Clinical outcomes of potential high responders after individualized FSH dosing based on anti-Müllerian hormone and body weight.

RESEARCH QUESTION: How does the efficacy and safety of individualized follitropin delta dosing compare with conventional dosing for ovarian stimulation in potential high responders? DESIGN: Retrospective analysis of 153 potential high responders identified on the basis of baseline serum anti-Müllerian hormone (AMH) levels above 35 pmol/l, who were originally randomized to an individualized fixed dose of follitropin delta based on AMH and body weight (n = 78) or to a daily starting dose of 150 IU follitropin alfa (n = 75). RESULTS: At the end of stimulation, patients treated with individualized follitropin delta or conventional follitropin alfa had 12.1 ± 7.0 and 18.3 ± 7.0 (P < 0.001) follicles measuring 12 mm or wider, and 27.3% and 62.7% had serum progesterone levels higher than 3.18 nmol/l (P < 0.001), respectively. Overall number of oocytes in these two respective arms was 9.3 ± 6.7 and 17.9 ± 8.7 (P < 0.001), and the ongoing pregnancy rate per started cycle after fresh blastocyst transfer was 28.2% and 24.0%. The risk of ovarian hyperstimulation syndrome (OHSS) for all cases was three times higher in the conventional follitropin alfa arm at 16.0% versus 5.1% with individualized follitropin delta treatment (P = 0.025) and 26.7% versus 7.7% (P = 0.001) for early moderate or severe OHSS, preventive interventions for early OHSS, or both. CONCLUSIONS: Treatment with individualized follitropin delta provides an improved efficacy-safety balance in women with high ovarian reserve, as it normalizes the ovarian response and decreases the risk of OHSS without compromising the chance of pregnancy.

Randomized, assessor-blind, antimüllerian hormone-stratified, dose-response trial in Japanese in vitro fertilization/intracytoplasmic sperm injection patients undergoing controlled ovarian stimulation with follitropin delta.

OBJECTIVE: To establish the relationship between follitropin delta doses (recombinant follicle-stimulating hormone produced from the human cell line PER.C6) and ovarian response in Japanese women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment and to evaluate the influence of initial antimüllerian hormone (AMH) levels. DESIGN: Randomized, controlled, assessor-blind, AMH-stratified (low 5.0-14.9 pmol/L; high 15.0-44.9 pmol/L) dose-response trial. SETTING: Reproductive medicine clinics. PATIENT(S): A total of 158 Japanese women (20-39 years of age). INTERVENTION(S): Controlled ovarian stimulation with 6, 9, or 12 µg/d of follitropin delta or 150 IU/d follitropin beta as a reference arm in a gonadotropin-releasing hormone antagonist cycle. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): Among all women who started stimulation, the mean number (± standard deviation) of oocytes retrieved in the 6 µg/d, 9 µg/d, and 12 µg/d follitropin delta groups was 7.0 ± 4.1, 9.1 ± 5.6, and 11.6 ± 5.6, respectively, and a significant dose-relation was established, which also remained significant within each AMH strata. Significant dose-responses also were observed for serum estradiol, inhibin A, and progesterone at end-of-stimulation with follitropin delta. The vital pregnancy rate per started cycle with follitropin delta was 19% for 6 µg/d, 20% for 9 µg/d, and 25% for 12 µg/d. The rate of early moderate/severe ovarian hyperstimulation syndrome with follitropin delta was 8% for 6 µg/d, 8% for 9 µg/d, and 13% for 12 µg/d, with 82% of the cases in the high AMH stratum. CONCLUSION(S): This trial establishes the dose-response relationship between follitropin delta and ovarian response in Japanese women. CLINICAL TRIAL REGISTRATION NUMBER: NCT02309671.

Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.

