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.

Best oral empirical treatment for pyelonephritis in children: Do we need to differentiate between age and gender?

BACKGROUND: Pyelonephritis is a common infection in childhood and may cause renal scarring. The aim was to determine an effective oral antibiotic treatment of first time pyelonephritis in children. METHODS: The study is a retrospective analysis of positive urine cultures collected at a Danish paediatric department from 2010-2013. Urine samples from 378 children aged 0-15.9 years, without renal anomalies and treated for first time pyelonephritis, were included. The urine pathogens and antimicrobial susceptibilities were analysed. RESULTS: The most common aetiologic agents found were Escherichia coli (85%), Klebsiella species and other Enterobacteriaecea (9.7%) and Enterococcus species (5.3%). Escherichia coli was significantly more common in girls than in boys (90% vs 74%, p < 0.001) and in children older than 6 months (89% vs 77%, p < 0.001). Children younger than 6 months had a higher prevalence of other Gram-negative rods (16% vs 7%, p < 0.001). These differences may be due to boys representing 63% of patients in the youngest age group compared to 16% of older children (p < 0.001). For all urine isolates, piv-mecillinam and amoxicillin-clavulanate had the lowest resistance rates of 6.9% and 7.2%, respectively, and 6% for both antimicrobials in patients older than 6 months. Uropathogens from boys above 6 months of age were more resistant to piv-mecillinam compared to girls (25% vs 2.4%, p < 0.001). CONCLUSION: This study recommends piv-mecillinam or amoxicillin-clavulanate as empirical treatment of first time pyelonephritis in Danish children from 6 months of age. Age and gender of patients should be taken into consideration when initiating empirical treatment.

Epidemiological factors associated with ESBL- and non ESBL-producing E. coli causing urinary tract infection in general practice.

The purpose of the study was to evaluate how use of antibiotics precedes the presence of ESBL-producing E.coli in general practice. The authors performed a triple-case-control study where three case groups were individually compared to a single control group of uninfected individuals. Urine samples were prospectively collected and retrospective statistical analyses were done. This study included 98 cases with urinary tract infection (UTI) caused by ESBL-producing E. coli, 174 with antibiotic-resistant (non-ESBL) E. coli, 177 with susceptible E. coli and 200 with culture negative urine samples. Case groups had significantly higher use of antibiotics than the control group within 30 days before infection (p < 0.0001). The ESBL group had significantly more hospital admissions than the other case groups (p < 0.05). Hospital admission was an independent risk factor for community onset UTI by ESBL-producing E. coli. Exposure to antibiotics was a risk factor for UTI with E. coli, while prior antibiotic usage was not an indisputable predictor for infection with ESBL-producing E.coli in general practice.

French results of the ARESC study: clinical aspects and epidemiology of antimicrobial resistance in female patients with cystitis. Implications for empiric therapy.

OBJECTIVE: Uncomplicated cystitis is one of the most frequent community infections. We report the French results of the international ARESC study on the clinical aspects, epidemiology, and antimicrobial susceptibility of uropathogens. PATIENT AND METHODS: Female patients between 18 and 65 years of age, with symptoms of uncomplicated cystitis, were investigated clinically with urinalysis and urine culture. Uropathogens were identified and their susceptibility was tested with nine antimicrobials. RESULTS: Four thousand and four hundred patients were included, 871 in France, forming the largest national cohort. Urine culture was positive (cfu≥10(4)/ml) in 550 (63.1%); 533 (96.9%) presented with a single bacterium infection. 488 uropathogens, collected from 479 patients, were analyzed. The most frequent were: Escherichia coli (83.8%), Staphylococcus saprophyticus (4.3%), Proteus mirabilis (3.1%), enterococci (1.2%), and Klebsiella pneumoniae (1.0%). E. coli was highly susceptible to fosfomycin (99.0%) (97.1%), nitrofurantoin (97.3%), and ciprofloxacin (98.3%). The lowest susceptibility rates were found for ampicillin (60.9%) and cotrimoxazole (87.8%). Fosfomycin (97.8%), ciprofloxacin (98.3%), and nitrofurantoin (91.5%) had the highest susceptibility rate. The lowest susceptibility rates were observed with ampicillin (61.4%) and cotrimoxazole (86.5%). CONCLUSIONS: Fosfomycin, pivmecillinam (not available in France), and nitrofurantoin have preserved their in vitro activity and are suitable for empiric therapy. Cotrimoxazole (trimethoprim+sulfamethoxazole) and fluoroquinolones are not usually recommended as first intention drugs for the empiric therapy of uncomplicated cystitis, because of increasing resistance rates.

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.

[Clinical efficacy of tebipenem pivoxil treatment in children with pneumonia, who had no relief despite having administered oral beta-lactam antibiotics].

We assessed the clinical efficacy of tebipenem pivoxil (TBPM-PI) in 30 children with pneumonia who, despite having received oral administration of beta-lactam antibiotics at the standard dose for at least 3 days, had no relief of symptoms and showed an abnormal shadow on the chest X-ray and elevated serum CRP levels of 3.0 mg/dl or more between December 2009 and November 2010. TBPM-PI was administered at a single dose of 4 mg/kg twice a day for 3 days. The children ranged in age from 8 months to 5 years. The serum CRP level ranged from 3.05 to 12.9 mg/dl. In 28 of the 30 children, either Streptococcus pneumoniae or Haemophilus influenzae or both were detected. Of the 28 children, 7 carried penicillin resistant S. pneumoniae; 9 carried beta-lactamase nonproducing ampicillin resistant H. influenzae; and 3 carried both. In all children, defervescence was observed within 48 hours of the start of TBPM-PI administration, and the severity of coughing/wheezing reduced significantly by the 3rd to 5th day. Thus, TBPM-PI was determined to be effective. Diarrhea or loose stool was observed as an adverse reaction in 4 children (13.3%).

