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. 2024 May 24;11(6):ofae296. doi: 10.1093/ofid/ofae296

Review of the In Vitro Microbiological Activity of Mecillinam Against Common Uropathogens in Uncomplicated Urinary Tract Infection: Focus on Resistant Pathogens

Thomas P Lodise 1,✉, Keith S Kaye 2, Anne Santerre Henriksen 3, Gunnar Kahlmeter 4,2
PMCID: PMC11167674  PMID: 38868308

Abstract

Antimicrobial resistance in uropathogens commonly causing urinary tract infections (UTIs) is a growing problem internationally. Pivmecillinam, the oral prodrug of mecillinam, has been used for over 40 years, primarily in Northern Europe and Canada. It is recommended in several countries as a first-line agent for the treatment of uncomplicated UTIs (uUTIs) and is now approved in the United States. We performed a structured literature search to review the available evidence on susceptibility of common uUTI-causing uropathogens to mecillinam. Among 38 studies included in this literature review, susceptibility rates for Escherichia coli to mecillinam—including resistant phenotypes such as extended-spectrum β-lactamase–producing E. coli—exceed 90% in most studies. High rates of susceptibility were also reported among many other uropathogens including Klebsiella spp., Enterobacter spp., and Citrobacter spp. In the current prescribing climate within the United States, pivmecillinam represents a viable first-line treatment option for patients with uUTI.

Keywords: Enterobacterales, ESBL, mecillinam, resistance, uncomplicated urinary tract infection

Pivmecillinam, used for >40 years to treat uncomplicated urinary tract infections, is supported by a wealth of microbiological data. Common uropathogens are highly susceptible to mecillinam at current susceptibility breakpoints, also in the face of the most common β-lactam resistance mechanisms.

Urinary tract infections (UTIs) are the most common bacterial infection in the United States and elsewhere, and Escherichia coli is the most common pathogen [1]. Although UTIs can be associated with serious illness [2], the majority of cases are considered uncomplicated UTI (uUTI) [3]. These predominantly affect adult women, in whom lifetime incidence is 50%–60% [1]. Aside from a peak in young women in their teens and early 20s (around one-fifth of whom experience a UTI annually [4]), the prevalence of UTIs increases with age [1]. It has been estimated that 150 million UTIs occur worldwide each year and that the associated societal costs (in 2015, including health care costs and time missed from work) in the United States alone are ∼$3.5 billion per year [2].

One major challenge associated with the management of uUTIs is the increasing proportion of infections caused by antibiotic-resistant gram-negative bacteria [5, 6]. It is estimated that one-fifth of adult outpatients with a uUTI will receive empiric treatment with an antibiotic to which the causative uropathogen is resistant [7]. Resistance to both fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX) among E. coli has been reported to exceed 20% in most regions of the United States [7–9]. The prevalence of extended-spectrum β-lactamase–producing Enterobacterales (ESBL Enterobacterales) in the community setting is also on the rise. In the United States, the percentage of isolates with an ESBL-producing phenotype increased by 30% between 2011 and 2020 (from 6.5% to 9.4%) [10]. Consequently, there is an urgent need to ensure prudent use of currently available antimicrobials, including those with low resistance profiles.

Pivmecillinam, an oral prodrug of mecillinam, has been approved for the treatment of uUTI in Canada and Europe since the 1980s [11–13]. It is recommended as a first-line agent for, the management of uUTIs in several expert guidelines including those from the Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases [3, 14, 15]. The efficacy and safety of pivmecillinam have been comprehensively documented over the years. Microbiological response rates for pivmecillinam in uUTI have been reported to be between 75% and 94% [16–19], with clinical response rates ranging from 82% to 95% [17, 19, 20]. A meta-analysis examining efficacy and safety data from 24 randomized controlled trials published between 1977 and 2009 concluded that the pivmecillinam regimens administered in the reviewed trials were too diverse to make any firm recommendations around dose, frequency of dose, or treatment duration and that all regimens had similar efficacy and safety [21].

Pivmecillinam has been used for decades in Denmark, Norway, and Sweden as the principal antibiotic for uUTI treatment; not only has it demonstrated clinical effectiveness, but resistance rates have also remained consistently low (4%–6%) over >40 years of use [22]. Despite this extensive clinical history of use in some countries, pivmecillinam has only recently (2024) received approval in the United States for the treatment of uUTIs by the US Food and Drug Administration (FDA) [23]. It is timely to review the evidence of the susceptibility of common uUTI-causing uropathogens to mecillinam and describe the available susceptibility surveillance data.

LITERATURE SEARCH METHODOLOGY

A structured literature search was conducted to identify available data on mecillinam/pivmecillinam microbiological activity against Enterobacterales. As pivmecillinam is an oral prodrug, antibiotic susceptibility testing (AST) is performed against mecillinam, and both pivmecillinam and mecillinam were captured in the literature review. The focus was to identify mecillinam/pivmecillinam susceptibility data against Enterobacterales isolates including urinary isolates from individuals with uUTI. As part of the literature review, we assessed whether there were any changes in the resistance profile of pivmecillinam over time among any studies that evaluated temporal trends in susceptibility.

A search was performed via PubMed on November 30, 2023, using the following terms: ((pivmecillinam) OR (mecillinam)) AND (urinary tract infection) AND ((susceptibility) OR (resistance) OR (efficacy)) AND ((ESBL) OR (lactamase) OR (Enterobacteriaceae) OR (Enterobacterales)) AND (English [Language]). No time limits were imposed on publication date to review any evidence of evolution of resistance over time. Only articles with abstracts available were considered (n = 112). Articles were reviewed at the abstract level for evidence of data on susceptibility/resistance rates of pivmecillinam/mecillinam in uUTI; those considered to provide representative data from adequately sized samples (≥10 isolates) were included, and duplicated data were excluded. Data relating to gram-positive bacteria (such as Staphylococcus saprophyticus and Enterococcus) and non-Enterobacterales gram-negative bacteria were excluded. Studies specifically conducted in men or pediatric patients were excluded. However, those without specific demographic criteria or with mixed populations including men or children were included. Publications cited by identified articles and any additional relevant published material not identified from the initial searches were included at the authors' discretion but were subjected to the same inclusion/exclusion criteria on screening.

Included studies were further limited to only those that apply breakpoints published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Clinical and Laboratory Standards Institute (CLSI) [24–26]. When analyzing AST data from studies using different susceptibility breakpoints, it is important to note that both EUCAST and CLSI identify 8 mg/L as the susceptibility breakpoint for uUTI [24]. Agar dilution is the reference method for mecillinam minimal inhibitory concentration (MIC) determination [25, 27]. On this basis, only studies using appropriate AST methodology were included in the review (eg, agar dilution or standardized and quality-controlled disk diffusion). Studies using broth microdilution were excluded as this methodology is not recommended for determination of mecillinam susceptibility [27]. Some of the studies performed before 2005 referred to nationally defined breakpoints (eg, Comité de l′ Antibiogramme de la Société Française de Microbiologie [CA-SFM] in France; Swedish Reference Group for Antibiotics [SRGA] in Sweden), but they were included because they used the EUCAST methodology.

