APMIS 122: 317–323
© 2013 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12147
Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women € TOR J MONSEN,1 STIG E HOLM,2 BJORN MAGNUS FERRY3 and SVEN A FERRY1,4 Department of Clinical Microbiology, Bacteriology, Ume a University, Ume a; 2Department of Medical 3 Microbiology and Immunology, University of Gothenburg, Gothenburg; Department of Education and 4 Family Medicine, Ume a University, Ume a, Sweden 1
Monsen TJ, Holm SE, Ferry BM, Ferry SA. Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women. APMIS 2014; 122: 317–323. Pivmecillinam (PIV) is a first-line antimicrobial for treatment of lower urinary tract infection in women (LUTIW). Mecillinam, the active substance of PIV, is bactericidal mainly against gram-negative uropathogens, whereas gram-positive species are considered intrinsically resistant. However, successful treatment of LUTIW caused by Staphylococcus saprophyticus has been reported, but more rarely for other gram-positive species. The aim of this study was to compare clinical and bacteriological outcome of PIV vs placebo treatment among uropathogens with special focus on mecillinam-resistant isolates. We analysed data from a prospective, multicentre, placebo-controlled, primary health care, therapy study performed in Sweden in 1995–1998 that included 1143 women with symptoms suggestive of LUTIW. Urine cultures were collected and symptoms registered at inclusion and at follow-up visits. Overall, the efficacy of PIV was superior to that of placebo. Clinical and bacteriological outcomes of PIV treatment were similar for S. saprophyticus, Escherichia coli as for most other uropathogens irrespective of their susceptibility to mecillinam. However, the occurrence of enterococci increased nearly fivefold shortly post PIV treatment, although with mild symptoms and a high spontaneous eradication. As susceptibility to mecillinam in vitro did not predict bacteriological and clinical outcome of PIV treatment, we suggest that the present breakpoints for mecillinam should be revised. Key words: Cystitis; mecillinam resistance; pivmecillinam treatment; uropathogens; women. Tor J Monsen, Department of Clinical Microbiology, University Hospital of Ume a, SE-90185 Ume a, Sweden. e-mail: [email protected]
Urinary tract infection (UTI) is annually estimated to cause more than 150 million of episodes worldwide (1), of which communityacquired, uncomplicated lower UTI in women (LUTIW) is by far most common (2–7). Among uropathogens, Escherichia coli and Staphylococcus saprophyticus are most frequent causing 80% and 5–10% of LUTIW, respectively, while enterococci are less common (2–7).
Received 21 December 2012. Accepted 10 June 2013
Among UTI antimicrobials, pivmecillinam (PIV) has shown high efficacy, few ecological side effects and adverse reactions and is a firstline antimicrobial in the Nordic countries (1, 8, 9). Its active substance mecillinam has a bactericidal activity mainly against gramnegative species, while gram-positives are considered intrinsically resistant in vitro (www. srga.org). Of particular interest are observations of efficacy in vivo by an agent showing resistance in vitro. When bearing in mind the global 317
MONSEN et al.
increase in resistance among antimicrobials, such agents may be of great importance (10–16). Actually, clinicians often experience clinical cure of LUTIW despite laboratoryreported resistance to the antimicrobials prescribed. Reports indicate that S. saprophyticus is eradicated by PIV treatment (15, 17, 18), while clinical and bacteriological outcomes of infections caused by other mecillinam-resistant species have rarely been reported (15). The aim of the present study was to compare the clinical and bacteriological outcomes of PIV vs placebo treatment among uropathogens in LUTIW with special focus on mecillinam-resistant isolates. MATERIAL AND METHODS
Mecillinam susceptibility tests were performed using multipoint inoculation of isolates on agar plates (21). Mecillinam resistance in E. coli was defined as isolates with a minimal inhibitory concentration (MIC) of >8 mg/L, while. S. saprophyticus, enterococci and other gram-positive uropathogens as well as Pseudomonas species were not tested as they were considered intrinsically resistant according to the Swedish Reference Group for Antibiotics (www.srga.org). Outcomes of therapy and definitions Clinical outcomes were evaluated by patient diaries in terms of mean symptoms score (MSS) and cure when the patient was free from symptoms at follow-up visits. Bacteriological outcome was evaluated by urine cultures at inclusion and at follow-up. Cure was defined as eradication of original species at follow-up.