OBJECTIVE: To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF. DESIGN: Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1). SETTING: Reproductive medicine clinics. PATIENT(S): A total of 1,329 women (aged 18-40 years). INTERVENTION(S): Follitropin delta (AMH <15 pmol/L: 12 µg/d; AMH ≥15 pmol/L: 0.10-0.19 µg/kg/d; maximum 12 µg/d), or follitropin alfa (150 IU/d for 5 days, potential subsequent dose adjustments; maximum 450 IU/d). MAIN OUTCOMES MEASURE(S): Ongoing pregnancy and ongoing implantation rates; noninferiority margins -8.0%. RESULT(S): Ongoing pregnancy (30.7% vs. 31.6%; difference -0.9% [95% confidence interval (CI) -5.9% to 4.1%]), ongoing implantation (35.2% vs. 35.8%; -0.6% [95% CI -6.1% to 4.8%]), and live birth (29.8% vs. 30.7%; -0.9% [95% CI -5.8% to 4.0%]) rates were similar for individualized follitropin delta and conventional follitropin alfa. Individualized follitropin delta resulted in more women with target response (8-14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs. 17.9%), fewer excessive responses (≥15 or ≥20 oocytes in patients with AMH ≥15 pmol/L) (27.9% vs. 35.1% and 10.1% vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield (10.0 ± 5.6 vs. 10.4 ± 6.5) and similar blastocyst numbers (3.3 ± 2.8 vs. 3.5 ± 3.2), and less gonadotropin use (90.0 ± 25.3 vs. 103.7 ± 33.6 µg). CONCLUSION(S): Optimizing ovarian response in IVF by individualized dosing according to pretreatment patient characteristics results in similar efficacy and improved safety compared with conventional ovarian stimulation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01956110.

Follicular and endocrine dose responses according to anti-Müllerian hormone levels in IVF patients treated with a novel human recombinant FSH (FE 999049).

OBJECTIVE: To study the association between serum anti-Müllerian hormone (AMH) levels and follicular development and endocrine responses induced by increasing doses (5·2-12·1 µg/day) of a novel recombinant human FSH (rhFSH, FE 999049) in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a GnRH antagonist protocol. DESIGN: Secondary analysis of a randomized controlled trial with stratified randomization according to AMH (lower stratum: 5·0-14·9 pmol/l; higher stratum: 15·0-44·9 pmol/l). PATIENTS: Infertile women of good prognosis (n = 265). MEASUREMENTS: Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. RESULTS: Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P < 0·001) positive dose responses were observed for the number of follicles ≥ 12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves for these hormones, and no clear dose-related increase was observed for the number of follicles in these patients. CONCLUSIONS: Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels at start of COS.

Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials.

OBJECTIVE: To compare antimüllerian hormone (AMH) and antral follicle count (AFC) as predictors of ovarian response to controlled ovarian stimulation at individual fertility clinics. DESIGN: Retrospective analysis of individual study center data in two multicenter trials. Centers that provided >10 patients were included in the analysis. SETTING: A total of 19 (n = 519 patients) and 18 study centers (n = 686 patients) participating in a long GnRH agonist trial (MERIT) and a GnRH antagonist trial (MEGASET), respectively. PATIENT(S): Infertile women of good prognosis. INTERVENTION(S): Long GnRH agonist or GnRH antagonist cycles. MAIN OUTCOME MEASURE(S): Correlation between AMH and AFC, and oocyte yield by each study center for each trial. RESULTS(S): Antimüllerian hormone was more strongly correlated with oocyte yield than AFC: r = 0.56 vs. r = 0.28 in the GnRH agonist cohort, and r = 0.55 vs. r = 0.33 in the GnRH antagonist cohort. The correlation was numerically higher for AMH than for AFC at a significantly higher proportion of study centers: 17 (89%) and 15 (83%) centers in the long GnRH agonist and GnRH antagonist trial, respectively. Assessment of the relative capacity of AMH and AFC for predicting oocyte yield demonstrated that AMH dominated the model: AMH, R(2) = 0.29 and 0.23; AFC: R(2) = 0.07 and 0.07; AMH + AFC: R(2) = 0.30 and 0.23 for long GnRH agonist and GnRH antagonist trials, respectively. CONCLUSIONS(S): Antimüllerian hormone was a stronger predictor of ovarian response to gonadotropin therapy than AFC at the study center level in both randomized trials utilizing GnRH agonist and GnRH antagonist protocols. Antral follicle count provided no added predictive value beyond AMH.

Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. DESIGN: Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. SETTING: Seven infertility centers in four countries. PATIENT(S): Two hundred sixty-five women aged ≤37 years. INTERVENTION(S): Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 µg of rhFSH, or 11 µg (150 IU) of follitropin alfa in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 µg/d to 12.2 ± 5.9 with 12.1 µg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. CONCLUSION(S): Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. CLINICAL TRIAL REGISTRATION NUMBER: NCT01426386.

The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin.

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n = 155 and n = 188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2 ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p = 0.025) and 31% versus 49% (p = 0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p = 0.074; antagonist protocol: 34% versus 23%, p = 0.075; overall population: 34% versus 22%, p = 0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.

Long-term durability of the response to desmopressin in female and male nocturia patients.