Susceptibility of uUTI-Causing Uropathogens to Mecillinam

The identification of literature via the structured search is summarized in Figure 1.

Figure 1.

Figure 1.

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Identification of literature for mecillinam susceptibility testing. *Identified through bibliographies of included publications or known to authors and included 2 publications that had previously been identified by the database search but had been excluded due to lack of abstract for screening.

A comprehensive summary of retrieved data is tabulated across Tables 1 and 2. In Table 1, all studies with published susceptibility data for E. coli against mecillinam are described, divided into 3 sections—overall, ESBL-producing phenotype, and carbapenem-resistant. Similarly, in Table 2, published susceptibility data for non–E. coli Enterobacterales against mecillinam are summarized, divided into the following 3 sections: overall, ESBL- or AmpC-producing phenotype, and carbapenem-resistant. The following text describes key themes arising from our review of these data.

Table 1.

Published Susceptibility Data for E. Coli Against Mecillinam: Overall and Resistant Phenotypes

Study
(Period Studied)		 Origin of Isolates Uropathogen No. of Isolates Percent Susceptibility (AST Method Used) MIC Information, mg/L
E. coli: overall …
Frimodt-Møller et al., 2023 [22]
(2010 to 2020)		 Denmark E. coli 649 639a 94.5 (disk diffusion) Not reported
Norway E. coli 15 018a 94.9
Sweden E. coli 977 400a 95.7
Farfour et al., 2022 [28]
(September 1, 2017, to August 31, 2018)		 France E. coli 96 597 91.4 (disk diffusion) Not reported
Tutone et al., 2022 [29]
(April 2019 to November 2019)		 Belgium, UK, Italy, Spain, and Russia E. coli 2061 91.8 (disk diffusion) Not reported
Kresken et al., 2022 [30]
(October 2019 to March 2020)		 Germany E. coli 414 95.2 (agar dilution) MIC50 0.5
MIC90 4
MIC range 0.06 to >32
Olenski et al., 2021 [31]
(July 1, 2018, to December 31, 2019)		 Australia E. coli susceptible to third-generation cephalosporin 101 83.2 (disk diffusion) Not reported
Thaulow et al., 2021 [32]
(2013 to 2017)		 Norway E. coli from children 403 96.0 (disk diffusion) Not reported
E. coli from adults 6105 94.3
Boel et al., 2019 [33]
(January 1, 2010 to September 30, 2016)		 Denmark E. coli 4837 3-d course: 97.8 (disk diffusion) Not reported
9411 5-d course: 97.3
7616 7-d course: 96.8
Jansåker et al., 2019 [34]
(January 1, 2010, to September 30, 2016)		 Denmark Non-ESBL E. coli 36 186 97.5 (disk diffusion) Not reported
Ny et al., 2019 [35]
(October 2015 to January 2017)		 Finland, Latvia,
Poland, Russia, and Sweden		 E. coli 775 95.9 (disk diffusion) Not reported
Duployez et al., 2016 [36]
(March 15 to July 4, 2015)		 France E. coli from pregnant women 235 86.4 (disk diffusion) Not reported
Kahlmeter et al., 2015 [37]
(2000, 2008, and 2014)		 France E. coli 166 97.0 (disk diffusion) Not reported
Germany E. coli 133 97.0
Spain E. coli 169 93.5
Sweden E. coli 137 98.5
UK E. coli 124 95.2
Giske et al., 2015 [38]
(2011 to 2013)		 Sweden E. coli 22 142–23 951 per year 95–96 (disk diffusion) Not reported
Etienne et al., 2014 [39]
(2009 to 2011)		 France E. coli 157 87 (disk diffusion) Not reported
Sundvall et al., 2014 [40]
(January to March of 2003 and 2012)		 Sweden E. coli 260 94.2 (disk diffusion) Not reported
Kahlmeter et al., 2012 [41]
(2007 to 2008)		 Austria E. coli 146 100 (disk diffusion) Not reported
Greece E. coli 209 98.6
Portugal E. coli 144 98.6
Sweden E. coli 203 99.5
UK E. coli 201 99.0
Lampri et al., 2012 [42]
(January 2005 to March 2006)		 Greece E. coli 1606 95.8 (agar dilution) Not reported
Lindbäck et al., 2010 [43]
(January to February 2008)		 Sweden E. coli 205 98.7 (disk diffusion) Not reported
Schito et al., 2009 [44]
(September 2003 to June 2006)		 Europe and Brazil E. coli 2313 95.8 (and 1.5 intermediate; agar dilution) MIC50 0.25
MIC90 2
MIC range <0.12 to >128
Issack et al., 2007 [45]
(January 15 to April 15, 2005)		 Mauritius E. coli 121 82.6 (and 14.0 intermediate; disk diffusion) Not reported
Abelson Storby et al., 2004 [46]
(1990 to 2001)		 Sweden E. coli Not reported >98 in 2001 (disk diffusion) Not reported
Kahlmeter et al., 2003 [47]
(January 1999 to December 2000)		 Europe and Canada E. coli 2478 98.8 (disk diffusion) Not reported
Mazzulli et al., 2001 [48]
(July to December 1997)		 Canada E. coli 1832 99.7 (agar dilution) Not reported
E. coli: ESBL-producing phenotype …
Plambeck et al., 2022 [49]
(March 2019 to January 2020)		 Germany ESBL E. coli 177 97.0 (agar dilution and disk diffusion) MIC50 2
MIC range 0.25 to 64
AmpC E. coli 11 100 MIC50 1
MIC range 0.5 to 4
Tutone et al., 2022 [29]
(April to November 2019)		 Belgium, UK, Italy, Spain, and Russia Cefpodoxime-resistant E. coli 348 82.5 (disk diffusion) Not reported
Kresken et al., 2022 [30]
(October 2019 to March 2020)		 Germany ESBL E. coli 46 91.3 (agar dilution) MIC50 1
MIC90 4
MIC range 0.25 to >32
Olenski et al., 2021 [31]
(July 1, 2018, to December 31, 2019)		 Australia E. coli nonsusceptible to third-generation cephalosporin 98 87.8 (disk diffusion) Not reported
Fuchs et al., 2019 [50]
(November 2016 to March 2017)		 Germany ESBL E. coli 86 96.5 (disk diffusion) MIC50 0.5
MIC90 1
Jansåker et al., 2019 [34]
(January 1, 2010, to September 30, 2016)		 Denmark ESBL E. coli 1619 89.3 (disk diffusion) Not reported
Priyadharshana et al., 2019 [51]
(December 2016 to March 2017)		 Sri Lanka ESBL E. coli 68 91 (and 6% intermediate; disk diffusion) Not reported
Raja, 2019 [52]
(September 2015
to September 2017)		 UK ESBL E. coli 889 96 (disk diffusion) Not reported
Bouxom et al., 2018 [53] (throughout 2016) France ESBL E. coli 100 92 (agar dilution) MIC50 1
MIC90 8
MIC range 0.06 to >128
Zykov et al., 2016 [54]
(2010 to 2011)		 Norway ESBL E. coli 105 94 (disk diffusion) MIC50 1
MIC90 4
MIC range 0.064 to 256
Giske 2015 [38]
(2011 to 2013)		 Sweden ESBL E. coli 637–830 ∼94–95 (disk diffusion) Not reported
Fournier et al., 2013 [55]
(June 2009 to September 2010)		 France ESBL E. coli 100 90 (agar dilution) MIC50 1
MIC90 8
MIC range 0.25 to >128
Lampri et al., 2012 [42]
(January 2005 to March 2006)		 Greece ESBL E. coli 48 97.9 (agar dilution) MIC50 1
MIC90 4
MIC range 0.25 to 16
Titelman et al., 2011 [56]
(2005)		 Sweden ESBL E. coli 149 87 (disk diffusion) MIC range 0.064 to >256
Tärnberg et al., 2011 [57]
(January 2002 to December 2007)		 Sweden CTX-M-producing E. coli 198 91.4 (disk diffusion) MIC50 1
MIC90 8
MIC range 0.125 to >128
E. coli: carbapenem-resistant …
Emeraud et al., 2022 [58]
(January 2019 to June 2021)		 France Carbapenem-resistant E. coli (all mechanisms) 1943 84.2 (disk diffusion) Not reported
ESBL/AmpC E. coli 276 75
OXA-48-like E. coli 1198 92.6
NDM E. coli 391 76.2
VIM E. coli 34 17.6
KPC E. coli 17 0
Tsakris et al., 2022 [59]
(2012 to 2019)		 Greece OXA-48-like-producing Enterobacterales 17 94.1 (MIC gradient strips on agar) MIC range 0.5 to 32
Fuchs et al., 2021 [60]
(not reported)		 Germany Carbapenemase-producing Enterobacterales 30 40 (agar dilution and disk diffusion) MIC50 32
MIC90 >256
MIC range 1 to >256
Mutters et al., 2015 [61]
(not reported)		 Germany E. coli with decreased susceptibility to carbapenem 20 65 (MIC gradient strips on agar) MIC50 6
MIC90 256
MIC range 1 to >256
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aNumbers represent 10 years of data, where yearly numbers for 2010–2020 have been added.

