fosfomycin and mecillinam emerged as highly effective oral baumanii (14). Although fosfomycin is only approved for the antimicrobials in-vitro against these multidrug resistant treatment of uncomplicated acute cystitis against susceptible pathogens and may be considered as useful oral treatment strains of E.coli and Enterococcus faecalis, recent reviews have options, particularly for high risk patients with community found it to be a viable option for the treatment of infections from acquired UTIs. a variety of body sites (15,16). Fosfomycin di-sodium salt is the Key words parenteral version. Enterobacteriaceae, ESBL, urinary tract infection, fosfomycin, Pivmecillinam is the prodrug which releases the active agent mecillinam mecillinam when absorbed. After oral administration mecillinam is rapidly absorbed, achieving peak plasma concentrations after N Z J Med Lab Sci 2014 ; 68 :  1 hour. In addition, much of the drug is excreted unchanged in the urine within the first 6 hours. Mecillinam is a β-lactam which Introduction uniquely binds to Gram negative penicillin binding protein 2 New Zealand is a country with relatively low rates of resistant (PBP-2), resulting in cell wall distortion, lysis and cell death clinical pathogens (1,2). However over the last decade there (17). The main indication of use for mecillinam has also been has been a dramatic increase in the isolation rate of extended for the treatment of acute uncomplicated cystitis.

NZ J Med Lab Science 2014 19 The aim of this study was to gather local data on the in-vitro Phoenix panels were controlled with E.coli ATCC 25922, E.coli susceptibilities of ESBL-producing Enterobacteriaceae from our ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. institution, against two potentially useful oral antibiotics: Susceptibility testing for fosfomycin and mecillinam was fosfomycin and mecillinam, and to compare the results with performed by disk diffusion using CLSI guidelines. Zone other routinely tested oral agents. interpretations were expanded to include all bacterial species tested. Fosfomycin disks (200μg) containing 50μg of glucose-6- Methods and materials phosphate and mecillinam (10 μg) were used (Oxoid, ThermoFisher NZ). Disks were controlled with E.coli ATCC Patient population 25922. For the purposes of this study, any intermediate The Canterbury District Health Board (CDHB) oversees publicly susceptibility result was considered as resistant. ESBL funded health services to a wide geographical area, with a production was confirmed by a modification of the double disk population in excess of 500,000. The largest of its fourteen synergy test of Jarlier (1988), incorporating ceftriaxone, hospitals is Christchurch Hospital, a 650 bed tertiary, teaching aztreonam, ceftazidime and cefepime around a central and research hospital. Canterbury Health Laboratories (CHL) augmentin disk (19). provides laboratory testing services to the CDHB, private medical centres and national referring laboratories. During the Results study period the Bacteriology Department provided an A total of 109 non duplicate isolates, from 102 patients were integrated processing service for all community urine samples included in this study. The patients consisted of 73 (71.6%) received by MedLab South Ltd (who were sharing CHL facilities female and 29 (28.4%) male patients, and ranged in age from 6 following the destruction of their own laboratory in the 22 weeks to 100 years old, with the median being 65.5 years. The February 2011 earthquake). majority of isolates were recovered from urine [88 (80.7%)], with a further 13 (11.9%) from wound swabs, 4 (3.7%) from blood Bacterial isolates culture and 4 (3.7%) from screening swabs. Two of the patients ESBL-producing Enterobacteriaceae isolates were collected at with septicaemia also had a concurrent UTI and a third patient CHL from July to December 2011 and stored at -80oC in was attending urology clinics. The differences in patient PROTECT cryopreservative fluid. Fosfomycin and mecillinam demographics most likely reflect the well recognised higher susceptibilities were retrospectively performed on non duplicate prevalence rates of UTIs in elderly women. Seventy four patient isolates. During the study period a total of 173 ESBL- (72.5%) patients were community based with only 28 (27.5%) producing isolates, from 112 patients, representing 3.45% of all classified as hospitalised. Patients were considered to be Enterobacteriaceae tested, were processed for identification community based if the sample was taken at a community and susceptibility testing using BD PhoenixTM (Phoenix) health care service, from an outpatient clinic, from the Automated Microbiology System (Becton Dickinson Diagnostic emergency department, or the patient had been