Pivmecillinam; an anbioc from the past, for the future: A retrospecve mulcentre observaonal study of comparave urine suscepbilies in a healthcare network in the United Kingdom. Hassan Farah1,Luke SP Moore1,2, Mark J Gilchrist1,2, James Hatcher1. 1 Imperial College London (UK) Imperial College Healthcare NHS Trust, London (UK) ,2 NIHR Health Protection Research Unit in Antimicrobial Resistance and Healthcare Associated Infection Introducon Methods Results Discussion

Lower urinary tract infecons comprise a A retrospecve study of urine suscepbility data was conducted 100,00% A large percentage of lower urinary tract significant amount of prescribed anbiocs in between March 2012 to February 2015 obtained from our instuon’s 90.7% 88.3% infecons (LUTI) are caused by E. coli, and 90,00% 87.2% 85.9% both primary and secondary care. Naonal large centralised microbiology laboratory that services a large populaon 84.7% mecillinam’s high suscepbility rate towards E. primary care data shows a high rate of resistance of north west London. From this data, only urine isolates that were 80,00% coli and other common uropathogens makes the to common oral anbiocs used to treat urinary regarded by roune laboratory standards to be significant urinary 70,00% empirical therapeuc use of mecillinam to treat 1 tract infecons. Resistance to trimethoprim is pathogens were included. 64.3% uncomplicated UTIs a welcome addion to the over a third of tested isolates and amoxicillin is 60,00% anbioc armamentarium. Although it has a no longer recommended unless sensivity In our instuon, the first line roune urine suscepbility tesng consists 50,00% high resistant rate to Proteus sp., it has proven. Empiric primary care guidelines for the of co-amoxiclav, nitrofurantoin, trimethoprim, gentamicin, ciprofloxacin fortunately only made up 4.4% of all our isolates. 40,00% treatment of urinary tract infecons have and cephalexin. Mecillinam suscepbility tesng was only performed as recently been updated to include pivmecillinam a second line anbioc when there was a resistance of ≥3 first line 30,00% With mecillinam being able to withstand

2 as a first line treatment opon in adults. anbiocs or if it had suspected extended-spectrum beta-lactamase hydrolysis by beta-lactamases present in Gra- 20,00% (ESBL) acvity. Suscepbility tesng was determined using disc diffusion negave species due to their low affinity to this

