Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study.

OBJECTIVES: To evaluate the importance of treatment duration for therapeutic efficacy of pivmecillinam for community-acquired urinary tract infections (UTIs) caused by Escherichia coli. METHODS: A retrospective cohort study was conducted between 1 January 2010 and 30 September 2016 in adults with community-acquired E. coli bacteriuria, treated empirically with pivmecillinam. Regimens of 3, 5 and 7 days were compared using clinical treatment failure (i.e. redemption of a new antibiotic or hospitalization due to UTI) within 14 and 30 days as outcome. HR and risk difference with 95% CI were estimated for treatment failure. Results were stratified by age (18-50, 51-70, >70 years) and sex. RESULTS: Of the 21864 cases of E. coli UTI that were analysed, 2524 (11.5%) were in men. In 954 cases (4.4%) E. coli produced ESBL and 125 (13.1%) of the cases were in men. The 3 day regimen increased the risk of treatment failure for all groups. The risk differences between the 3 and 5 day regimens were <10% for women, but >10% for men. Comparing the 7 day and 5 day regimens, only women aged >50 years demonstrated an increased risk of treatment failure within 14 days with the 5 day regimen, but not within 30 days. CONCLUSIONS: With the current data, where data on clinical classification of the E. coli UTI were missing, a 5 day treatment with pivmecillinam at 400 mg three times daily seems to be the rational recommendation for lower UTI in men, pregnant women and women >50 years old. A 3 day regimen seems sufficient for non-pregnant women <50 years old.

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Risk of miscarriage for pregnant users of pivmecillinam: a population-based case-control study.

Few data exist on the risk of miscarriage after exposure to pivmecillinam. We therefore conducted a population-based case-control study in a Danish county with 0.5 million inhabitants during the period 1997-2002. We included 1,599 women with a miscarriage recorded in the Hospital Discharge Registry and selected 10 controls per case among primiparous women who had a live birth during the study period. Controls were selected from the Danish Medical Birth Registry. We obtained data on use of pivmecillinam and sulfamethizole from a prescription database. Five cases (0.30%) and 24 controls (0.15%) were exposed to pivmecillinam in the last week before the miscarriage/index date. After adjustment for maternal age, use of antidiabetics or antiepileptics, the odds ratio for miscarriages among users of pivmecillinam compared with non-users was 2.03 (95% confidence interval: 0.77-5.33) and the corresponding odds ratio for use of sulfamethizole was 1.53 (95% confidence interval: 0.76-3.09). Exposure within 2 to 12 weeks before the miscarriage was not associated with an increased risk. We concluded that use of pivmecillinam was associated with an increased risk of miscarriage, but the risk was not significantly (p=0.64) different from the risk associated with use of sulfamethizole.

Management of enteric fever with amdinocillin.

Twenty-six patients with enteric fever treated with amdinocillin and/or its pivaloyloxymethyl ester in 1975 to 1978 were compared with 21 patients with enteric fever treated with trimethoprim-sulfamethoxazole in 1972 to 1974. Diagnosis was based on clinical illness and isolation of Salmonella typhi or S. paratyphi A/B from blood cultures or stool cultures. The dosage of pivamdinocillin in adults was 400 to 800 mg, every 6 hours, for 10 to 16 days; dosage in children was half this amount for 11 to 15 days. Of the 21 patients treated with trimethoprim-sulfamethoxazole, 18 (86 percent) showed a satisfactory clinical response; 13 of these 18 had negative stools immediately after therapy, and two more were negative at the time of discharge (total: 83 percent). Mean hospital stay of these patients was 34.5 days. Of the 26 patients treated with amdinocillin, 23 showed a satisfactory clinical response; 20 of those responding clinically were still excreting the causative organism at the end of therapy; seven of the group remained as convalescent patients who continued to excrete the causative organism in feces at the time of discharge. Mean hospital stay was 43 days. The results of initial trials of amdinocillin and ampicillin in combination suggest that such therapy may be preferable to use of amdinocillin alone, although the excretion of the causative organism during convalescence has not been adequately assessed.