Abbreviations: AST, antibiotic susceptibility test; ESBL, extended-spectrum β-lactamase; MIC, minimal inhibitory concentration; UK, United Kingdom.

Table 2.

Published Susceptibility Data for Non–E. coli Enterobacterales (Includes Unspecified Bacteria) Against Mecillinam: General and Resistant Phenotypes

Study (Period Studied) Origin of Isolates Uropathogen No. of Isolates Percent Susceptibility (AST Method Used) MIC Information, mg/L
Non–E. coli (includes unspecified) Enterobacterales: overall
Farfour et al., 2022 [28]
(September 1, 2017, to August 31, 2018)		 France K. pneumoniae complex 13 014 88.7 (disk diffusion) Not reported
P. mirabilis 7781 73.2
Enterobacter cloacae complex 3891 88.4
C. koseri 3086 97.9
K. oxytoca 2549 89.2
M. morganii 2012 29.5
K. aerogenes 1744 85.3
C. freundii 1342 87.4
P. vulgaris 805 68.2
S. marcescens 402 30.8
Issack et al., 2007 [45]
(January 15 to April 15, 2005)		 Mauritius Klebsiella spp. 36 80.6 (and 16.7 intermediate; disk diffusion) Not reported
Proteus spp. and other Enterobacterales 55 85.5 (and 12.7 intermediate)
Kahlmeter et al., 2003 [47]
(January 1999 to December 2000)		 Europe and Canada P. mirabilis 192 95.8 (disk diffusion) Not reported
Klebsiella spp. 97 94.8
Other Enterobacterales 122 98.4
Mazzulli et al., 2001 [48]
(July to December 1997)		 Canada Klebsiella spp. 78 100 (agar dilution) Not reported
Enterobacter spp. 19 100
Proteus spp. 41 97.6
Citrobacter spp. 14 92.8
Anderson et al., 1976 [62]
(not reported)		 UK Enterobacterales 705 General practice/antenatal: 99.6 (disk diffusion) Not reported
227 Hospital outpatients: 99.6
1068 Hospital inpatients: 96.9
Non–E. coli (includes unspecified) Enterobacterales: ESBL- or AmpC-producing phenotypes
Plambeck et al., 2022 [49]
(March 2019 to January 2020)		 Germany MDR Klebsiella spp. 87 69.0 (agar dilution and disk diffusion) MIC50 8
MIC range 0.5 to >128
MDR K. pneumoniae (60/66 ESBL) 66 76.0 MIC50 4
MIC range 0.5 to >128
MDR Enterobacter spp. (50/52 AmpC) 52 96.0 MIC50 1
MIC range 0.125 to >128
MDR C. freundii (24/33 AmpC) 33 73.0 MIC50 2
MIC range 0.125 to >128
MDR M. morganii (10/11 AmpC) 11 0.0 MIC50 >128
MIC range 128 to >128
Fuchs et al., 2019 [50]
(November 2016 to March 2017)		 Germany MDR Klebsiella spp. 18 88.9 (disk diffusion) MIC50 0.5
MIC90 6
Raja, 2019 [52]
(September 2015
to September 2017)		 UK ESBL Enterobacterales 986 95 (disk diffusion) Not reported
ESBL Klebsiella spp. 71 83
Bouxom et al., 2018 [53]
(throughout 2016)		 France ESBL K. pneumoniae 50 90 (agar dilution) MIC50 2
MIC90 8
MIC range 0.5 to >128
O’Kelly et al., 2016 [63]
(2012 to 2013)		 UK ESBL Enterobacterales 95 94.74 (MIC gradient) MIC range 0.25 to 256
Deshpande et al., 2013 [64] (not reported) UK ESBL Enterobacterales 336 87.8 (disk diffusion) Not reported
Non–E. coli (includes unspecified) carbapenem-resistant Enterobacterales …
Plambeck et al., 2022 [49]
(March 2019 to January 2020)		 Germany OXA-48-like (C. freundii, E. coli, and K. pneumoniae) 8 50.0 (agar dilution and disk diffusion) MIC50 8
MIC90 64
MIC range 1 to 128
VIM/NDM (P. mirabilis and C. freundii) 3 0.0 MIC50 >128
MIC90 >128
MIC range >128
KPC (C. freundii) 1 0.0 MIC range >128
Emeraud et al., 2022 [58]
(January 2019 to June 2021)		 France Carbapenem-resistant K. pneumoniae 2511 66.9 (disk diffusion) Not reported
Carbapenem-resistant E. cloacae complex 1775 75
Carbapenem-resistant Citrobacter spp. 1295 64.7
Carbapenem-resistant K. oxytoca 262 60.7
Carbapenem-resistant K. aerogenes 257 64.6
Carbapenem-resistant Serratia spp. 86 33.7
Carbapenem-resistant M. morganii 43 11.6
Carbapenem-resistant Proteus spp. 46 84.8
Fuchs et al., 2021 [60]
(not reported)		 Germany Carbapenemase-producing Enterobacterales: K. pneumoniae 47 8.5 (agar dilution and disk diffusion) MIC50 256
MIC90 >256
MIC range 4 to >256
Carbapenemase-producing Enterobacterales: E. cloacae 13 53.8 MIC50 8
MIC90 >256
MIC range 2 to >256
Tsakris et al., 2022 [59]
(2012 to 2019)		 Greece OXA-48-like carbapenemase-producing Enterobacterales 180 94.4 (MIC gradient strips on agar) MIC range 0.5 to >256
Mutters et al., 2015 [61]
(not reported)		 Germany K. pneumoniae with decreased susceptibility to carbapenem 20 30 (MIC gradient strips on agar) MIC50 256
MIC90 256
E. cloacae with decreased susceptibility to carbapenem 20 80 MIC50 3
MIC90 256
Enterobacter aerogenes with decreased susceptibility to carbapenem 17 65 MIC50 6 MIC90 256
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Abbreviations: AST, antibiotic susceptibility test; ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MIC, minimal inhibitory concentration.

