Microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections caused by ESBL-producing Escherichia coli.

The aim of this study was to identify microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections (ca-UTIs) caused by ESBL-producing Escherichia coli. Eighty-nine ESBL-producing E. coli isolated from women suffering from ca-UTIs were included. The susceptibilities to mecillinam were determined using MIC gradient strip. Whole genome sequencing was performed on a MiSeq platform, and genome assembly was performed using SPAdes v3.11.0. Neither mecillinam MICs nor ESBL genotypes were associated with treatment outcome of patients treated with pivmecillinam. Specific STs, however, showed significant differences in treatment outcome. Patients infected with ST131 were more likely to experience treatment failure compared to patients infected with non-ST131 (p 0.02) when adjusted for pivmecillinam dose, mecillinam MIC and severity of infection. Patients infected with ST69 were more often successfully treated compared to patients infected with non-ST69 (p 0.04). Patients infected with blaCTX-M-15 ST131 strains were more likely to experience treatment failure than those infected with non-blaCTX-M-15 ST131 strains (p 0.02). The results suggest that specific STs are associated with the clinical efficacy of pivmecillinam. Further studies with a larger number of strains, including a larger number of mecillinam resistant strains, are needed to confirm these results.

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.

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.

Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women.

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 1995­1998 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.

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.

Inequality in quality? Regional and educational differences in treatment with fluoroquinolone in urinary tract infection of 236,376 Swedish patients.

BACKGROUND: In an international effort to reduce antibiotic resistance, in part suggested to be the effect of inappropriate antibiotic use, several quality indicators for outpatient antibiotic use have been proposed. In this study, geographical and educational differences in fluoroquinolone prescription in the treatment of urinary tract infection in women are presented. METHODS: The age-adjusted ratio of women who were dispensed fluoroquinolones (ciprofloxacin or norfloxacin) among all 236,376 women dispensed any of the following antibiotics used in the treatment of lower urinary tract infection were studied: ciprofloxacin, norfloxacin, pivmecillinam, trimethoprim and nitrofurantoin. Only the first prescription during July 2006 to June 2007 was studied. Prescription data were linked to information on geographical area, marital status, country of birth and educational attainment, which allowed multivariate analysis of the importance of these factors. RESULTS: The rate of fluoroquinolone prescription varied from 29.5% to 17.1% in the 21 regions in Sweden. Middle-aged women with ≥15 years of schooling were more often prescribed fluoroquinolones compared to those with only 9 years (OR 1.28, 95% CI 1.23 to 1.34). CONCLUSION: Quality indicators in healthcare should be developed bearing in mind the overall level of adherence to guidelines and whether there are regional or socioeconomic or other differentials in their distribution in the population because such differentials in healthcare quality might further contribute to inequalities in health.

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.

Antibiotics for the treatment of dysentery in children.

BACKGROUND: Ciprofloxacin, ceftriaxone and pivmecillinam are the antibiotics currently recommended by the World Health Organization (WHO) for the treatment of dysentery in children; yet there have been no reviews of the clinical effectiveness of these antibiotics in recent years. METHODS: We reviewed all literature reporting the effect of ciprofloxacin, ceftriaxone and pivmecillinam for the treatment of dysentery in children in the developing countries. We used a standardized abstraction and grading format and performed meta-analyses to determine the effect of treatment with these antibiotics on rates of treatment failure, bacteriological failure and bacteriological relapse. The CHERG Standard Rules were applied to determine the final effect of treatment with these antibiotics on diarrhoea mortality. RESULTS: Eight papers were selected for abstraction. Treatment with ciprofloxacin, ceftriaxone or pivmecillinam resulted in a cure rate of >99% while assessing clinical failure, bacteriological failure and bacteriological relapse. CONCLUSIONS: The antibiotics recommended by the WHO--ciprofloxacin, ceftriaxone and pivmecillinam--are effective in reducing the clinical and bacteriological signs and symptoms of dysentery and thus can be expected to decrease diarrhoea mortality attributable to dysentery.

Association between antimicrobial consumption and resistance in Escherichia coli.

