Mutational change of CTX-M-15 to CTX-M-127 resulting in mecillinam resistant Escherichia coli during pivmecillinam treatment of a patient.

Pivmecillinam (amdinocillin pivoxil) is the recommended first-choice antibiotic used to treat urinary tract infections (UTIs) in Denmark. The frequency of mutation to mecillinam (MEC) resistance is described as high in vitro; however, treatment of UTI has a good clinical response and prevalence of mecillinam resistance in Escherichia coli remains low despite many years of use. We describe occurrence of in vivo mecillinam resistance in a clinical isolate of ESBL-producing E. coli following pivmecillinam treatment. The identified phenotypic differences in the mecillinam resistant isolate compared with the original mecillinam susceptible isolate were a full-length LPS with O-antigen (O25), mecillinam resistance and a lower MIC for ceftazidime. Regarding genotype, the resistant isolate differed with a mutation in blaCTX-M-15 to blaCTX-M-127 , loss of a part of a plasmid and a genomic island, respectively, and insertion of a transposase in wbbL, causing the rough phenotype. The observed mecillinam resistance is expected to be caused by the mutation in blaCTX-M-15 with additional contribute from the serotype shift. We continue to recommend the use of pivmecillinam as first-line treatment for UTI.

Emerging clinical role of pivmecillinam in the treatment of urinary tract infections caused by Extended Spectrum ßeta-lactamase (ESBL) producing Enterobacteriaceae.

BACKGROUND: Extended Spectrum ßeta-lactamase (ESBL)-producing Enterobacteriaceae causing urinary tract infections (UTIs) appear resistant to many common oral agents. There is a growing need to discover new antibiotics to combat with emerging antibiotic resistance problem. Until the discovery of new antimicrobials, we can bring back forgotten antibiotics to our clinical formulary. Pivmecillinam (prodrug of mecillinam), an oral antimicrobial agent is effective against ESBL producing organisms. We analysed the sensitivity rates of ESBL-producing Enterobacteriaceae from urine samples to mecillinam and to document if pivmecillinam is a suitable alternative option in the treatment of UTI. MATERIALS/METHODS: This retrospective study was conducted from September 2015 to September 2017. Data were collected from the pathology information system. Antimicrobial sensitivity testing on ESBL-producing Enterobacteriaceae isolates was carried out by disc diffusion method in accordance with The European Committee on Antimicrobial Susceptibility Testing. RESULTS: A total of 986 ESBL-producing Enterobacteriaceae were tested for mecillinam during the study period. Of 986 organisms, Escherichia coli was the most common organism (889); followed by Klebsiella species (71) and others Enterobacteriaceae (26). Mecillinam sensitivity was found in 96% Escherichia coli (855/889 isolates), 83% Klebsiella species (59/71 isolates) and 88% other Enterobacteriaceae (23/26 isolates). Overall 95% (935/986 isolates) of ESBL-producing urinary isolates were sensitive to mecillinam. CONCLUSIONS: Pivmecillinam appears to be suitable option to treat ESBL-producing Enterobacteriaceae causing uncomplicated UTI. Our results showed low resistance rate to mecillinam. We recommend the use of pivmecillinam in uncomplicated UTIs because of ESBL-producing Enterobacteriaceae. More studies on in vitro activity of mecillinam against ESBL producing organism and its use and clinical outcome should be tried in future.

Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland.

BACKGROUND: The prevalence of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin. METHODS: A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents. RESULTS: Sixty-nine percent of patients (N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively. CONCLUSIONS: This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.

Efficacy of pivmecillinam for treatment of lower urinary tract infection caused by extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

