New methodology to assess the excess burden of antibiotic resistance using country-specific parameters: a case study regarding E. coli urinary tract infections.

OBJECTIVES: Antimicrobial resistant (AMR) infections are a major public health problem and the burden on population level is not yet clear. We developed a method to calculate the excess burden of resistance which uses country-specific parameter estimates and surveillance data to compare the mortality and morbidity due to resistant infection against a counterfactual (the expected burden if infection was antimicrobial susceptible). We illustrate this approach by estimating the excess burden for AMR (defined as having tested positive for extended-spectrum beta-lactamases) urinary tract infections (UTIs) caused by E. coli in the Netherlands in 2018, which has a relatively low prevalence of AMR E. coli, and in Italy in 2016, which has a relatively high prevalence. DESIGN: Excess burden was estimated using the incidence-based disability-adjusted life-years (DALYs) measure. Incidence of AMR E. coli UTI in the Netherlands was derived from ISIS-AR, a national surveillance system that includes tested healthcare and community isolates, and the incidence in Italy was estimated using data reported in the literature. A systematic literature review was conducted to find country-specific parameter estimates for disability duration, risks of progression to bacteraemia and mortality. RESULTS: The annual excess burden of AMR E. coli UTI was estimated at 3.89 and 99.27 DALY/100 0000 population and 39 and 2786 excess deaths for the Netherlands and Italy, respectively. CONCLUSIONS: For the first time, we use country-specific and pathogen-specific parameters to estimate the excess burden of resistant infections. Given the large difference in excess burden due to resistance estimated for Italy and for the Netherlands, we emphasise the importance of using country-specific parameters describing the incidence and disease progression following AMR and susceptible infections that are pathogen specific, and unfortunately currently difficult to locate.

Impact of the COVID-19 pandemic on prevalence of highly resistant microorganisms in hospitalised patients in the Netherlands, March 2020 to August 2022.

BackgroundThe COVID-19 pandemic resulted in adaptation in infection control measures, increased patient transfer, high occupancy of intensive cares, downscaling of non-urgent medical procedures and decreased travelling.AimTo gain insight in the influence of these changes on antimicrobial resistance (AMR) prevalence in the Netherlands, a country with a low AMR prevalence, we estimated changes in demographics and prevalence of six highly resistant microorganisms (HRMO) in hospitalised patients in the Netherlands during COVID-19 waves (March-June 2020, October 2020-June 2021, October 2021-May 2022 and June-August 2022) and interwaves (July-September 2020 and July-September 2021) compared with pre-COVID-19 (March 2019-February 2020).MethodsWe investigated data on routine bacteriology cultures of hospitalised patients, obtained from 37 clinical microbiological laboratories participating in the national AMR surveillance. Demographic characteristics and HRMO prevalence were calculated as proportions and rates per 10,000 hospital admissions.ResultsAlthough no significant persistent changes in HRMO prevalence were detected, some relevant non-significant patterns were recognised in intensive care units. Compared with pre-COVID-19 we found a tendency towards higher prevalence of meticillin-resistant Staphylococcus aureus during waves and lower prevalence of multidrug-resistant Pseudomonas aeruginosa during interwaves. Additionally, during the first three waves, we observed significantly higher proportions and rates of cultures with Enterococcus faecium (pooled 10% vs 6% and 240 vs 120 per 10,000 admissions) and coagulase-negative Staphylococci (pooled 21% vs 14% and 500 vs 252 per 10,000 admissions) compared with pre-COVID-19.ConclusionWe observed no substantial changes in HRMO prevalence in hospitalised patients during the COVID-19 pandemic.

Routinely available antimicrobial susceptibility information can be used to increase the efficiency of screening for carbapenemase-producing Enterobacteriaceae.

Introduction. Increased carbapenem resistance is often caused by carbapenemase production.Aim. The objective of our study was to assess which antibiotic susceptibility patterns, as tested by automated systems, are highly associated with the absence of carbapenemase production in Enterobacteriaceae isolates, and could therefore be used as a screening tool.Methodology. Routine antibiotic susceptibility testing data from 42 medical microbiology laboratories in the Netherlands in the period between January 2011 and June 2017 were obtained from the national antimicrobial resistance surveillance programme. Data on Enterobacteriaceae isolates that had an elevated minimum inhibitory concentration (MIC) for carbapenems (meropenem >0.25 mg l-1 or imipenem >1.0 mg l-1) were selected and subjected to phenotypic or genotypic carbapenemase production testing. Routinely available amoxicillin/clavulanic acid, piperacillin/tazobactam, cefuroxime and ceftriaxone/cefotaxime susceptibilities were studied in relation to carbapenemase production by calculating the negative predictive value.Results. No evidence for carbapenemase-producing Enterobacteriaceae (CPE) was found in 767 of 1007 (76 %) isolates. The negative predictive value was highest for amoxicillin/clavulanic acid (99.6 %) and piperacillin/tazobactam (98.8 %).Conclusion. Enterobacteriaceae isolates with elevated carbapenem MICs that are susceptible to amoxicillin/clavulanic acid or piperacillin/tazobactam are unlikely to be carbapenemase producers. Preselection based on this susceptibility pattern may lead to increased laboratory efficiency and reduction of costs. Whether this is also true for countries with a different distribution of CPE species and types or a higher prevalence of CPE needs to be studied.