AIMS: To explore the durability of efficacy and gender differences during chronic administration of desmopressin in nocturia. METHODS: This pooled analysis of three short-term efficacy studies, with extensions, of desmopressin administered as orally disintegrating tablet (ODT) or solid tablet in nocturia treatment, comprised 351 patients completing 40-56 weeks' treatment. Efficacy endpoints of change in number of nocturnal voids and duration of initial undisturbed sleep period from baseline were analyzed to determine response durability and gender differences. RESULTS: The mean decrease in number of nocturnal voids during short-term treatment was maintained and further reduced during the long term. At 52 weeks, the mean decrease in number of nocturnal voids from baseline reached 1.4-2.1 voids for desmopressin ODT 25-100 µg. Following 40-week tablet treatment, the decrease in number of nocturnal voids was 0.8-1.5 for desmopressin 100-400 µg. The mean decrease in nocturnal voids (25-50 µg ODT) was greater for females than males. For females, the improvement in initial period of undisturbed sleep was 2.5-3 hr for desmopressin ODT 25-100 µg, compared with 1.3-2.6 hr for males. No gender difference in efficacy was seen in the tablet studies. CONCLUSIONS: The decrease in nocturnal voids and improvement in sleep with short-term desmopressin treatment were maintained throughout long-term treatment. A durable gender difference in efficacy in favor of females was observed with desmopressin ODT 25 µg. Further, large-scale long-term trials are needed to confirm the durability of efficacy with gender-specific doses of desmopressin.

The value of anti-Mullerian hormone measurement in the long GnRH agonist protocol: association with ovarian response and gonadotrophin-dose adjustments.

BACKGROUND: This study evaluated the predictive value of serum and follicular fluid (FF) concentrations of anti-Müllerian hormone (AMH) with respect to treatment outcome variables in an IVF cycle. METHODS: A retrospective analysis was performed with data from 731 normogonadotrophic women undergoing controlled ovarian stimulation after stimulation with highly purified menotrophin (HP-hMG) or rFSH following a long GnRH agonist protocol. RESULTS: In both treatment groups, the serum AMH concentration at the start of the stimulation was significantly (P < 0.001) positively correlated with the serum levels of estradiol (HP-hMG: r = 0.45; rFSH: r = 0.55), androstenedione (HP-hMG: r = 0.50; rFSH: 0.49) and total testosterone (HP-hMG: r = 0.40; rFSH: r = 0.36) at the end of the stimulation as well as the number of oocytes retrieved (HP-hMG: r = 0.48; rFSH: r = 0.62), the AMH concentration in FF (HP-hMG: r = 0.55; rFSH: 0.61) and the serum progesterone concentration (HP-hMG: r = 0.39; rFSH: r = 0.50) at oocyte retrieval. For both treatments, serum AMH at the start of the stimulation was a good predictor of the need to increase or decrease the gonadotrophin dose on stimulation day 6 and of ovarian response below (<7 oocytes) or above (>15 oocytes) the target. No significant relationships were observed between serum AMH and embryo quality or ongoing pregnancy. CONCLUSION: The serum AMH concentration at the start of the stimulation in IVF patients down-regulated with GnRH agonist in the long protocol revealed a positive relationship with ovarian response to gonadotrophins in terms of oocytes retrieved and accompanying endocrine response. AMH is a good predictor of the need for gonadotrophin-dose adjustment on stimulation day 6 for patients with a fixed starting dose, but a poor predictor of embryo quality and pregnancy chances in individual patients.

Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial.

AIMS: The primary objective was to investigate the efficacy of desmopressin orally disintegrating tablet versus placebo in patients with nocturia. Pharmacodynamics, safety and patient-reported quality of life (QoL) outcomes were also evaluated. One of several benefits of the new formulation is increased bioavailability. Exploring lower doses allows for a better evaluation of therapeutic effect versus tolerability. METHODS: This was a 4-week, randomized, double-blind study comparing 10, 25, 50, or 100 µg desmopressin versus placebo in adults with defined nocturia. RESULTS: The intent to treat population comprised 757 patients experiencing ∼3 voids/night and a high prevalence of nocturnal polyuria (∼90%). Increasing doses of desmopressin were associated with decreasing numbers of nocturnal voids and voided volume, greater proportions of subjects with >33% reduction in nocturnal voids, and increased duration of first sleep period. The lowest dose reaching statistical significance (P < 0.05 vs. placebo) varied by endpoint. Improvements were clinically meaningful, meaning that patients actually had fewer nightly voids. Post hoc analyses by gender suggested a lower minimum effective dose for women. Desmopressin was generally well tolerated. Reductions in serum sodium to <125 mmol/L in six women (taking >25 µg desmopressin) and two men (aged 67 and 82) taking 100 µg, support lower and gender-specific dosing to reduce the small but clinically significant risk of hyponatraemia. Each void reduced/hour of sleep gained was associated with significant improvements in QoL. CONCLUSIONS: Desmopressin orally disintegrating tablet is an effective and well-tolerated treatment for patients with nocturia. Further exploration of the lower dose range is warranted.

