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

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.

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][8][9].The prevalence of extendedspectrum 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][12][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][17][18][19], with clinical response rates ranging from 82% to 95% [17,19,20].A metaanalysis 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 Susceptibility to Pivmecillinam in uUTI • OFID • 1 Open Forum Infectious Diseases R E V I E W A R T I C L E 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 gramnegative 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][25][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 qualitycontrolled 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.
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 carbapenemresistant.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 AmpCproducing phenotype, and carbapenem-resistant.The following text describes key themes arising from our review of these data.

Susceptibility of E. coli (Overall) to Mecillinam
Twenty-two studies reported data on the overall susceptibility of mecillinam for E. coli (Table 1) [22,.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].
Among the 15 studies reporting data on resistant phenotypes of E. coli excluding carbapenem-resistant strains, mainly ESBLproducing 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 (≥10 3 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 ESBLproducing 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,   [31].

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).

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 countryspecific 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%).
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 MIC 50 and MIC 90 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 MIC 50 and MIC 90 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 MIC 50 and MIC 90 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 MIC 50 and MIC 90 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][59][60][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 amoxicillinclavulanic 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.

Figure 1 .
Figure1.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.