Study design The present study was a prospective, multicentre, randomized, double-blind, placebo-controlled therapy study (the LUTIW project) performed during 1995–1998 (19, 20). Patients with symptoms suggestive of LUTIW were included at 18 primary health care centres in northern Sweden with exclusion criteria as previously reported (19). Patients were randomized to three different regimens of PIV (Selexidâ, LEO Pharma, Copenhagen, Denmark: 200 mg 9 3 9 7 days, 200 mg 9 2 9 7 days or 400 mg 9 2 9 3 days) or placebo. All PIV regimens were pooled to one treatment group. UTI symptoms (urgency, dysuria, suprapubic or loin pain) were registered using patient diaries with the scores 0–3 (none, mild, moderate, or severe respectively) at inclusion and at follow-up visits 8–10 and 35–49 days post inclusion (19). Bacteriological methods and susceptibility tests Midstream urine samples were collected at inclusion and follow-up visits and transported to the Laboratory of Clinical Bacteriology, University Hospital of Ume a for culture. Uropathogens were quantified as colony-forming units (CFU)/L and identified as previously described (19). Significant bacteriuria (SBU) was according to European guidelines: in patients with symptoms as ≥106 CFU/L for primary pathogens, ≥107 for secondary pathogens, and ≥108 for doubtful pathogens as in patients free from symptoms (5). In cultures with mixed flora and one predominant species, the latter species was defined as an uropathogen (19). Non-significant bacteriuria was defined as negative cultures as well as samples with mixed flora without predominant species.
318
Statistical analysis Comparison of proportions was done using chisquare test or Fisher’s exact test. Analysis of variance was used for comparison of mean symptoms scores. Post-hoc analysis was performed using Bonferroni correction at inclusion and Dunnette′s T3 at the first and last follow-up visit respectively. P-values
© 2013 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12147
Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women € TOR J MONSEN,1 STIG E HOLM,2 BJORN MAGNUS FERRY3 and SVEN A FERRY1,4 Department of Clinical Microbiology, Bacteriology, Ume a University, Ume a; 2Department of Medical 3 Microbiology and Immunology, University of Gothenburg, Gothenburg; Department of Education and 4 Family Medicine, Ume a University, Ume a, Sweden 1
Monsen TJ, Holm SE, Ferry BM, Ferry SA. Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women. APMIS 2014; 122: 317–323. Pivmecillinam (PIV) is a first-line antimicrobial for treatment of lower urinary tract infection in women (LUTIW). Mecillinam, the active substance of PIV, is bactericidal mainly against gram-negative uropathogens, whereas gram-positive species are considered intrinsically resistant. However, successful treatment of LUTIW caused by Staphylococcus saprophyticus has been reported, but more rarely for other gram-positive species. The aim of this study was to compare clinical and bacteriological outcome of PIV vs placebo treatment among uropathogens with special focus on mecillinam-resistant isolates. We analysed data from a prospective, multicentre, placebo-controlled, primary health care, therapy study performed in Sweden in 1995–1998 that included 1143 women with symptoms suggestive of LUTIW. Urine cultures were collected and symptoms registered at inclusion and at follow-up visits. Overall, the efficacy of PIV was superior to that of placebo. Clinical and bacteriological outcomes of PIV treatment were similar for S. saprophyticus, Escherichia coli as for most other uropathogens irrespective of their susceptibility to mecillinam. However, the occurrence of enterococci increased nearly fivefold shortly post PIV treatment, although with mild symptoms and a high spontaneous eradication. As susceptibility to mecillinam in vitro did not predict bacteriological and clinical outcome of PIV treatment, we suggest that the present breakpoints for mecillinam should be revised. Key words: Cystitis; mecillinam resistance; pivmecillinam treatment; uropathogens; women. Tor J Monsen, Department of Clinical Microbiology, University Hospital of Ume a, SE-90185 Ume a, Sweden. e-mail: [email protected]
Urinary tract infection (UTI) is annually estimated to cause more than 150 million of episodes worldwide (1), of which communityacquired, uncomplicated lower UTI in women (LUTIW) is by far most common (2–7). Among uropathogens, Escherichia coli and Staphylococcus saprophyticus are most frequent causing 80% and 5–10% of LUTIW, respectively, while enterococci are less common (2–7).