During a 9-year study period from 1997 through 2005, the association between antimicrobial resistance rates in Escherichia coli and outpatient antimicrobial consumption was investigated in 20 hospital districts in Finland. A total of 754,293 E. coli isolates, mainly from urine samples, were tested for antimicrobial resistance in 26 clinical microbiology laboratories. The following antimicrobials were studied: ampicillin, amoxicillin-clavulanate, cephalosporins, fluoroquinolones, trimethoprim, trimethoprim-sulfamethoxazole, pivmecillinam, and nitrofurantoin. We applied a protocol used in earlier studies in which the level of antimicrobial consumption over 1 year was compared with the level of resistance in the next year. Statistically significant associations were found for nitrofurantoin use versus nitrofurantoin resistance (P < 0.0001), cephalosporin use versus nitrofurantoin resistance (P = 0.0293), amoxicillin use versus fluoroquinolone resistance (P = 0.0031), and fluoroquinolone use versus ampicillin resistance (P = 0.0046). Interestingly, we found only a few associations between resistance and antimicrobial consumption. The majority of the associations studied were not significant, including the association between fluoroquinolone use and fluoroquinolone resistance.

Hyperimmune bovine colostrum in the treatment of shigellosis in children: a double-blind, randomized, controlled trial.

UNLABELLED: Immunological approaches have been considered as an alternative therapeutic option for the treatment of enteric infections over the past few years. Hyperimmune bovine colostrum (HBC) is a potentially innovative immunological option in the management of shigellosis together with traditional antibiotic therapy. Children aged 1-12 y with a history of bloody mucoid diarrhoea of less than 5 d duration were enrolled after their stool specimen was found to be positive for Shigella dysenteriae type I antigen by a rapid diagnostic fluorescent antibody staining test. They were randomized to receive either HBC containing very high titres of antibody against S. dysenteriae type I antigen or bovine colostrum (BC) without any antibody. The study group received 100 ml of HBC three times a day orally for 3 d and control group received BC. Children also received pivmecillinam in a dose of 50 mg kg(-1) d(-1) in four divided doses orally for 5 d. Admission characteristics of the 34 children in the HBC group and 35 in the BC group were comparable. No significant differences were observed in duration of diarrhoea, fever, anorexia, abdominal pain, tenesmus, stool frequency or visible blood in the stool between the groups. Two (6%) children in the study and five (14%) in the control group remained stool culture positive for S. dysenteriae type 1, even after 5 d of sensitive antimicrobial therapy. CONCLUSION: The results indicate that HBC as an adjuvant is unable to show any beneficial effect in reducing the stool frequency, duration or severity of childhood shigellosis due to S. dysenteriae type I infection.

Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis.

BACKGROUND: Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. The fluoroquinolone agent ciprofloxacin is active in vitro against these strains of bacteria, but has not been routinely used to treat acute childhood infections because of concern that quinolones may cause arthropathy in children. We undertook a randomised double-blind study to test the effects of ciprofloxacin treatment in children with shigella dysentery. METHODS: We compared the efficacy and toxic effects of ciprofloxacin suspension (10 mg/kg every 12 h for 5 days, maximum individual dose 500 mg) with those of pivmecillinam tablets (15-20 mg/kg every 8 h for 5 days, maximum individual dose 300 mg). We enrolled 143 children aged 2-15 years with dysentery of 72 h or less duration. Patients stayed in hospital for 6 days, and were followed up 7, 30, and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentery on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. FINDINGS: 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 (80%) of 60 patients who received ciprofloxacin and in 39 (65%) of 60 patients who received pivmecillinam (p=0.10). Treatment was bacteriologically successful in all of the patients receiving ciprofloxacin, and in 54 (90%) of the patients receiving pivmecillinam (p=0.03). Joint pain after treatment began in 13 (18%) of 71 patients who received ciprofloxacin and 16 (22%) of 72 patients who received pivmecillinam (p>0.2), and no patient had signs of arthritis. INTERPRETATION: In our trial, ciprofloxacin suspension and pivmecillinam had the same clinical efficacy. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. We conclude that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

[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.

Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults.