Susceptibility of E. coli (Overall) to Mecillinam

Twenty-two studies reported data on the overall susceptibility of mecillinam for E. coli (Table 1) [22, 28–48]. In most of these studies, the susceptibility to mecillinam exceeded 95%. Only 4 reported susceptibilities of <90% (and all were >80%). The largest study sample (>1 500 000 isolates studied over a decade), and one of the most recent, was examined in an analysis of mecillinam resistance rates in E. coli gathered between 2010 and 2020 from the monitoring programs of Denmark, Norway, and Sweden [22]. Susceptibility to mecillinam remained stable over the 11-year period between 94% and 96%. The authors also extracted consumption data and analyzed the association between consumption and resistance; interestingly, consumption of pivmecillinam increased significantly over time in Denmark with no attendant rise in resistance—in fact, resistance rates significantly decreased [22]. A multinational, prospective, multicenter study (ECO-SENS) investigated the prevalence and antimicrobial susceptibility of community-acquired uropathogens at long-range intervals in women aged 18–65 years with symptoms of uncomplicated lower UTI [47]. A total of 2478 E. coli isolates from women with uUTI in primary care in 17 countries were examined from 1999 to 2000. All susceptibility tests were performed in 1 laboratory, and overall resistance to mecillinam was 1.2% [47]. In a follow-up ECO-SENS study in 2008, resistance to mecillinam in 903 E. coli isolates from women with community-acquired UTIs in Austria, Greece, Portugal, Sweden, and the United Kingdom ranged from 0% to 1.4% (0.9% overall) [41]. In a 2015 publication of ECO-SENS data, Kahlmeter et al. reported that susceptibility of E. coli to mecillinam remained above 95% between 2000 and 2014 in France, Germany, Sweden, and the United Kingdom. In Spain, the value dropped from 99.0% in 2000 to 93.5% in 2014 [37]. Slightly lower susceptibility of E. coli to mecillinam was reported in a 2022 cross-sectional study of samples from nonhospitalized women (91.8%) across Europe, with the highest susceptibility reported in Russia (94.8%) and the lowest in Italy (89.2%) [29].

Data from a large university laboratory in Sweden were reported in a review article by Giske et al. in 2015 [38]. These data showed that overall resistance in E. coli for the years 2011 to 2013 (based on >20 000 tested isolates per year) was between 4% and 5%. A study investigating resistance to mecillinam in E. coli isolates from urine specimens of adult primary care patients in Germany (86.0% of samples from female patients) in 2019 and 2020 reported that 394 of 414 (95.2%) non-ESBL isolates were inhibited by mecillinam [30].

Susceptibility of ESBL-Producing Phenotypes of E. coli to Mecillinam

Nineteen publications were identified as reporting data on the susceptibility of resistant phenotypes of E. coli to mecillinam (Table 1) [29–31, 34, 38, 42, 49–61]. Four of these studies reported susceptibility data relating to carbapenem-resistant E. coli [58–61].

Among the 15 studies reporting data on resistant phenotypes of E. coli excluding carbapenem-resistant strains, mainly ESBL-producing E. coli, most reported susceptibility to mecillinam of >90%, and all reported rates of at least 82.5%. The largest sample of isolates was reported in a Danish retrospective cohort study comprising men and women with significant bacteriuria for E. coli (≥103 colony-forming units/mL) to whom a simultaneous oral empirical antibiotic for UTI had been given [34]. A total of 1619 cases of community-acquired UTIs attributable to ESBL-producing E. coli were identified, and resistance to mecillinam was reported to be 10.7% [34]. In a retrospective study of data from 2015 to 2017 in the United Kingdom using samples from patients from the community and hospital with confirmed UTIs due to ESBL-producing Enterobacterales, mecillinam sensitivity was observed in 96% (855/889) of ESBL-producing E. coli isolates [52]. A study in a Swedish university hospital conducted by Giske et al. reported 637–830 ESBL-producing E. coli isolates per year, with overall resistance to mecillinam of 5%–6% [38]. A German study investigating resistance to mecillinam in E. coli isolates from urine specimens of adult primary care patients in Germany in 2019/2020 reported that 42 of 46 (91.3%) ESBL-producing isolates (80.4% of samples from female patients) were inhibited by mecillinam [30]. In an Australian study of urinary specimens with microscopy consistent with UTI, mecillinam susceptibility of E. coli resistant to third-generation cephalosporin was actually marginally higher than that reported for E. coli susceptible to third-generation cephalosporin (87.8% [86/98] vs 83.2% [84/101], respectively) [31].

The comparative susceptibility of mecillinam was evaluated in 394 multidrug-resistant (MDR) Enterobacterales species, with different resistance mechanisms, isolated (in 2019 and 2020) from urinary specimens with elevated MICs of third-generation cephalosporins [49]. The most common species was E. coli (n = 198), and the most common resistance mechanism was ESBL (n = 273), followed by AmpC (n = 132) and carbapenemases (n = 12). Of the 198 MDR E. coli, mecillinam showed 97% susceptibility to the 177 ESBL strains [49].

Susceptibility of Carbapenem-Resistant E. coli to Mecillinam

In a German study investigating the activity of several antibiotics against carbapenem-nonsusceptible Enterobacterales without carbapenemase production (isolates identified from a national reference library), mecillinam was active against 65% of E. coli isolates [61]. Another German study reported a lower susceptibility rate, using samples from a collection of molecularly characterized carbapenemase-producing Enterobacterales from different clinical specimens; 40% of 30 carbapenemase-producing E. coli isolates were susceptible to mecillinam [60]. In the former study [61], resistance mechanisms included CTX-M, TEM-ESBL, and AmpC. In the latter [60], different mechanisms were at play, and the predominant carbapenemase in the 12 susceptible E. coli isolates was OXA-48 (n = 6).