Determination of the time-dependent association between ciprofloxacin consumption and ciprofloxacin resistance using a weighted cumulative exposure model compared with standard models.

OBJECTIVES: To obtain comprehensive insight into the association of ciprofloxacin use at different times in the past with the current risk of detecting resistance. METHODS: This retrospective nested case-control study of ciprofloxacin users used Dutch data from the PHARMO Database Network and one laboratory for the period 2003-14. Cases and controls were selected as patients with an antibiotic susceptibility test (AST) indicating ciprofloxacin resistance or susceptibility, respectively. We performed univariable and multivariable conditional logistic regression analyses, defining time-dependent exposure using standard definitions (current ciprofloxacin use, used 0-30, 31-90, 91-180 and 181-360 days ago) and a flexible weighted cumulative effect (WCE) model with four alternative time windows of past doses (0-30, 0-90, 0-180 and 0-360 days). RESULTS: The study population consisted of 230 cases and 909 controls. Under the standard exposure definitions, the association of ciprofloxacin use with resistance decreased with time [current use: adjusted OR 6.8 (95% CI 3.6-12.4); used 181-360 days ago: 1.3 (0.8-1.9)]. Under the 90 day WCE model (best-fitting model), more recent doses were more strongly associated with resistance than past doses, as was longer or repeated treatment. The 180 day WCE model, which fitted the data equally well, suggested that doses taken 91-180 days ago were also significantly associated with resistance. CONCLUSIONS: The estimates for the association between ciprofloxacin use at different times and resistance show that ciprofloxacin prescribers should consider ciprofloxacin use 0-180 days ago to ensure that patients receive suitable treatment. The OR of ciprofloxacin resistance could be reduced by eliminating repeated ciprofloxacin prescription within 180 days and by treating for no longer than necessary.

National laboratory-based surveillance system for antimicrobial resistance: a successful tool to support the control of antimicrobial resistance in the Netherlands.

An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the scientific impact and the possibility of detecting outbreaks may be amplified by merging the AMR surveillance database with databases from selected pathogen-based surveillance programmes containing patient data and genotypic typing data.

Identification of biomarkers for intake of protein from meat, dairy products and grains: a controlled dietary intervention study.

In the present controlled, randomised, multiple cross-over dietary intervention study, we aimed to identify potential biomarkers for dietary protein from dairy products, meat and grain, which could be useful to estimate intake of these protein types in epidemiological studies. After 9 d run-in, thirty men and seventeen women (22 (SD 4) years) received three high-protein diets (aimed at approximately 18% of energy (en%)) in random order for 1 week each, with approximately 14 en% originating from either meat, dairy products or grain. We used a two-step approach to identify biomarkers in urine and plasma. With principal component discriminant analysis, we identified amino acids (AA) from the plasma or urinary AA profile that were distinctive between diets. Subsequently, after pooling total study data, we applied mixed models to estimate the predictive value of those AA for intake of protein types. A very good prediction could be made for the intake of meat protein by a regression model that included urinary carnosine, 1-methylhistidine and 3-methylhistidine (98% of variation in intake explained). Furthermore, for dietary grain protein, a model that included seven AA (plasma lysine, valine, threonine, α-aminobutyric acid, proline, ornithine and arginine) made a good prediction (75% of variation explained). We could not identify biomarkers for dairy protein intake. In conclusion, specific combinations of urinary and plasma AA may be potentially useful biomarkers for meat and grain protein intake, respectively. These findings need to be cross-validated in other dietary intervention studies.