OBJECTIVE: To compare the efficacy of cefixime with that of pivamdinocillin in the treatment of adults with acute dysentery caused by Shigella infection. DESIGN: Randomized, double-blind clinical trial. SETTING: A diarrhea treatment center in Dhaka, Bangladesh. PATIENTS: 30 men with dysentery lasting 72 hours or less. INTERVENTIONS: Patients were randomly assigned to receive either 400 mg of cefixime every 24 hours (n = 15) or 400 mg of pivamdinocillin every 6 hours (n = 15) for 5 days. All patients were hospitalized for 6 days. Patients in whom initial drug therapy failed received alternative antimicrobial therapy. MEASUREMENTS: Physical examinations were done and symptoms were recorded daily, and body temperatures were measured every 6 hours. Stools were counted and examined for consistency and for the presence of blood and mucus. Therapy failed if symptoms of dysentery persisted for more than 72 hours or if, on study day 5, a patient had six stools, one watery or bloody-mucoid stool, or an oral temperature higher than 37.8 degrees C. Bacteriologic failure of therapy occurred if Shigella could be isolated from a stool sample on or after study day 3. RESULTS: Therapy failed in seven (47%) patients given cefixime but in none of the patients given pivamdinocillin (P = 0.006). Patients given cefixime had longer duration of fever (median, 6 hours compared with 0 hours, P = 0.019), longer duration of the period with dysenteric stools (median, 4 days compared with 1 day, P = 0.001), and more stools during the 6 study days (median, 65 compared with 28, P = 0.002) than patients treated with pivamdinocillin. Bacteriologic failure of therapy occurred in 60% of patients (9 of 15) given cefixime and 13% of those (2 of 15) given pivamdinocillin (P = 0.009). CONCLUSION: Cefixime is ineffective in treating shigellosis in adults when used in the standard recommended dosage.

Comparative trial of five antimicrobial compounds in the treatment of cholera in adults.

To compare the efficacy of ciprofloxacin, erythromycin, nalidixic acid and pivmecillinam in the treatment of tetracycline-resistant strains of Vibrio cholerae O1 in adults, a randomized, open, clinical trial was conducted. A tetracycline group was used for comparison. Seventy-five adult men infected with V. cholerae O1 were randomly assigned to receive either 400 mg pivmecillinam or 500 mg of one of each of the other drugs. Ciprofloxacin was given every 12 h and the others every 6 h for 3 d. The mean total stool volume per kg was 155 mL for the ciprofloxacin group, 212 mL for the erythromycin and pivmecillinam groups, 246 mL for nalidixic acid, and 293 mL for tetracycline. The difference between ciprofloxacin and tetracycline was significant (P = 0.045). After 72 h, diarrhoea had stopped in 14 patients (93%) in the ciprofloxacin group and 12 (80%) in the erythromycin group, compared to 5 (42%) of those receiving tetracycline (P = 0.006 and 0.049, respectively). Bacteriological clearance was 100% at 24 h in patients treated with ciprofloxacin compared to 20% and 8.3% (P < 0.001 for both comparisons) in the erythromycin and tetracycline groups. Ciprofloxacin in conjunction with appropriate fluid therapy was the most effective treatment for cholera in adults; erythromycin was the next best.

Short-term treatment of acute urinary tract infection in girls. Copenhagen Study Group of Urinary Tract Infections in Children.

The efficiency of treatment of acute urinary tract infections with sulfamethizole for 3 days, sulfamethizole for 10 days, and pivmecillinam for 3 days was compared in a randomized multicentre study comprising 264 girls aged 1-15 years. For ethical reasons children with complicated diseases were not included. In these treatment groups no significant growth after treatment was found in 81%, 77%, and 74%, respectively (NS). New bacteria after treatment were found less frequently after sulfamethizole for 3 days (4%) when compared to sulfamethizole for 10 days (14%) and pivmecillinam for 3 days (13%) (p = 0.048). After pivmecillinam treatment 75% of new bacteria were Streptococcus faecalis versus 25% after sulfamethizole for 3 days and 18% after sulfamethizole for 10 days (p = 0.016). In the subgroup with nephro-urological abnormalities no significant growth after treatment was found in 68% of the sulfamethizole 3-day treated group, 54% of the sulfamethizole 10-day treated group, and 67% of the pivmecillinam 3-day treated group (NS). All treatments resulted in a change in the bacterial sensitivity pattern when bacteria isolated 1-10 days after treatment was compared to those found before treatment. This was more pronounced after the 10-day treatment when compared to the 3-day treatment. The sensitivity patterns of the bacteria isolated from recurrences were similar to those seen before treatment. After treatment there was no difference in the actuarial percentage recurrence-free curves of the 3 treatment groups. Side effects were rare in the sulfamethizole treated groups, and seen more often in the pivmecillinam treated group. 3-day treatment with sulfamethizole or alternatively pivmecillinam is recommended as first choice for treatment of uncomplicated acute urinary tract infections in girls.