10,00% Pivmecillinam, an oral anbioc and the prodrug methodology recommended by the European Commiee on penicillin; and having a different binding site as of mecillinam, is an extended-spectrum penicillin Anmicrobial Suscepbility Tesng (EUCAST). All urine pathogens were to other beta-lactams wherein it binds 0,00% Mecillinam Nitrofurantoin Augmenn Cephalexin Ciprofloxacin Trimethoprim that is acve against Gram-negave bacteria. It disnguished using Oxoid® Brilliance UTI Clarity agar (chromogenic preferenally to pencillin-binding protein 2 has been available for years, but only extensively media), however, if it was a coliform resistant to ≥3 first line anbiocs Chart 1. Visual comparison of mecillinam sensivity percenle to other roune instead of proteins 1a, 1b or 3; it has the prescribed in Scandinavian countries3, and has or possibly an ESBL, the isolate was idenfied using MALDI-ToF (Bruker oral anbiocs. potenal to have greater therapeuc acvity not been rounely prescribed in the United Diagnoscs®). Interrogaon of the local laboratory informaon towards Enterobacteriacae uropathogens Kingdom. There is a paucity of reliable sensivity management system (LIMS) extracted urine isolate data, whereby Of the 5831 isolates that were tested against mecillinam, 3761 (64.5%) compared to other beta-lactam anbiocs2. data on pivmecillinam in the UK. In 2000, a study Microso Excel® was used to perform descripve analysis. were E. coli, 721 (12.4%) were Klebsiella species, 629 (10.8%) were evaluang anbioc suscepbilies to Enterobacter species, 255 (4.4%) were Proteus species, 143 (2.5%) were Our results suggest that a large percentage of community-acquired urinary tract pathogens in Results Citrobacter species, 137 (1.9%) were Serraa species, and the rest of the urinary tract Gram-negave Enterobacteriacae Europe showed a total resistance rate of 1.2% to isolates (5.5%) were other Gram-negave organisms reported as coliform are suscepble to mecillinam, and therefore 2478 isolates of Escherichia coli from seventeen A total of 437,868 urine samples were received between March 2012 to species. Of these organisms, mecillinam had the greatest acvity against supports empirical treatment of community- countries. In this study 180 of these isolates were February 2015, of which, 50,755 (11.5%) cultured pure bacterial growth. E. coli, Enterobacter species, and Citrobacter species, with its weakest acquired LUTI. Compared to all the other first line from the UK with a 1.7 % resistance4,5,6. Aer the exclusion of non-Enterobactericae, it was found that of 5831 acvity towards Proteus species as demonstrated in Table 2. oral agents tested, mecillinam has demonstrated bacterial isolates tested against mecillinam, 5290 (90.7%) of these the highest rate of suscepbility for pathogenic With the potenal rise in pivmecillinam use, and isolates were suscepble. Comparison to other oral anbiocs showed urinary tract Gram-negave organisms. to address this paucity in suscepbility data, we rates of suscepbility of 88.3% nitrofurantoin (34489/39068); 87.2% co- Organism Number of isolates Percentage of performed a retrospecve mulcentre amoxiclav (34046/39059); 85.9% cephalexin (33597/39116); 84.7% Mecillinam Mecillinam mecillinam observaonal study to invesgate the ciprofloxacin (33137/39114) and 64% trimethoprim (25182/39151) as resistant sensive sensive Conclusions suscepbility of community acquired urinary illustrated in Table 1 and Graph 1. isolates isolates Total isolates tract pathogens to mecillinam compared to other Mecillinam resistance of less than ten percent in Escherichia coli 178 3583 3761 95.3% commonly prescribed anbiocs. Percentag our local populaon reassures clinicians who Anbioc Resistant Sensive Grand Total e Sensive Klebsiella sp. 172 549 721 76.1% prescribe pivmecillinam. Reports on mecillinam References Mecillinam 541 5290 5831 90.7% resistance mechanisms from Scandinavia need to 1. English surveillance programme for anmicrobial ulisaon and Enterobacter sp. 26 603 629 95.9% be integrated into the UK reference laboratory resistance (ESPAUR) 2010 to 2014. Public Health England. Report Nitrofurantoin 4579 34489 39068 88.3% 2015. www.gov.uk [accessed 23rd March 2016] Proteus sp. 100 155 255 60.8% tesng algorithms so potenal clonal spread of 2. Management of Infecon Guidance for Primary Care. Guidance by Augmenn 5013 34046 39059 87.2% th resistance can be detected. Public Health England. July 2015. www.gov.uk [accessed 29 Cephalexin 5519 33597 39116 85.9% Coliform sp. 33 152 185 85.6% November 2015] Ciprofloxacin 5977 33137 39114 84.7% 3. Corporaon, H.P et al. Suscepbility of community gram-negave The low side effect profile including Clostridium urinary tract isolates to Mecillinam and other oral agents, Trimethoprim 13969 25182 39151 64.3% Citrobacter sp. 7 136 143 95.1% 2012,Canadian Journal of Infecous Diseases; 12 (5), 289-292. difficile disease risk in elderly populaons make Grand Total 35057 160451 195508 82.1% 4. Kahlmeter G; ECO.SENS. An internaonal survey of the anmicrobial Serraa sp. 25 112 137 81.8% pivmecillinam an aracve anbioc opon. suscepbility of pathogens from uncomplicated urinary tract infecons: the ECO.SENS Project. J Anmicrob Chemother. 2003 Jan; Table 1. Percentage of sensive suscepbilies for mecillinam in comparison to Grand Total 541 5290 5831 90.7% Increased usage will undoubtedly drive 51(1):69-76 other roune oral opons. Table 2. Community-acquired Gram-negave uropathogens in vitro suscepbility resistance and robust surveillance is essenal to 5. Kahlmeter G. Prevalence and anmicrobial suscepbility of pathogens

in uncomplicated cyss in Europe. The ECO.SENS study. Int J to mecillinam. monitor unintended consequences. Prospecve

Anmicrob Agents. 2003 Oct;22 Suppl 2:49-52 first line suscepbility tesng is essenal to 6. Kahlmeter G, Pulsen H. Anmicrobial suscepbility of Escherichia coli from community-acquired urinary tract infecons in Europe: the inform future anbioc prescribing for LUTI.

ECO·SENS study revisited. Int J Anmicrob Agents. 2012;39(1):45-51.

Author contact: [email protected]. Acknowledgements: Microbiology department at Imperial College London.