No need for biopsies: comparison of three sample techniques for wound microbiota determination.

The aim of the study was to compare three sampling techniques used in routine diagnostics to identify the microbiota in chronic venous leg ulcers. A total of 46 patients with persisting venous leg ulcers were included in the study. At inclusion, swab, biopsy and filter paper pad samples were collected. After 4 weeks, additional biopsy and filter paper pad samples were collected. Bacteria were isolated and identified at species level by standard methods. The most common bacterial species detected was Staphylococcus aureus found in 89% of the ulcers. No methicillin-resistant S. aureus isolates were found. We did not find any significant differences regarding the bacterial species isolated between the three sampling techniques. However, using multiple techniques led to identification of more species. Our study suggests that it is sufficient to use swab specimens to identify the bacterial species present in chronic wounds, thus avoiding complications during and after biopsy sampling.

The role of Campylobacter jejuni cytolethal distending toxin in gastroenteritis: toxin detection, antibody production, and clinical outcome.

The role of Campylobacter jejuni cytolethal distending toxin (CDT) on clinical outcome after gastroenteritis was investigated. Clinical data, blood serum samples, and Campylobacter spp. isolated, from each of 30 patients were collected over a period of 6 months. The CDT encoding genes, cdtABC, characterized by PCR, revealed that all but one of the C. jejuni strains had the wild-type sequence. Sequencing of cdtABC from this strain showed two major deletions. From all of the strains, CDT titers were determined, and toxin neutralizing antibodies were documented using an in vitro assay. Three of the thirty clinical isolates, including the one with the mutant cdtABC coding genes, did not have a detectable CDT activity. Analyzing the relationship between CDT titer, serum neutralization of CDT, and the clinical outcome showed that campylobacteriosis caused by CDT-negative strains was clinically indistinguishable from that of patients infected with an isolate that produced high levels of CDT. These results suggest that CDT does not solely determine severity of infection and clinical outcome.

Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia.

PURPOSE: Nocturnal polyuria is a common but often overlooked cause of nocturia. We investigated the proportion of adults with 2 or greater voids nightly who had nocturnal polyuria in 2 cohorts from the United States and Europe. MATERIALS AND METHODS: Data on nocturnal polyuria were obtained from 3 or 7-day frequency-volume charts completed by patients as part of screening for inclusion in subsequent trials of nocturia therapy. Patients recorded the time and volume of each void. Nocturnal polyuria was defined as nocturnal urine volume greater than 33% of 24-hour volume, including the first morning void. RESULTS: In the first cohort 1,003 patients were screened, of whom 846 provided evaluable diary data, including 641 (76%) with nocturnal polyuria. Of the total screened population of 1,003 patients 641 (64%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. In the second cohort 1,412 patients were screened, of whom 917 provided evaluable diary data, including 806 (88%) with nocturnal polyuria. Of the total screened population of 1,412 patients 806 (57%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. Of 158 patients receiving benign prostatic hyperplasia and/or overactive bladder medication 141 (89%) had nocturnal polyuria. In each cohort the nocturnal polyuria prevalence was high in all ethnic groups (63% or greater). CONCLUSIONS: In this large study nocturnal polyuria was present in most patients with nocturia regardless of gender, age, ethnicity, country and concomitant benign prostatic hyperplasia/overactive bladder therapy.

Development and validation of an ATP method for rapid estimation of viable units in lyophilised BCG Danish 1331 vaccine.

An assay for quantifying viability in BCG vaccine by determining intracellular ATP content was developed and validated. ATP content was determined by measuring bioluminescence in the presence of luciferin/luciferase. During development and validation the ATP method was compared to the conventional viable count method. A key step to obtain correlation between ATP content and CFU was found to be a period of pre-incubation in a growth medium before ATP determination. During the validation, the robustness, linearity, accuracy, precision, and range were studied. The method validation study showed that the method applied was robust and applicable to determine ATP content in lyophilised BCG for estimating viability in the BCG samples. By comparison with a conventional viable count method, a high correlation between ATP content and the viable count was found; this relationship can be applied in routine quality control to estimate viable count from the ATP content determined in a sample.