Received 21 December 2012. Accepted 10 June 2013
Among UTI antimicrobials, pivmecillinam (PIV) has shown high efficacy, few ecological side effects and adverse reactions and is a firstline antimicrobial in the Nordic countries (1, 8, 9). Its active substance mecillinam has a bactericidal activity mainly against gramnegative species, while gram-positives are considered intrinsically resistant in vitro (www. srga.org). Of particular interest are observations of efficacy in vivo by an agent showing resistance in vitro. When bearing in mind the global 317
MONSEN et al.
increase in resistance among antimicrobials, such agents may be of great importance (10–16). Actually, clinicians often experience clinical cure of LUTIW despite laboratoryreported resistance to the antimicrobials prescribed. Reports indicate that S. saprophyticus is eradicated by PIV treatment (15, 17, 18), while clinical and bacteriological outcomes of infections caused by other mecillinam-resistant species have rarely been reported (15). The aim of the present study was to compare the clinical and bacteriological outcomes of PIV vs placebo treatment among uropathogens in LUTIW with special focus on mecillinam-resistant isolates. MATERIAL AND METHODS
Mecillinam susceptibility tests were performed using multipoint inoculation of isolates on agar plates (21). Mecillinam resistance in E. coli was defined as isolates with a minimal inhibitory concentration (MIC) of >8 mg/L, while. S. saprophyticus, enterococci and other gram-positive uropathogens as well as Pseudomonas species were not tested as they were considered intrinsically resistant according to the Swedish Reference Group for Antibiotics (www.srga.org). Outcomes of therapy and definitions Clinical outcomes were evaluated by patient diaries in terms of mean symptoms score (MSS) and cure when the patient was free from symptoms at follow-up visits. Bacteriological outcome was evaluated by urine cultures at inclusion and at follow-up. Cure was defined as eradication of original species at follow-up.
Study design The present study was a prospective, multicentre, randomized, double-blind, placebo-controlled therapy study (the LUTIW project) performed during 1995–1998 (19, 20). Patients with symptoms suggestive of LUTIW were included at 18 primary health care centres in northern Sweden with exclusion criteria as previously reported (19). Patients were randomized to three different regimens of PIV (Selexidâ, LEO Pharma, Copenhagen, Denmark: 200 mg 9 3 9 7 days, 200 mg 9 2 9 7 days or 400 mg 9 2 9 3 days) or placebo. All PIV regimens were pooled to one treatment group. UTI symptoms (urgency, dysuria, suprapubic or loin pain) were registered using patient diaries with the scores 0–3 (none, mild, moderate, or severe respectively) at inclusion and at follow-up visits 8–10 and 35–49 days post inclusion (19). Bacteriological methods and susceptibility tests Midstream urine samples were collected at inclusion and follow-up visits and transported to the Laboratory of Clinical Bacteriology, University Hospital of Ume a for culture. Uropathogens were quantified as colony-forming units (CFU)/L and identified as previously described (19). Significant bacteriuria (SBU) was according to European guidelines: in patients with symptoms as ≥106 CFU/L for primary pathogens, ≥107 for secondary pathogens, and ≥108 for doubtful pathogens as in patients free from symptoms (5). In cultures with mixed flora and one predominant species, the latter species was defined as an uropathogen (19). Non-significant bacteriuria was defined as negative cultures as well as samples with mixed flora without predominant species.
318
Statistical analysis Comparison of proportions was done using chisquare test or Fisher’s exact test. Analysis of variance was used for comparison of mean symptoms scores. Post-hoc analysis was performed using Bonferroni correction at inclusion and Dunnette′s T3 at the first and last follow-up visit respectively. P-values