A French study evaluated mecillinam susceptibility in a large collection of carbapenem-resistant Enterobacterales isolates (n = 8310) from the national reference center, including OXA-48-like and other carbapenemase producers [58]. Across 1943 carbapenem-resistant E. coli isolates, 84.2% were susceptible to mecillinam. In this E. coli group, susceptibility rates were 92.6%, 76.2%, 17.6%, and 0% for OXA-48-like, NDM, VIM, and KPC producers, respectively, and 75% for carbapenem-resistant non-carbapenemase-producing Enterobacterales (ESBL/AmpC) [58]. In a Greek study, 197 isolates containing OXA-48-like carbapenemase-producing Enterobacterales were identified from samples collected from individual patients in 9 tertiary care hospitals during 2012–2019, from clinical sites including the urinary tract, bloodstream, and central venous catheter [59]. In this study, 16 of the 17 E. coli isolates (94.1%) were susceptible to mecillinam.

Susceptibility of Non–E. coli Uropathogens (Overall) to Mecillinam

Five studies reported the overall susceptibility of non–E. coli Enterobacterales to mecillinam [28, 45, 47, 48, 62] (Table 2). Across 3 of these studies, susceptibility to mecillinam ranged from 92.8% to 100% [47, 48, 62]. This included data from ECO-SENS, which reported resistance to mecillinam in 4.2%, 5.2%, and 1.6% of isolated Proteus mirabilis, Klebsiella spp., and other Enterobacterales species, respectively. The limited number of isolates of species other than E. coli did not permit country-specific analysis of these data [47]. A large UK study published more than 40 years ago investigated resistance to mecillinam in different settings, reporting resistance rates of <1% in general practice and antenatal settings, as well as among hospital outpatients; resistance was 3.1% among hospital inpatients [62]. A 2017/2018 study assessed the prevalence of antimicrobial resistance in Enterobacterales isolates recovered from urinary tract samples in France, including 134 162 Enterobacterales isolates, of which 28% were non–E. coli species [28]. Mecillinam had the highest susceptibility to Citrobacter koseri (97.9%), with several other species also showing low resistance to mecillinam. The lowest susceptibility rates were seen for mecillinam in Serratia marcescens (30.8%) and Morganella morganii (29.5%).

Susceptibility of ESBL- or AmpC-Producing Phenotypes of Non–E. coli Uropathogens to Mecillinam

A total of 10 studies reported susceptibility data for resistant phenotypes of non–E. coli uropathogens [49, 50, 52, 53, 58–61, 63, 64] (Table 2).

UK studies have reported that mecillinam susceptibility among ESBL-producing Enterobacterales ranged from 83% to 95%, using samples from a range of clinical settings (eg, community and hospital, male and female) [52, 63, 64]. Data from clinical samples (including some bloodstream infections) collected in France indicate that the susceptibility of ESBL-producing Klebsiella pneumoniae (K. pneumoniae) to mecillinam is ∼90% [53]. A German analysis of 394 MDR Enterobacterales included Klebsiella spp. (n = 87), Enterobacter spp. (n = 52), Citrobacter spp. (n = 34), and others [49]. Mecillinam susceptibility rates were 96% for Enterobacter spp., where the predominant resistance mechanism was AmpC. Susceptibility rates were between 69% and 76% for Klebsiella spp. (resistance mechanism not specified), Citrobacter freundii (largely AmpC), and K. pneumoniae (>90% ESBL), while M. morganii (>90% AmpC) was completely resistant to mecillinam [49].

Susceptibility of Carbapenem-Resistant Non–E. coli Enterobacterales to Mecillinam

Five studies provided data for non–E. coli carbapenem-resistant Enterobacterales [49, 58–61] (Table 2). As with the carbapenem-resistant E. coli data, a much greater degree of heterogeneity was apparent in susceptibility rates, with variability seen across strains, carbapenemase type, and geography.

Reported susceptibility rates for carbapenem-resistant or carbapenemase-producing K. pneumoniae varied from a low of 8.5% in 1 study [60] to a high of 66.9% in another [58]. The latter study examined different mechanisms of carbapenemase-related resistance, showing that mecillinam susceptibility for K. pneumoniae was highest with OXA-48-like (84.2%) or NDM (72.1%) resistance mechanisms and lowest where the carbapenemase was VIM or KPC (16.2% or 0%, respectively) [58]. Another French study also reported 0% susceptibility of mecillinam to VIM, NDM, and KPC strains, although it should be noted that the numbers of isolates were <10 [49]. Levels of susceptibility to mecillinam in carbapenem-resistant Enterobacter cloacae in several studies ranged from 53.8% to 80% [58, 60, 61].

Susceptibility to Mecillinam in the United States

To support the clinical development of pivmecillinam in the United States for the treatment of uUTI, the activity of mecillinam has been compared with other antibiotics against Enterobacterales isolates from patients with UTI in the United States during 2018 and 2019 [65, 66]. A total of 1090 isolates were tested for the 2018 analysis, and 1075 were tested for the 2019 analysis. The activity of the antibiotics was tested by CLSI methodology, and susceptibility was interpreted according to CLSI guidelines. In the 2018 analysis, mecillinam MIC50 and MIC90 were 0.25 µg/mL and 4 µg/mL, respectively, and 94.5% of isolates were susceptible [65]. In the 2019 analysis, presence of ESBLs were found in 9.6% of E. coli and 50% of K. pneumoniae isolates [66]. Susceptibility to mecillinam was 95%, and MIC50 and MIC90 values for mecillinam were 0.25 μg/mL and 2 μg/mL, respectively [66]. In this same 2019 analysis, 22.6% and 26.2% of isolates were nonsusceptible to ciprofloxacin and TMP-SMX, respectively. Among the ciprofloxacin-nonsusceptible isolates, 91.4% were susceptible to mecillinam, and the MIC50 and MIC90 values for mecillinam were 0.5 and 8 mg/L, respectively. Among the TMP-SMX-nonsusceptible isolates, 93.6% were susceptible to mecillinam, and the MIC50 and MIC90 values for mecillinam were 1 and 4 mg/L, respectively [66].

The Role of Pivmecillinam in the Management of uUTIs: Concluding Remarks

This systematic review shows that mecillinam, historically and currently, demonstrates a good level of activity against E. coli and several other Enterobacterales that cause uUTIs—even those with resistance to other antimicrobials. Across 21 published studies, the susceptibility of mecillinam to E. coli exceeded 83% in each of those studies, exceeded 90% in 17 of the studies, and exceeded 95% in 15 of the studies (Table 1).

Susceptibility rates of mecillinam for ESBL E. coli range from 82.5% to 97.9% (Table 1). Further, we show that mecillinam has good activity in non–E. coli Enterobacterales, with susceptibility rates frequently in the region of ≥90% (Table 2). For example, the susceptibility of mecillinam to ESBL-producing K. pneumoniae (n = 50 isolates) was 90% in a 2018 French study [53]. While most studies observed pivmecillinam susceptibility rates in excess of 80% against ESBL-producing E. coli and other Enterobacterales [29–31, 34, 38, 42, 49–57, 63, 64], the microbiological activity of pivmecillinam against carbapenem-resistant Enterobacterales (CRE) was found to be highly variable across strains, carbapenemase types, and geographic regions. Available data suggest that the microbiological activity of pivmecillinam against CRE at its current susceptibility breakpoint is largely restricted to isolates producing OXA-48-like carbapenemases and some NDM-1 carbapenemases and that pivmecillinam activity against CRE is more frequent in E. coli and E. cloacae than in other species [58–61]. Pivmecillinam has limited microbiological activity at its current breakpoint against CRE that produce KPC or VIM [58]. While the microbiological data presented in this paper suggest that pivmecillinam may be an option for some CRE uUTIs if the pathogen is reported to be susceptible to mecillinam, there are currently no preclinical pharmacokinetic/pharmacodynamic data and limited clinical data to indicate that pivmecillinam is effective for patients with uUTIs caused by CRE. Further research is needed to determine if pivmecillinam can be used for CRE uUTIs when they are determined to be susceptible to mecillinam.