To evaluate the clinical and bacteriological efficacy of pivmecillinam against lower urinary tract infection (UTI) caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, patients treated for lower UTI with pivmecillinam (n=8) were studied. Patients treated with nitrofurantoin (n=3) and trimethoprim (n=3) or a combination of these agents with pivmecillinam (n=3) were included as a control group. Antimicrobial susceptibility was determined with EUCAST methodology. Bacteriologic cure was defined as <10(3) CFU/ml at follow-up (30 days), and clinical cure as resolved UTI symptoms after completed treatment. All patients receiving pivmecillinam had good clinical response (8/8), but bacteriological cure rates were low (2/8). However, none of the patients with persisting bacteriuria had a relapse of UTI symptoms within 6 months. All isolates were susceptible to the given antimicrobial. Most isolates belonged to the CTX-M-1 group (n=11, 65%) or CTX-M-9-group (n=4, 24%). Four E. coli isolates belonged to the international clone O25b-ST131 (25%). In conclusion, pivmecillinam had good clinical activity against lower UTI caused by ESBL-producing Enterobacteriaceae, but bacteriological cure rates were low. The persistent bacteriuria appears to be of little clinical importance, but larger clinical studies are needed to determine the usefulness of pivmecillinam in infections caused by ESBL-producing bacteria.

Oral treatment options for ambulatory patients with urinary tract infections caused by extended-spectrum-beta-lactamase-producing Escherichia coli.

An increase in extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli has been observed in outpatient settings. Consequently, 100 ESBL-positive E. coli isolates from ambulatory patients with clinically confirmed urinary tract infections were collected by a single laboratory between October 2004 and January 2008. Antimicrobial susceptibility testing was carried out using the oral antibiotics fosfomycin, pivmecillinam, and nitrofurantoin and the parenteral antibiotic ertapenem. Susceptibility rates indicate that fosfomycin (97%), nitrofurantoin (94%), and pivmecillinam (85%) could be considered important oral treatment options.

[Antibiotic treatment of acute gastroenteritis]. / Tratamiento antibiótico de la gastroenteritis aguda.

The empiric antibiotic therapy for acute gastroenteritis (AGE) is indicated only in patients with underlying diseases or risk for bacteremia. The clinical characteristics, clinical efficiency of antibiotic therapy with pivmecillinam (52 patients) or ciprofloxacin (75 patients) and its effects on the fecal carrier state of Salmonella spp. were studied in 127 adult patients with AGE and antibiotic therapy indication. The initial stool culture was positive in 90 patients (71%). The microorganism recovered most frequently was Salmonella spp., with a bacteremia rate in these patients of 5%. The susceptibility of Salmonella spp. to ciprofloxacin and mecillinam was 100% and 90%, respectively. Therapy with ciprofloxacin or pivmecillinam showed a similar efficiency. Fecal excretion lasted no longer than five weeks and no chronic carriers were observed.

Comparative efficacies of pivmecillinam and ampicillin in acute shigellosis.

The clinical efficacies of pivmecillinam and ampicillin were compared in a randomized double-blind trial in the treatment of acute shigellosis. Of 44 adult male patients, all culture positive for Shigella strains, 22 patients received 400 mg of pivmecillinam and 22 patients received 500 mg of ampicillin every 6 h. Both drugs were administered orally for 5 days. Four patients receiving ampicillin were infected with Shigella strains that were resistant to ampicillin but susceptible to pivmecillinam, and two patients receiving pivmecillinam were infected with Shigella strains resistant to both ampicillin and pivmecillinam. The mean duration of diarrhea in all patients receiving pivmecillinam was 3.3 days compared with 4.5 days in patients receiving ampicillin (P less than 0.05). When patients infected with the resistant strains were excluded, the mean duration of diarrhea in patients receiving pivmecillinam was 3.2 days compared with 4.1 days in patients receiving ampicillin. The patients infected with strains susceptible to both antibiotics had mean durations of fecal excretion of Shigella strains of 1.2 days for those treated with pivmecillinam and 1.4 days for those treated with ampicillin. The patients infected with organisms resistant to both drugs had longer durations of diarrhea and fecal excretion of Shigella strains. The results suggest that pivmecillinam is as effective as ampicillin and can be a useful drug for the treatment of shigellosis.

Pivmecillinam in treatment of Staphylococcus saprophyticus urinary tract infections.

In a non-randomised trial 15 women with Staphylococcus saprophyticus bacteriuria were treated with pivmecillinam 200 mg t.i.d. for 1 week. At follow-up 2-4 weeks post treatment only 11 patients were cured. As a complement to the study the occurrence of Staph. saprophyticus bacteriuria was analysed according to age, sex and season. Mecillinam MIC's and viability curves of Staph. saprophyticus were investigated. It is concluded that mecillinam should only be used to treat urinary tract infections caused by bacteria sensitive in vitro.