In vitro sensitivity of organisms causing urinary tract infections to four common oral antibiotics and to pivmecillinam

The in-vitro sensitivity to ampicillin, cotrimoxazole, nitrofuratoin, nalidixic acid and mecillinam was determined for 511 organisms isolated from 399 consecutive urine specimens. Urine specimens were divided into those of hospital in-patient origin (group A) and those from comunity patients(group B). Group B organisms were more sensitive than group A organisms. Over 75% of all group B organisms were sensitive to nitrofurantoin, nalidixic acid and mecillinam. Organisms resistant to multiple antibiotics were more frequently isolated from group A catheterized patients and are now less frequently isolated than in 1983. The antibiotic implications of these findings are discussed

In-vitro sensitivity of organisms causing urinary tract infections to four common oral antibiotics and to pivmecillinam

The in-vitro sensitivity to ampicillin, cotrimoxazole, nitrofuratoin, nalidixic acid and mecillinam was determined for 511 organisms isolated from 399 consecutive urine specimens. Urine specimens were divided into those of hospital in-patient origin (group B). Group B organisms were more sensitive than group A organisms. Over 75 percent of all group B organisms were sensitive to nitrofurantoin, nalidixic acid and mecillinam. Organisms resistant to multiple antibiotics were more frequently isolated from group A catheterized patients and are now less frequently isolated than in 1983. The antibiotic implications of these findings are discussed (AU)

The effectiveness of a short perioperative course with pivampicillin/pivmecillinam in transurethral prostatic resection: bacteriological results.

We analysed the bacteriological findings in 261 patients undergoing transurethral prostatic resection (TUR) and receiving either an oral course of pivampicillin/pivmecillinam (PAPM) or parenteral cefotaxime (CFT) in a randomized clinical trial. 123/261 patients had bacteriuria before TUR; 80% of the bacteria were gram-negative strains and 20% gram-positive. 88% of the strains were sensitive to PAPM and 93% to CFT but only 58% to ampicillin. The sensitivity of recurring bacteria was not influenced by the short course of PAPM or CFT. The faecal flora was influenced by the treatment with PAPM in terms of growth of Pseudomonas aeruginosa and fungi in some patients, but no resistant strains of Enterobacteriaceae were observed. The peak serum concentrations of ampicillin and mecillinam were obtained 2 hours after intake of the drug and were 4.5 micrograms/ml and 1.7 micrograms/ml respectively. The prostate tissue concentration of ampicillin and mecillinam (AM) was low.

Nalidixic acid and pivmecillinam for treatment of acute lower urinary tract infections.

Women, 15-45 years of age, with symptoms of lower urinary tract infection (UTI) were randomly treated with nalidixic acid (1 g X 3) or pivmecillinam (200-400 mg X 3) for three or seven days, respectively. Therapeutic failure, relapse, or reinfection occurred among 18% of 82 women, even though the isolated strains of gram-negative rods in these patients were susceptible in vitro to the antibiotics used. Therapeutic failure, i.e. no effect or at best only a minor effect on the symptoms, was registered in 10 of 13 cases of UTI caused by Staphylococcus saprophyticus and treated with nalidixic acid, which was consistent with the high minimum inhibitory concentrations (MIC) (128-512 micrograms/ml) of this antibiotic. S. saprophyticus was isolated in 9 of 12 patients during treatment with nalidixic acid. On the other hand, pivmecillinam therapy was clinically effective in 16 of 18 patients with UTI caused by S. saprophyticus, even though the MIC of mecillinam to these strains was considerably higher (8-64 micrograms/ml) than that vis-à-vis gram-negative rods. Thus the clinical effect of pivmecillinam was significantly better than that of nalidixic acid in cases of UTI caused by S. saprophyticus. The organism was not isolated from 14 patients receiving pivmecillinam therapy.