Recommendations for the choice of antimicrobial for treating uUTIs have needed to evolve in recognition of increasing numbers of resistant microbial strains. Notably, resistance to both fluoroquinolones and TMP-SMX, 2 of the most used therapeutic agents in adult patients with uUTIs, exceeds 20% in most US regions among adult patients with uUTIs due to E. coli [6, 8, 67]. With limited numbers of novel antimicrobials entering clinical practice for uUTI, there is attention on revival of older agents that could be used more widely [38]. Pivmecillinam, the oral prodrug of mecillinam, has been successfully used to treat uUTI in Europe and Canada for decades and is well placed to be considered as one of the empiric agents in adult patients with a suspected or documented uUTI due to Enterobacterales [22, 38]. Clinical practice guidelines from the IDSA recommend pivmecillinam as a first-line antibiotic treatment option, and in 2024 pivmecillinam received US FDA approval for the treatment of uUTI (185 mg orally 3 times daily for 3 to 7 days as clinically indicated) [14, 23]. Short (3-day) courses of pivmecillinam have demonstrated high levels of clinical success and may have the potential to reduce management costs of uUTIs [21]. An analysis using US-focused conceptual health care decision-analytic modeling has suggested that pivmecillinam has the potential to reduce the economic burden associated with inappropriate treatment of adult outpatients with uUTIs, especially in patients at high risk for resistance [7].

Several things should be noted when interpretating the findings of this literature review. National surveillance programs that examine susceptibility of key antibiotics annually are established in some countries, for example, in Norway, Sweden, and Denmark, as described in a recent review [22]. However, this is not the case for all countries, and the current review is limited to available published data. That said, we did not observe any evidence or trend toward changes in resistance to mecillinam at different time periods, as is well documented with other first-line uUTI agents with high usage [9]. It is important to acknowledge that all susceptibility data described herein are based on breakpoints of 8 mg/L and that these findings may need to be revisited if recommended breakpoints change in the future.

While not the focus of this review, more data are needed to fully understand the activity of pivmecillinam against Enterobacterales that are resistant to fluoroquinolones or TMP-SMX. In a 2019 US surveillance study of uropathogens recovered from patients with uUTIs, susceptibility to mecillinam among the ciprofloxacin and TMP-SMX-nonsusceptible isolates was 91.4% and 93.6%, respectively [66]. In view of the widespread use of and increasing resistance toward fluoroquinolones and TMP-SMX in the treatment of uUTI, further research would be valuable to determine the utility of pivmecillinam in patients with uUTIs caused by Enterobacterales that are resistant to fluoroquinolones or TMP-SMX. Finally, clinical and microbiological success rates were not examined within this review, the scope of which was limited to examination of antibiotic resistance as determined by currently approved AST methodology, and susceptibility is not necessarily a direct correlate of clinical success.

In conclusion, data from this literature review suggest that pivmecillinam has high microbiological activity at its current susceptibility breakpoints against E. coli and other Enterobacterales, including those that produce ESBLs. Importantly, there is no clear evidence to suggest that resistance to mecillinam among common uropathogens has increased during the >40 years of its use in practice. There is a wealth of existing clinical experience available for pivmecillinam, particularly from Nordic countries. In these regions, pivmecillinam use is reserved for uUTIs, and adoption of pivmecillinam as the standard treatment option for the majority of uUTI cases has spared the use of other antibiotic agents such as quinolones, co-trimoxazole, and amoxicillin-clavulanic acid for this highly prevalent condition. These considerations would suggest that pivmecillinam is an appropriate first-line treatment option for patients with uUTI in the current prescribing climate.

Acknowledgments

Medical writing support was provided by Becky Fox-Spencer, PhD, and Anna Palmer, PhD, contracted by LiNK Health Group.

Financial support . UTILITY therapeutics funded the provision of medical writing assistance to the authors.

Author contributions. All authors conceived and designed this study and designed and reviewed the literature search methodology and results. A.S.H. oversaw the creation of the first draft, and all authors reviewed and revised all drafts of the manuscript. All authors take responsibility for the data presented and their interpretation and approved the final version of the manuscript for submission.

Patient consent. This manuscript is a review article of published literature and does not include factors necessitating either patient consent or ethical approval.

Contributor Information

Thomas P Lodise, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.

Keith S Kaye, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

Anne Santerre Henriksen, Maxel Consulting ApS, Jyllinge, Denmark.

Gunnar Kahlmeter, Department of Clinical Microbiology, Central Hospital, Växjö, Sweden.