Pivalic acid-induced carnitine deficiency and physical exercise in humans.

To study the effect of carnitine depletion on physical working capacity, healthy subjects were administered pivaloyl-conjugated antibiotics for 54 days. The mean carnitine concentration in serum decreased from 35.0 to 3.5 mmicromol/L, and in muscle from 10 to 4.3 micromol/g noncollagen protein (NCP). Exercise tests were performed before and after 54 days' administration of the drug. At submaximal exercise, there was a slight increase in the concentration of 3-hydroxybutyrate in serum, presumably caused by decreased fatty acid oxidation in the liver. There was also a decreased consumption of muscle glycogen, indicating decreased glycolysis in the skeletal muscle. The muscle presumably had enough energy available, since there was no significant decrease in the concentration of adenosine triphosphate (ATP) and creatine phosphate during exercise. The work at maximal oxygen uptake (VO2max) and the maximal heart rate were reduced. Since VO2max is considered dependent on heart function, carnitine depletion seemed to affect cardiac function.

Symptomatic vaginal candidiasis after pivmecillinam and norfloxacin treatment of acute uncomplicated lower urinary tract infection.

The comparative incidence of symptomatic vaginal candidiasis associated with pivmecillinam and norfloxacin treatment in women with acute symptomatic uncomplicated UTI was determined in two randomised, double-blind, clinical trials. Adverse events reported following general enquiry were reviewed. Presence of Candida vaginitis was based upon the specification as such by investigators, the presence of specific symptoms such as genital pruritus and/or the prescription of specific anti Candida therapy. The incidences of Candida vaginitis were as follows; Study 1 pivmecillinam 200 mg tid for 7 days 13 (4.6%), pivmecillinam 200 mg bid for 7 days 7 (2.4%), pivmecillinam 400 mg bid for 3 days 6 (2.1%) and placebo 6 (2.1%), P=0.19. Study 2 pivmecillinam 400 mg bid for 3 days 7 (1.5%), norfloxacin 400 mg bid for 3 days 20 (4.3%), P=0.016. The incidence of Candida vaginitis in women with acute symptomatic uncomplicated UTI given 3 days treatment with pivmecillinam 400 mg bid is similar to that seen with placebo and is significantly less than the incidence with norfloxacin 400 mg bid for 3 days.

Comparison of pivmecillinam and cephalexin in acute uncomplicated urinary tract infection.

The clinical and bacteriological efficacy of a 3-day course of pivmecillinam, 200 mg three times daily, was compared with that of a 7-day course of cephalexin, 250 mg four times daily, in 216 patients with a bacteriologically confirmed, acute, uncomplicated, urinary tract infection. Both treatments were similarly effective. Clinical cure or improvement was obtained in 95.3% of patients given pivmecillinam and in 93.6% of patients given cephalexin. Bacteriological success was achieved in 89.7 and 81.7% patients taking pivmecillinam or cephalexin, respectively. Eradication rates for Escherichia coli were 90.1% for pivmecillinam and 80.6% for cephalexin. Both treatments were well tolerated. This study has confirmed that a 3-day course of pivmecillinam is effective and well tolerated in uncomplicated cystitis.

Comparative efficacy of 3-day and 7-day chemotherapy with twice-daily pivmecillinam in urinary tract infections seen in general practice.

In a multi-centre general practice study, 183 females suffering from symptoms of acute urinary tract infection were randomly assigned to receive 400 mg pivmecillinam twice-daily for either 3 or 7 days. The clinical response was equally good in both treatment groups with a mean reduction in symptom scores of 88%. Positive pre-treatment bacteriological cultures were obtained from 48 (36%) of the 134 patients for whom data were complete. Bacteriological cure was achieved in all these patients except for 1 in the 3-day treatment group. Pivmecillinam was well tolerated, with side-effects reported by 7 (7%) patients in the 3-day group and 12 (13%) patients in the 7-day group. One patient in the 3-day group and 2 patients in the 7-day group stopped treatment prematurely due to side-effects.

Randomised trial of pivampicillin plus pivmecillinam vs. pivampicillin in children and young adults with chronic obstructive pulmonary disease and infection with Haemophilus influenzae.