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.

Urine bactericidal activity against Escherichia coli isolates exhibiting different resistance phenotypes/genotypes in an in vitro pharmacodynamic model simulating urine concentrations obtained after oral administration of a 400-milligram single dose of cefditoren-pivoxil.

Activity of simulated cefditoren urinary concentrations was determined against seven Escherichia coli isolates. Bactericidal activity was obtained from 4 to 24 h against TEM-1 (penicillinase production/hyperproduction), TEM-34 (IRT-6), and TEM-116 (extended-spectrum beta-lactamase [ESBL]) and from 6 to 8 h against SHV/TEM-116 (ESBL) but never against SHV/TEM-1 (ESBL). Extension of bactericidal activity depended on the resistance genotype/phenotype tested.

New media for the semiselective isolation and enumeration of Xanthomonas campestris pv. mangiferaeindicae, the causal agent of mango bacterial black spot.

AIMS: Mango bacterial black spot, caused by Xanthomonas campestris pv. mangiferaeindicae, is a potentially severe disease in several tropical and subtropical areas. Data describing the life cycle of the pathogen are needed for improving integrated pest management strategies. Because of the important bacterial microflora associated with mango leaves, isolation of the pathogen is often difficult using nonselective agar media. METHODS AND RESULTS: A previously developed medium, BVGA, failed to inhibit several Gram-negative saprophytic bacteria, especially those belonging to Enterobacteriaceae. Two new semiselective media were developed. The selectivity of KC and NCTM3 media was achieved using cephalexin 40 mg l(-1), kasugamycin 20 mg l(-1) and neomycin 1 mg l(-1), cephalexin 100 mg l(-1), trimethoprime 5 mg l(-1), pivmecillinam 100 mg l(-1) respectively. Plating efficiencies ranged from 76 to 104% and from 78 to 132% for KC and NCTM3 respectively. CONCLUSIONS: The new media allowed the growth of X. campestris pv. mangiferaeindicae whatever its country of isolation. The pathogen was repeatedly isolated with these media from asymptomatic leaves sampled in growth chamber experiments. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides a description of new semiselective media, which should be valuable tools to study the ecology and epidemiology of X. campestris pv. mangiferaeindicae.

Ecological effects of perorally administered pivmecillinam on the normal vaginal microflora.

The knowledge of the effects of antimicrobial agents on the normal vaginal microflora is limited. The objective of the present study was to study the ecological impact of pivmecillinam on the normal vaginal microflora. In 20 healthy women, the estimated day of ovulation was determined during three subsequent menstrual cycles. Microbiological and clinical examinations were performed on the estimated day of ovulation and on day 3 in all cycles and also on day 7 after ovulation in cycles 1 and 2. Anaerobic and facultative anaerobic gram-positive rods, mainly species of lactobacilli and actinomycetes, dominated the microflora. One woman was colonized on the third day of administration with a resistant Escherichia coli strain, and Candida albicans was detected in one woman on days 3 and 7 in cycle 2. No other major changes in the normal microflora occurred during the study. Administration of pivmecillinam had a minor ecological impact on the normal vaginal microflora.

[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.

Impaired ketogenesis in carnitine depletion caused by short-term administration of pivalic acid prodrug.

Long-term treatment with pivalic acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty acid oxidation in the liver during short-term treatment with drugs conjugated with pivalic acid.

Comparative efficacy of pivmecillinam and cotrimoxazole in acute shigellosis in children.

In a prospective randomized double-blind trial, pivmecillinam was compared with cotrimoxazole (TMP-SMX), both given orally for a period of 5 days, for the treatment of 59 children with shigellosis. 29 patients were treated with pivmecillinam and 30 with cotrimoxazole. 14% of shigella organisms isolated were resistant to pivmecillinam and 21% to TMP-SMX. The diarrhea persisted for a mean (+/- SD) period of 74 +/- 24.8 h in the pivmecillinam-treated patients versus 73.8 +/- 34 h in the TMP-SMX-treated patients. Duration of fever, positive stool culture, visible blood, occult blood, and pus cells in the stools were similar for both treatment groups. Five patients (17%) in the pivmecillinam group and 4 patients (13%) in the cotrimoxazole group fulfilled the clinical criteria that defined treatment failure. One patient (3.4%) in the pivmecillinam group and 2 (6.6%) in the TMP-SMX group evidenced recurrence of the diarrheal symptoms at the follow-up visit. No major drug-related side effects were observed in either group. We concluded that pivmecillinam is equivalent to cotrimoxazole in the treatment of shigellosis in children.

Pivampicillin/pivmecillinam in the treatment of shigella carriers.

24 patients (4-65 years old; median age 29 years) excreting shigella bacteria greater than 8 weeks were treated with the combination pivampicillin (0.25 g)/pivmecillinam (0.20 g), 2 tablets 3 times a day for 14 days. 23/24 patients (96%) were culture negative after treatment. The one patient that did not respond to treatment carried a strain with intermediate sensitivity to mecillinam and resistance to ampicillin. It is concluded that pivampicillin/pivmecillinam is effective for patients excreting shigella bacteria.

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.

The influence of long-term treatment with mecillinam on fecal Escherichia coli.

The influence of long-term treatment with a low dose of pivmecillinam on the fecal flora was investigated. Before treatment Escherichia coli was detected in about 88% of 30 outpatients with chronic recurrent urinary tract infections, but after 1-2 months only about 55% had detectable E. coli in the intestinal flora. E. coli resistant to mecillinam were not selected during the therapy. A similar group of patients treated with nitrofurantoin showed neither changes in the E. coli flora nor in the resistance pattern.

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.