References

  • 1. Medina  M, Castillo-Pino  E. An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol  2019; 11:1756287219832172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Flores-Mireles  AL, Walker  JN, Caparon  M, Hultgren  SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol  2015; 13:269–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Wagenlehner  F, Nicolle  L, Bartoletti  R, et al.  A global perspective on improving patient care in uncomplicated urinary tract infection: expert consensus and practical guidance. J Glob Antimicrob Resist  2021; 28:18–29. [DOI] [PubMed] [Google Scholar]
  • 4. Simmering  JE, Tang  F, Cavanaugh  JE, Polgreen  LA, Polgreen  PM. The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998–2011. Open Forum Infect Dis  2017; 4:ofw281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Bader  MS, Loeb  M, Leto  D, Brooks  AA. Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents. Postgrad Med  2020; 132:234–50. [DOI] [PubMed] [Google Scholar]
  • 6. Sanchez  GV, Babiker  A, Master  RN, Luu  T, Mathur  A, Bordon  J. Antibiotic resistance among urinary isolates from female outpatients in the United States in 2003 and 2012. Antimicrob Agents Chemother  2016; 60:2680–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Lodise  TP, Henriksen  AS, Hadley  T, Patel  N. US-focused conceptual health care decision-analytic models examining the value of pivmecillinam relative to current standard-of-care agents among adult patients with uncomplicated urinary tract infections due to Enterobacterales. Open Forum Infect Dis  2021; 8:ofab380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Rank  EL, Lodise  T, Avery  L, et al.  Antimicrobial susceptibility trends observed in urinary pathogens obtained from New York state. Open Forum Infect Dis  2018; 5:ofy297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Kaye  KS, Gupta  V, Mulgirigama  A, et al.  Antimicrobial resistance trends in urine Escherichia coli isolates from adult and adolescent females in the United States from 2011 to 2019: rising ESBL strains and impact on patient management. Clin Infect Dis  2021; 73:1992–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Dunne  MW, Aronin  SI, Yu  KC, Watts  JA, Gupta  V. A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011–2020. BMC Infect Dis  2022; 22:194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Selexid product monograph including patient medical information. 2018. Available at: https://pdf.hres.ca/dpd_pm/00044078.PDF. Accessed January 2024.
  • 12.Pivmecillinam 200 mg film-coated tablets, summary of product characteristics. 2018. Available at: https://www.medicines.org.uk/emc/product/4982/smpc. Accessed January 2024.
  • 13.Selexid 200 mg film-coated tablets, summary of product characteristics. 2019. Available at: https://www.medicines.org.uk/emc/product/3799/smpc. Accessed January 2024.
  • 14. Gupta  K, Hooton  TM, Naber  KG, et al.  International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis  2011; 52:e103–120. [DOI] [PubMed] [Google Scholar]
  • 15. Bonkat  G, Bartoletti  R, Bruyere  F, et al. EAU guidelines on urological infections. 2021. Available at: https://uroweb.org/wp-content/uploads/EAU-Guidelines-on-Urological-infections-2021.pdf. Accessed January 2024.
  • 16. Ferry  SA, Holm  SE, Stenlund  H, Lundholm  R, Monsen  TJ. Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim Health Care  2007; 25:49–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Menday  AP. Comparison of pivmecillinam and cephalexin in acute uncomplicated urinary tract infection. Int J Antimicrob Agents  2000; 13:183–7. [DOI] [PubMed] [Google Scholar]
  • 18. Nicolle  LE, Madsen  KS, Debeeck  GO, et al.  Three days of pivmecillinam or norfloxacin for treatment of acute uncomplicated urinary infection in women. Scand J Infect Dis  2002; 34:487–92. [DOI] [PubMed] [Google Scholar]
  • 19. Vik  I, Bollestad  M, Grude  N, et al.  Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—a double-blind, randomized non-inferiority trial. PLoS Med  2018; 15:e1002569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Nicolle  L. Antimicrobials are effective for treatment of uncomplicated urinary infection. Clin Microbiol Infect  2021; 27:1381–2. [DOI] [PubMed] [Google Scholar]
  • 21. Pinart  M, Kranz  J, Jensen  K, et al.  Optimal dosage and duration of pivmecillinam treatment for uncomplicated lower urinary tract infections: a systematic review and meta-analysis. Int J Infect Dis  2017; 58:96–109. [DOI] [PubMed] [Google Scholar]
  • 22. Frimodt-Møller  N, Simonsen  GS, Larsen  AR, Kahlmeter  G. Pivmecillinam, the paradigm of an antibiotic with low resistance rates in Escherichia coli urine isolates despite high consumption. J Antimicrob Chemother  2023; 78:289–95. [DOI] [PubMed] [Google Scholar]
  • 23.PIVYA (pivmecillinam) tablets, for oral use. Prescribing information. 2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216483s000lbl.pdf. Accessed April 2024.
  • 24. Schito  GC, Gualco  L, Naber  KG, et al.  Do different susceptibility breakpoints affect the selection of antimicrobials for treatment of uncomplicated cystitis?  J Chemother  2010; 22:345–54. [DOI] [PubMed] [Google Scholar]
  • 25. European Committee on Antimicrobial Susceptibility Testing (EUCAST) . Clinical breakpoints—breakpoints and guidance. Available at: https://www.eucast.org/clinical_breakpoints/. Accessed January 2024.
  • 26. Clinical & Laboratory Standards Institute (CLSI) . Available at: https://clsi.org/. Accessed January 2024.
  • 27. European Committee on Antimicrobial Susceptibility Testing (EUCAST) . Routine and extended internal quality control for MIC determination and disk diffusion as recommended by EUCAST. Available at: https://aurosan.de/images/mediathek/servicematerial/EUCAST_RefStaemme_Sollwerte.pdf. Accessed January 2024.
  • 28. Farfour  E, Dortet  L, Guillard  T, et al.  Antimicrobial resistance in Enterobacterales recovered from urinary tract infections in France. Pathogens  2022; 11:356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Tutone  M, Bjerklund Johansen  TE, Cai  T, Mushtaq  S, Livermore  DM. Susceptibility and resistance to fosfomycin and other antimicrobial agents among pathogens causing lower urinary tract infections: findings of the SURF study. Int J Antimicrob Agents  2022; 59:106574. [DOI] [PubMed] [Google Scholar]
  • 30. Kresken  M, Pfeifer  Y, Wagenlehner  F, Werner  G, Wohlfarth  E, Therapy  OR. Resistance to mecillinam and nine other antibiotics for oral use in Escherichia coli isolated from urine specimens of primary care patients in Germany, 2019/20. Antibiotics (Basel)  2022; 11:751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Olenski  M, Jardine  D, Poy Lorenzo  YS, Crowe  A. Mecillinam susceptibility in Victorian third generation cephalosporin-nonsusceptible Escherichia coli urinary isolates. Pathology  2021; 53:803–5. [DOI] [PubMed] [Google Scholar]
  • 32. Thaulow  CM, Lindemann  PC, Klingenberg  C. Antibiotic resistance in paediatric UTIs in Norway. Tidsskr Nor Laegeforen  2021; 141. [DOI] [PubMed] [Google Scholar]
  • 33. Boel  JB, Jansaker  F, Hertz  FB, et al.  Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study. J Antimicrob Chemother  2019; 74:2767–73. [DOI] [PubMed] [Google Scholar]
  • 34. Jansåker  F, Boel  JB, Thonnings  S, et al.  Pivmecillinam compared to other antimicrobials for community-acquired urinary tract infections with Escherichia coli, ESBL-producing or not—a retrospective cohort study. Infect Drug Resist  2019; 12:1691–702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Ny  S, Edquist  P, Dumpis  U, et al.  Antimicrobial resistance of Escherichia coli isolates from outpatient urinary tract infections in women in six European countries including Russia. J Glob Antimicrob Resist  2019; 17:25–34. [DOI] [PubMed] [Google Scholar]