A prospective, randomised, single-blind comparative trial was carried out to determine whether double beta-lactam treatment with pivampicillin plus pivmecillinam is more effective than pivampicillin alone in the treatment of recurrent and chronic lung infections with Haemophilus influenzae in patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Fifty-six children and young adults with COPD or CF were randomised to the clinical study. The patients were allocated at random to receive perorally either pivmecillinam, 40 mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or pivampicillin 50 mg/kg/day alone for 14 days. A cross-over pharmacokinetic study using the same drugs was carried out in 10 CF patients to determine the antibiotic concentrations in serum and sputum after a single dose of each drug. The clinical study showed no significant differences in clinical scoring, lung function tests or adverse events after treatment with pivampicillin plus pivmecillinam or pivampicillin alone. Follow-up microbiological evaluation 2 and 6 weeks after the end of treatment showed that the offending pathogen was eradicated in 68% of the patients treated with pivampicillin plus pivmecillinam and in 67% of the patients treated with pivampicillin alone. Reinfection with another biotype was more common in the combination group (50% vs. 21%) than in the pivampicillin group. In the pharmacokinetic study the median peak serum concentration occurred two hours after intake of tablets. The efficacy of double beta lactam treatment in lung infections with H. influenzae appears to be equivalent to that of ampicillin on clinical lung symptoms, lung function tests, adverse effects and bacteriology.

An open evaluation of a 3-day course of pivmecillinam (ten 200 mg tablets) in women with acute uncomplicated cystitis.

One hundred and eighty-four women, with acute uncomplicated cystitis, received a 3-day course of pivmecillinam comprising an initial 400 mg (two tablets) dose, followed by 200 mg every 8 hours; a total of ten tablets. A satisfactory clinical response was achieved in 91% of patients. Bacteriological success was observed in 94% of sixty-eight patients with a proven infection. Side-effects were reported in sixteen patients (8.4%). Two patients ceased therapy prematurely. Pivmecillinam did not select out resistant Gram-negative organisms. A trend towards reinfection with Gram-positive cocci was observed. The possible significance of reinfection with different organisms is discussed.

A general practice evaluation of selexid suspension as a treatment for acute urinary tract infection.

Fifty-seven general practice patients (fifty-five females and two males) with acute uncomplicated cystitis received a 5-day course of pivmecillinam suspension at a dose of 200 mg (2 sachets) three times a day. Positive bacteriological cultures were obtained from twenty-eight patients (49%) before treatment. The bacteriological cure rate was 100%. All patients experienced some relief of symptoms and thirty-nine patients (68%) were completely symptom-free after treatment. Selexid suspension was generally well tolerated. Side-effects were reported in only four patients(6%) and no patient had to stop treatment prematurely.

Long-term treatment with pivmecillinam in patients with recurrent bacteriuria.

Thirty out-patients with chronic recurrent urinary tract infections, who had failed to respond to 10 days treatment with either pivmecillinam and/or amoxycillin, received a 3-month course of pivmecillinam at a dose of 200 mg, three times daily. Twenty-seven patients had bacteriuria due to Enterobacteriaceae, mainly Escherichia coli, sensitive to mecillinam in vitro. Pivmecillinam eradicated all the initial urinary pathogens. Reinfections occurred during treatment in three patients, who remained asymptomatic. Four subjects complained of gastro-intestinal side-effects, and therapy was withdrawn in three instances. Another three patients described unusual adverse events towards the end of the course of treatment, described as an odd sensation in the body and a desire for salt. The sensation disappeared a few days after the end of treatment. Treatment with pivmecillinam had no adverse effect on haematopoietic, hepatic or renal function.

A clinical comparison of pivmecillinam plus pivampicillin (Miraxid) and a triple tetracycline combination (Deteclo) in respiratory infections treated in general practice.