admitted for Systems, Australia). Results were stored on BD EpiCenter less than 48 hours. However, it was noted that many of the software database V6.10A. Identification of isolates other than patients had previous hospital admissions in the preceding 3-6 E.coli, Klebsiella oxytoca or Klebsiella pneumoniae was months, so a hospital acquired infection could not be confirmed with Bruker MALDI-TOF, using Biotyper FlexControl completely ruled out. 3.0 software (Science Directions Limited, New Zealand). A total of 109 non duplicate isolates, from 102 patients were available The percent susceptible results for all oral antimicrobials tested for inclusion in the study. The isolates consisted of E.coli 78 are summarised in Table 1. Parenteral antibiotics gentamicin (71.6%), Klebsiella pneumoniae 21 (19.3%), Klebsiella oxytoca and meropenem are also listed for comparison purposes. 2 (1.8%), Enterobacter cloacae 3 (1.8%), Citrobacter farmeri 2 Fosfomycin and mecillinam were the most effective oral (1.8%), Citrobacter brakaii 1 (0.9%), Rauoltella ornitholytica 1 antimicrobials in-vitro, compared to other oral agents tested. (0.9%), and Serratia fonticola 1 (0.9%). The susceptibility of fosfomycin against all isolates tested was 96.3%, with E.coli showing the highest susceptibility rate of Antimicrobial susceptibility testing 98.7% and 19/21 (90.5%) K.pneumoniae isolates susceptible. Routine susceptibility testing was performed with BD Phoenix, Mecillinam also performed well, with 99/109 (90.8%) of all using either NMIC/ID-75 (448087) or NMIC/ID-95 (448783) isolates classified as susceptible and it was particularly effective combo panels. Interpretation criteria for susceptibility results against 74/78 (94.9%) E.coli and 20/21 (95.2%) K.pneumoniae. were applied using the Clinical and Laboratory Standards Nitrofurantoin was active against 72/78 (92.3%) E.coli but had Institute (CLSI) guidelines and Phoenix BDXpert rules (18). diminished susceptibility against the other isolates tested.

Table 1. Susceptibility results of ESBL-producing strains to fosfomycin, mecillinam and other oral agents

NZ J Med Lab Science 2014 20 The remaining oral agents: augmentin, ciprofloxacin, to a resurgence of fosfomycin use in the community setting trimethoprim, and trimethoprim/sulphamethoxazole, performed (30). It is also possible, however, that the spike in fosfomycin poorly against the isolates tested, with overall susceptibilities resistance was aligned with a local clonal spread of CTX-M-15- ranging from as little as 22.9% for trimethoprim to 33.9% for producing E.coli ST131. A multicenter evaluation in Japan of ciprofloxacin. ESBL-carrying plasmids often contain other 192 CTX-M-producing E.coli found some transferable resistance mechanisms, making the isolates more likely to be fosfomycin resistance enzymes co-existing on the CTX-M multi-resistant, particularly to quinolones such as norfloxacin enzyme plasmid, indicating that dual transmission could occur. and ciprofloxacin. This co-resistance was demonstrated in our However, fosfomycin has been used for many years in Japan, study by the low level of susceptibility to ciprofloxacin by both and the overall activity of fosfomycin was 96.4% (26). E.coli and K.pneumoniae (29.5% and 28.6% respectively). Resistance to fosfomycin was recently extensively reviewed by Furthermore, isolates that were resistant to ciprofloxacin were Karageorgopoulos et al. (31). They concluded that fosfomycin also more likely to be resistant to other antimicrobials including appeared to be a reliable agent for the treatment of UTIs, due to aminoglycosides. Results are summarised in Table 2. high levels of drug excreted into urine, together with an acidic urine environment and low level of biological fitness of Table 2. Percent of resistance to other antimicrobials as fosfomycin-resistant mutants. They cautioned against its use as determined by ciprofloxacin resistance a sole agent in serious infections and against organisms other than E.coli. Although mecillinam has performed well in in-vitro studies against ESBL-producing Enterobacteriaceae, authors have warned against its use as mono therapy due to the apparent effect of high bacterial inoculum, and hence high concentrations of β-lactamase production, which increases the MIC level of mecillinam (32,33). Thomas et al. and Brenwald et al. both suggest that mecillinam would be more effective if given in combination with a β-lactam inhibitor such as clavulanate. Similarly, in a more recent study from Greece, mecillinam was found to be highly active in-vitro against 47 of 48 (97.9%) ESBL -producing E.coli uropathogens, with the authors also Of the parenterally administered antimicrobials, gentamicin, a suggesting the administration of a β-lactam inhibitor in common empirical