  • 36. Duployez  C, Loiez  C, Cattoen  C, et al.  In vitro susceptibility to mecillinam of Escherichia coli strains isolated from the urine of pregnant women. Med Mal Infect  2016; 46:436–41. [DOI] [PubMed] [Google Scholar]
  • 37. Kahlmeter  G, Ahman  J, Matuschek  E. Antimicrobial resistance of Escherichia coli causing uncomplicated urinary tract infections: a European update for 2014 and comparison with 2000 and 2008. Infect Dis Ther  2015; 4:417–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Giske  CG. Contemporary resistance trends and mechanisms for the old antibiotics colistin, temocillin, fosfomycin, mecillinam and nitrofurantoin. Clin Microbiol Infect  2015; 21:899–905. [DOI] [PubMed] [Google Scholar]
  • 39. Etienne  M, Lefebvre  E, Frebourg  N, et al.  Antibiotic treatment of acute uncomplicated cystitis based on rapid urine test and local epidemiology: lessons from a primary care series. BMC Infect Dis  2014; 14:137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Sundvall  PD, Elm  M, Gunnarsson  R, et al.  Antimicrobial resistance in urinary pathogens among Swedish nursing home residents remains low: a cross-sectional study comparing antimicrobial resistance from 2003 to 2012. BMC Geriatr  2014; 14:30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Kahlmeter  G, Poulsen  HO. Antimicrobial susceptibility of Escherichia coli from community-acquired urinary tract infections in Europe: the ECO.SENS study revisited. Int J Antimicrob Agents  2012; 39:45–51. [DOI] [PubMed] [Google Scholar]
  • 42. Lampri  N, Galani  I, Poulakou  G, et al.  Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. J Antimicrob Chemother  2012; 67:2424–8. [DOI] [PubMed] [Google Scholar]
  • 43. Lindbäck  H, Lindbäck  J, Sylvan  S, Melhus  A. Low frequency of antibiotic resistance among urine isolates of Escherichia coli in the community, despite a major hospital outbreak with Klebsiella pneumoniae producing CTX-M-15 in Uppsala County. Scand J Infect Dis  2010; 42:243–8. [DOI] [PubMed] [Google Scholar]
  • 44. Schito  GC, Naber  KG, Botto  H, et al.  The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections. Int J Antimicrob Agents  2009; 34:407–13. [DOI] [PubMed] [Google Scholar]
  • 45. Issack  MI, Yee Kin Tet  HY, Morlat  P. Antimicrobial resistance among Enterobacteriaceae causing uncomplicated urinary tract infections in Mauritius: consequences of past misuse of antibiotics. J Chemother  2007; 19:222–5. [DOI] [PubMed] [Google Scholar]
  • 46. Abelson Storby  K, Osterlund  A, Kahlmeter  G. Antimicrobial resistance in Escherichia coli in urine samples from children and adults: a 12 year analysis. Acta Paediatr  2004; 93:487–91. [DOI] [PubMed] [Google Scholar]
  • 47. Kahlmeter  G; ECO.SENS . An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS project. J Antimicrob Chemother  2003; 51:69–76. [DOI] [PubMed] [Google Scholar]
  • 48. Mazzulli  T, Skulnick  M, Small  G, et al.  Susceptibility of community gram-negative urinary tract isolates to mecillinam and other oral agents. Can J Infect Dis  2001; 12:289–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Plambeck  L, Fuchs  F, Sattler  J, Hamprecht  A. In vitro activity of mecillinam, temocillin and nitroxoline against MDR Enterobacterales. JAC Antimicrob Resist  2022; 4:dlac059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Fuchs  F, Hamprecht  A. Results from a prospective in vitro study on the mecillinam (amdinocillin) susceptibility of Enterobacterales. Antimicrob Agents Chemother  2019; 63:e02402–02418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Priyadharshana  U, Piyasiri  LB, Wijesinghe  C. Prevalence, antibiotic sensitivity pattern and genetic analysis of extended spectrum beta lactamase producing Escherichia coli and Klebsiella spp among patients with community acquired urinary tract infection in Galle district, Sri Lanka. Ceylon Med J  2019; 64:140–5. [DOI] [PubMed] [Google Scholar]
  • 52. Raja  NS. Oral treatment options for patients with urinary tract infections caused by extended spectrum βeta-lactamase (ESBL) producing Enterobacteriaceae. J Infect Public Health  2019; 12:843–6. [DOI] [PubMed] [Google Scholar]
  • 53. Bouxom  H, Fournier  D, Bouiller  K, Hocquet  D, Bertrand  X. Which non-carbapenem antibiotics are active against extended-spectrum beta-lactamase-producing Enterobacteriaceae?  Int J Antimicrob Agents  2018; 52:100–3. [DOI] [PubMed] [Google Scholar]
  • 54. Zykov  IN, Sundsfjord  A, Smabrekke  L, Samuelsen  O. The antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin and comparative analysis of resistance patterns in a nationwide collection of ESBL-producing Escherichia coli in Norway 2010–2011. Infect Dis (Lond)  2016; 48:99–107. [DOI] [PubMed] [Google Scholar]
  • 55. Fournier  D, Chirouze  C, Leroy  J, et al.  Alternatives to carbapenems in ESBL-producing Escherichia coli infections. Med Mal Infect  2013; 43:62–6. [DOI] [PubMed] [Google Scholar]
  • 56. Titelman  E, Iversen  A, Kahlmeter  G, Giske  CG. Antimicrobial susceptibility to parenteral and oral agents in a largely polyclonal collection of CTX-M-14 and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. APMIS  2011; 119:853–63. [DOI] [PubMed] [Google Scholar]
  • 57. Tärnberg  M, Ostholm-Balkhed  A, Monstein  HJ, Hallgren  A, Hanberger  H, Nilsson  LE. In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli. Eur J Clin Microbiol Infect Dis  2011; 30:981–7. [DOI] [PubMed] [Google Scholar]
  • 58. Emeraud  C, Godmer  A, Girlich  D, et al.  Activity of mecillinam against carbapenem-resistant Enterobacterales. J Antimicrob Chemother  2022; 77:2835–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Tsakris  A, Koumaki  V, Baka  S, Balakrishnan  I. Activity of mecillinam against OXA-48-like carbapenemase-producing Enterobacterales. J Antimicrob Chemother  2022; 77:537–8. [DOI] [PubMed] [Google Scholar]
  • 60. Fuchs  F, Ahmadzada  A, Plambeck  L, Wille  T, Hamprecht  A. Susceptibility of clinical Enterobacterales isolates with common and rare carbapenemases to mecillinam. Front Microbiol  2021; 11:627267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Mutters  NT, Zimmermann  S, Kaase  M, Mischnik  A. Activity of temocillin, mecillinam, ceftazidime, and ceftazidime/avibactam against carbapenem-non-susceptible Enterobacteriaceae without carbapenemase production. Eur J Clin Microbiol Infect Dis  2015; 34:2429–37. [DOI] [PubMed] [Google Scholar]
  • 62. Anderson  JD, Adams  MA, Barrington  JC, Spence  WN, Sheperd  CA. Comparison of the epidemiology of bacterial resistance to mecillinam and ampicillin. Antimicrob Agents Chemother  1976; 10:872–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. O'Kelly  F, Kavanagh  S, Manecksha  R, Thornhill  J, Fennell  JP. Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland. BMC Infect Dis  2016; 16:620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Deshpande  A, Inkster  T, Speekenbrink  A, Cottom  L. Susceptibility of gram-negative urinary tract isolates to mecillinam in a large Glasgow teaching hospital. J Glob Antimicrob Resist  2013; 1:47–8. [DOI] [PubMed] [Google Scholar]
  • 65. Hawser  S, Morrissey  I, Charrier  C, De Piano  C, Alexander  M, Henriksen  AS. Mecillinam susceptibility against Enterobacterales isolated from urinary tract infections from US patients in 2018. Open Forum Infect Dis  2020; 7:S801–2. [Google Scholar]
  • 66. Hawser  S, Morrissey  I, Henriksen  AS. Activity of mecillinam against enterobacterales isolates collected from patients with urinary tract infections in the USA during 2019. Open Forum Infect Dis  2021; 8:S611–4. [Google Scholar]
  • 67. Sanchez  GV, Master  RN, Karlowsky  JA, Bordon  JM. In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010. Antimicrob Agents Chemother  2012; 56:2181–3. [DOI] [PMC free article] [PubMed] [Google Scholar]

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