Seven-day courses of either pivmecillinam 200 mg plus pivampicillin 250 mg (Miraxid) or a combination of tetracycline hydrochloride, chlortetracycline hydrochloride and demeclocycline hydrochloride (Deteclo) 300 mg, both given twice daily, were compared in a multicentre general practice study in 408 patients with symptoms of upper or lower respiratory tract infection. Patients were stratified into four diagnostic groups: sinusitis, otitis media, throat infections, and acute bronchitis and randomly allocated to treatment within these groups. Assessment at 7 days showed no difference in clinical efficacy between the two treatments where 193 of the 208 infections receiving Miraxid (93%) were rated as either cured or improved compared with 181 of the 201 infections treated with Deteclo (90%). At 7 days, the percentage of patients completely free of symptoms was the same for both groups (66%). The mean time for symptoms to clear was 3.9 days in the Miraxid group and 4.0 days in the Deteclo group. Side-effects were reported by significantly fewer patients in the Miraxid group (9.3%) than the Deteclo group (17.5%) (p less than 0.05) and six patients in the latter group failed to complete the course of treatment. Miraxid given twice daily for respiratory tract infections is as effective as Deteclo but causes significantly fewer side-effects.

A comparison of pivmecillinam/pivampicillin and amoxycillin in acute exacerbations of chronic bronchitis.

Courses of 7 days on either 200 mg pivmecillinam/250 mg pivampicillin given twice daily or 250 mg amoxycillin given three times daily were compared in 3783 general practice patients with acute exacerbations of chronic bronchitis in a single-blind parallel group study. Patients on pivmecillinam/pivampicillin had significantly more 'excellent' responses, although there was no difference in overall response between treatments. Post-treatment sputum colour and consistency and peak expiratory flow rates were significantly better with pivmecillinam/pivampicillin. The incidence of side-effects was the same for both groups (approximately 10%), although significantly more patients reported lower gastro-intestinal problems with amoxycillin. Treatment was withdrawn due to side-effects in 47 (2.5%) patients on pivmecillinam/pivampicillin and 51 (2.7%) patients on amoxycillin. Amoxycillin is a standard therapy in the treatment of patients with acute exacerbations of chronic bronchitis. In this study, however, it was shown that pivmecillinam/pivampicillin offers benefits over amoxycillin in these patients.

[Clinical evaluation of pivmecillinam in the maintenance therapy of chronic urinary tract infection (author's transl)].

In order to evaluate the efficacy and safety of pivmecillinam (melysin tablet, PMPC), PMPC was administered to 78 chronic UTI cases in the field of obstetrics and gynecology (posthysterectomy infection, chronic cystitis, chronic pyelonephritis and etc.). In principle, daily 400 mg of PMPC was administered for 2 weeks. (1) Overall clinical efficacy judged by doctor was evaluated in 78 cases and the result was; excellent in 17, good in 37, fair in 10, poor in 13 and unknown in 1 case with the effectiveness rate of 69.2%. (2) Overall clinical efficacy judged by 'criteria for clinical evaluation in complicated UTI' recommended by UTI study member was evaluated in 54 cases and the result was; excellent in 15, good in 20 and poor in 19 cases with the overall efficacy rate of 64.8%, the result of which was similar to that of doctor's judgement. (3) Efficacy on pyuria was evaluated in 72 cases and it was cleared in 27, decreased in 25, unchanged in 20 and unknown in 6 cases. Efficacy on bacteriuria was evaluated in 72 cases and it was eliminated in 44, decreased in 9, replaced in 8, unchanged in 8 and unknown in 9 cases. (4) Side effect, considered by doctors to be caused by PMPC administration, was noticed in 3 out of 78 cases (3.8%), all of which was mild gastrointestinal disturbance and the administration of PMPC was continued. Abnormal change of laboratory finding considered by doctors to be caused by PMPC administration was noticed in 1 out of 78 cases, which was slight elevation of GOT and GPT values. It is therefore considered that PMPC appear to be useful drug for the maintenance therapy of chronic UTI in the field of obstetrics and gynecology.

[Clinical evaluation of the new type pivmecillinam tablet (contains 100 MG) on the treatment for female acute simple urinary tract infections (author's transl)].