choice in a patient with suspected urosepsis, combination with mecillinam for more effective treatment (34). was only active in 50.5% of the isolates studied, but all isolates were susceptible to meropenem. On a side note, we have also found fosfomycin to be a useful agent against Enterococcus faecalis and some E.faecium. In a Discussion separate in-house study, an evaluation of fosfomycin against Urinary tract infections are one of the most common bacterial 100 consecutive Enterococci isolated from urine (consisting of infections in both hospital and community settings, with E.coli 91 E.faecalis and 9 E.faecium), showed excellent activity of remaining the most predominant uropathogen. It is a fosfomycin against E.faecalis (97.8% susceptible), but less concerning trend that ESBL-producing E.coli strains have activity against E.faecium (63.6% susceptible). These gained such a foothold, especially in community acquired organisms can cause UTI in elderly patients, many of whom infections. Many UTIs can progress to serious illnesses can have limited treatment options due comorbidities such as including bacteraemia: in which there is a recognised higher renal insufficiency or penicillin allergy, perhaps ruling out the mortality rate for patients who have multidrug resistant isolates use of nitrofurantoin or ampicillin respectively. coupled with a delay in receiving appropriate antibiotic therapy (20-22). In this study the predominant organism/source group The poor results of other antimicrobials in this study highlighted was E.coli isolated from urine. While there were only four the limited oral treatment choices against ESBLs. Nitrofurantoin isolates recovered from blood culture during the study period, has been used for the treatment of simple cystitis and for three of the four patients had either a concurrent UTI or urology prophylaxis for more than 50 years, and it did show high rates comorbidity, and we have seen an increasing prevalence of of susceptibility against E.coli. However, it was not as effective patients infected with ESBL-producing E.coli septicaemia over against K.pneumoniae and is not suitable for the treatment of the last 12 months at our institution (data not shown). members of the Proteus/Providencia/Morganella genera. Nitrofurantoin is contraindicated in patients with renal failure – Enterobacteriaceae are spread by hand carriage, contaminated which can be common in elderly patients; and its longer dosing food and water. Risk factors for acquisition of ESBL-producing regimen may have implications for patient noncompliance. The Enterobacteriaceae include previous exposure to antibiotics, poor performance of ciprofloxacin, trimethoprim and previous health care intervention or resident of a long term care trimethoprim/sulphamethoxazole do not make these antibiotics facility, or urinary catheter use (22,23). In New Zealand, a preferred choice, especially not for empirical treatment in Freeman et al. found that travel to the Indian subcontinent was patients with high risk factors of ESBL infections. a risk factor for community-onset UTI (24). A recent study in Sweden showed a high rate of faecal flora colonisation with Although susceptibility against parenteral meropenem was ESBL-producing Enterobacteriaceae following international 100%, it would seem prudent to conserve the use of travel (25). Destinations of highest risk included the Indian carbapenems to selective cases only, or to limit their use to an subcontinent and Asia, with travellers being unlucky enough to initial 24 hour empirical treatment, changing to an oral agent suffer a gastrointestinal illness and those aged ≥65 years being once the results of laboratory susceptibility testing are known. the most vulnerable. Further investigation on our study isolates could include the In this study we have found both fosfomycin and mecillinam to analysis of ESBL enzyme type, phylogenic group or sequence have a high in-vitro activity against a range of ESBL-producing type, to determine any clonal relationship or association with Enterobacteriaceae, especially against E.coli. These results are multidrug resistance in our population. similar to those found in other studies (13,26-28). A recent study in Turkey of 52 patients with UTI showed a successful Conclusions clinical response at follow up in 49 patients, after 3 doses of With the prevalence rate of ESBL-producing fosfomycin (29). Notably many of these patients had Enterobacteriaceae continuing to climb, there is a need complicated infections. Of some concern is the study by Oteo et to seek suitable alternative treatment options to al. that showed increasing fosfomycin resistance, possibly due carbapenems and other IV administered drugs.

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