Multiple bacterial species reside in chronic wounds: a longitudinal study.

The aim of the study was to investigate the bacterial profile of chronic venous leg ulcers and the importance of the profile to ulcer development. Patients with persisting venous leg ulcers were included and followed for 8 weeks. Every second week, ulcer samples were collected and the bacterial species present were identified. More than one bacterial species were detected in all the ulcers. The most common bacteria found were Staphylococcus aureus (found in 93.5% of the ulcers), Enterococcus faecalis (71.7%), Pseudomonas aeruginosa (52.2%), coagulase-negative staphylococci (45.7%), Proteus species (41.3%) and anaerobic bacteria (39.1%). Resident bacterial species were present in all the ulcers. In 76% of the ulcers, two or more (up to five) resident bacterial species were found. The most common resident bacterial species were S. aureus and P. aeruginosa. Furthermore, ulcers with P. aeruginosa were found to be significantly larger than ulcers without the presence of P. aeruginosa (P < 0.005). Our study demonstrated that the chronic wound is colonised by multiple bacterial species and that once they are established many of them persist in the wound. Our results suggest that the presence of P. aeruginosa in venous leg ulcers can induce ulcer enlargement and/or cause delayed healing.

In vitro biofilm formation of commensal and pathogenic Escherichia coli strains: impact of environmental and genetic factors.

Our understanding of Escherichia coli biofilm formation in vitro is based on studies of laboratory K-12 strains grown in standard media. However, pathogenic E. coli isolates differ substantially in their genetic repertoire from E. coli K-12 and are subject to heterogeneous environmental conditions. In this study, in vitro biofilm formation of 331 nondomesticated E. coli strains isolated from healthy (n = 105) and diarrhea-afflicted children (n = 68), bacteremia patients (n = 90), and male patients with urinary tract infections (n = 68) was monitored using a variety of growth conditions and compared to in vitro biofilm formation of prototypic pathogenic and laboratory strains. Our results revealed remarkable variation among the capacities of diverse E. coli isolates to form biofilms in vitro. Notably, we could not identify an association of increased biofilm formation in vitro with a specific strain collection that represented pathogenic E. coli strains. Instead, analysis of biofilm data revealed a significant dependence on growth medium composition (P < 0.05). Poor correlation between biofilm formation in the various media suggests that diverse E. coli isolates respond very differently to changing environmental conditions. The data demonstrate that prevalence and expression of three factors known to strongly promote biofilm formation in E. coli K-12 (F-like conjugative pili, aggregative adherence fimbriae, and curli) cannot adequately account for the increased biofilm formation of nondomesticated E. coli isolates in vitro. This study highlights the complexity of genetic and environmental effectors of the biofilm phenotype within the species E. coli.

Increase and change in pattern of hospital antimicrobial use, Denmark, 1997-2001.

OBJECTIVES: To analyse the changes and compare antimicrobial consumption in public hospitals in Denmark over the period 1997-2001. METHODS: Data on the number of WHO defined daily doses (DDD) were obtained from the Danish Medicines Agency. Data on the number of bed-days were obtained from the National Board of Health. We calculated antimicrobial consumption in hospitals as the number of DDD per 100 bed-days for all antibacterials for systemic use i.e. group J01 of the Anatomical Therapeutic Chemical (ATC) classification and for classes of this group. RESULTS: During 1997-2001, antimicrobial use in hospitals in Denmark significantly increased by 18%, from 38.0 to 44.8 DDD per 100 bed-days (P < 0.005). Most of this increase (55%) was attributed to an increase in consumption of commonly used classes of antimicrobials, mainly penicillins with extended spectrum (ATC group J01CA), beta-lactamase-sensitive penicillins (J01CE) and beta-lactamase-resistant penicillins (J01CF). The 'broad-spectrum' and newer antimicrobials, i.e. combinations of penicillins with beta-lactamase inhibitor (J01CR), cephalosporins (J01DA), carbapenems (J01DH) and fluoroquinolones (J01MA) contributed to 36% of the increase. Together, these amounted to 16% of total consumption in hospitals in Denmark in 1997, rising to 19% in 2001. CONCLUSIONS: Although antimicrobial consumption in public hospitals in Denmark is low compared with other countries, the steady increase and change in pattern of their use are causes of concern, deserving close monitoring and further investigations.