Clinical studies of the new type pivmecillinam tablet (contains 100 mg) was performed on 24 patients with female acute simple urinary tract infections, receiving 300 mg 3 times daily for 7 days orally. Causative organisms in the cystitis cases were isolated singly as E. coli in 18 cases, Staph. aureus in 1 case and Staph. epidermidis in 1 case. From only 1 case with cystitis, E. coli and Staph. epidermidis were isolated mixedly. Clinical efficacy of the new type pivmecillinam tablet was evaluated as excellent in all 21 cases with female acute simple cystitis and 3 cases with female acute pyelonephritis. Side effect was not observed in the all cases.

Comparative controlled clinical trial of pivmecillinam and nalidixic acid in patients with acute simple urinary tract infections.

We performed a controlled double-blind clinical study with PMPC to investigate its therapeutic usefulness in acute simple cystitis in comparison with NA, with the results as follows: 1. In both treatment groups, PMPC proved to be remarkably more active (MIC) than NA against the bacterial isolates tested in vitro. 2. PMPC, administered in dosis (200 mg per day) one-tenth those of NA (2,000 mg per day), produced a greater improvement (therapeutic effects) than NA. 3. Side-effects were apparently less frequent with PMPC, as compared to NA. The results indicate a remarkable usefulness of PMPC in the treatment of acute simple cystitis.

Clinical evaluation of pivmecillinam in intractable urinary-tract infections with complications. A comparative study with amoxicillin by a randomized double-blind technique.

A comparative study was made by the double-blind technique in order to make clear the usefulness of pivmecillinam in the treatment of intractable complicated urinary-tract infections using amoxicillin as a reference drug. Pivmecillinam was given in dosage of 400 mg (potency) per day which was one-fifth the dose of amoxicillin 2,000 mg (potency) per day. In global judgement, pivmecillinam was found superior to amoxicillin. It showed a "significant" superiority over amoxicillin for the treatment of, among others, the urinary-tract infections after prostatectomy, which are intractable diseases. When evaluated by symptoms, pivmecillinam improved bacteriuria "significantly" better than amoxicillin. When seen by causative organisms, the pivmecillinam treatment was "significantly" superior to the amoxicillin treatment against E. coli infections. Pivmecillinam was active against amoxicillin-resistant E. coli. Incidence of adverse reactions was less frequent with pivmecillinam than with amoxicillin. These results indicate that pivmecillinam is a drug of high usefulness for the treatment of intractable complicated urinary-tract infections when evaluated using amoxicillin as a reference drug.

[Prophylactic and chemotherapeutic efficacy of pivmecillinam (PMPC) against infections after TUR-P and prostatectomy].

The prophylactic and chemotherapeutic efficacy of PMPC against infections after TUR-P has been investigated. Bacteriological evaluation: PMPC , 200-300 mg/day for 2-12 weeks, was administered to 49 patients, who had over 10(3)CFU/ml of microorganisms after CET or CEC treatment for 3-7 days. The eradication rate of microorganisms was 40.8% after 2 weeks, 52.2% after 4 weeks, 64.1% after 6 weeks, 65.0% after 8 weeks and 70.6% after 12 weeks. Effectiveness on pyuria : The improvement rate of pyuria against 59 patients who had over 10(5)/hpf of pyuria , was 15.3% after 2 weeks, 16.4% after 4 weeks, 25.4% after 6 weeks, 58.5% after 8 weeks, 72.7% after 10 weeks and 75.0% after 12 weeks. Overall clinical efficacy on PMPC was examined in 26 patients. The results of efficacy were 27.3% after 2 weeks, 48.0% after 4 weeks, 50.0% after 6 weeks, 69.2% after 8 weeks, 75.0% after 10 weeks and 77.0% after 12 weeks. The clinical response was evaluated according to a criterion for clinical evaluation of antimicrobial agent on chronic complicated UTI proposed by UTI committee in Japan. No severe adverse effect including allergic reaction was found. Following administration of PMPC , three patients experienced adverse gastric reactions, and drug administration was discontinued at week 6 or 8. PMPC was effective as a prophylactic chemotherapeutic drug against infections after TUR-P and prostatectomy.