Protein intake in relation to risk of hypertension and microalbuminuria in patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

BACKGROUND: A beneficial association between dietary protein intake (especially from plant sources) with incident hypertension, being strongly correlated to microalbuminuria, has been suggested in healthy populations. Evidence from diabetic populations, in which the prevalence of these diseases is high, is lacking. We examined the associations of total, animal and plant protein intake with incident hypertension (n = 1319) and microalbuminuria (n = 1045) in patients from 16 European countries with type 1 diabetes from the clinic-based EURODIAB Prospective Complications study. METHODS: Odds ratios (OR) with 95% confidence intervals (CI) for incident hypertension after 7 years of follow-up were calculated in tertiles of protein intake (energy%) with adjustments for age, sex, diabetes duration, HbA1c, BMI, physical activity, smoking, alcohol, total energy, total fat and carbohydrate intake. RESULTS: After adjustment for potential confounders, total, animal and plant protein intakes were not related to incident hypertension (298 cases). OR's (95% CI) across increasing tertiles of total protein were 1.00 (ref), 0.86 (0.60-1.25) and 0.91 (0.59-1.43). Furthermore, no relation was observed with incident microalbuminuria (135 cases), with ORs (95% CI) across increasing tertiles of total protein being 1.00 (ref), 0.88 (0.53-1.48) and 1.08 (0.57-2.04). CONCLUSION: Results from our study did not provide evidence that a protein intake commonly consumed by European patients with type 1 diabetes is associated with incident hypertension or microalbuminuria. Prospective studies with more detailed information on dietary intake (including mineral intake) are needed to confirm these findings, and to investigate the impact on vascular and renal complications of a long-term very high protein intake in patients with type 1 diabetes.

Dietary amino acids and the risk of hypertension in a Dutch older population: the Rotterdam Study.

BACKGROUND: Inverse associations between dietary protein and hypertension have been reported, which may be attributed to specific amino acids. OBJECTIVE: We examined whether the intake of glutamic acid, arginine, cysteine, lysine, or tyrosine was associated with blood pressure (BP) levels (n = 3086) and incident hypertension (n = 1810) in the Rotterdam Study. DESIGN: We calculated BP levels in quartiles of amino acid intake as a percentage of total protein intake (% of protein) with adjustment for age, sex, BMI, smoking, alcohol intake, education, and dietary factors. Subsequently, we used Cox proportional models that included the same confounders to evaluate the associations between specific amino acid intake and hypertension incidence. RESULTS: Glutamic acid contributed most to protein intake (21% of protein), whereas lysine provided 7%, arginine 5%, tyrosine 4%, and cysteine 1.5%. A higher intake of tyrosine (∼0.3% of protein) was significantly related to a 2.4-mm Hg lower systolic BP (P-trend = 0.05) but not to diastolic BP (P = 0.35). The other amino acids were not significantly associated with BP levels in a cross-sectional analysis. During 6 y of follow-up (7292 person-years), 873 cases of hypertension developed. None of the amino acids were significantly associated with incident hypertension (HR: 0.81-1.18; P-trend > 0.2). CONCLUSION: Our data do not suggest a major role for glutamic acid, arginine, lysine, tyrosine, or cysteine intake (as % of protein intake) in determining population BP or risk of hypertension.

Sources of dietary protein in relation to blood pressure in a general Dutch population.

BACKGROUND: Little is known about the relation of different dietary protein types with blood pressure (BP). We examined whether intake of total, plant, animal, dairy, meat, and grain protein was related to BP in a cross sectional cohort of 20,820 Dutch adults, aged 20-65 y and not using antihypertensive medication. DESIGN: Mean BP levels were calculated in quintiles of energy-adjusted protein with adjustment for age, sex, BMI, education, smoking, and intake of energy, alcohol, and other nutrients including protein from other sources. In addition, mean BP difference after substitution of 3 en% carbohydrates or MUFA with protein was calculated. RESULTS: Total protein and animal protein were not associated with BP (p(trend) = 0.62 and 0.71 respectively), both at the expense of carbohydrates and MUFA. Systolic BP was 1.8 mmHg lower (p(trend)<0.01) in the highest (>36 g/d) than in the lowest (<27 g/d) quintile of plant protein. This inverse association was present both at the expense of carbohydrates and MUFA and more pronounced in individuals with untreated hypertension (-3.6 mmHg) than in those with normal (+0.1 mmHg) or prehypertensive BP (-0.3 mmHg; p(interaction)<0.01). Meat and grain protein were not related to BP. Dairy protein was directly associated with systolic BP (+1.6 mmHg, p(trend)<0.01), but not with diastolic BP (p(trend) = 0.24). CONCLUSIONS: Total protein and animal protein were not associated with BP in this general untreated Dutch population. Plant protein may be beneficial to BP, especially in people with elevated BP. However, because high intake of plant protein may be a marker of a healthy diet and lifestyle in general, confirmation from randomized controlled trials is warranted.

Sources of dietary protein and risk of hypertension in a general Dutch population.

Evidence suggests a small beneficial effect of dietary protein on blood pressure (BP), especially for plant protein. We examined the relationship between several types of dietary protein (total, plant, animal, dairy, meat and grain) and the risk of hypertension in a general population of 3588 Dutch adults, aged 26-65 years, who were free of hypertension at baseline. Measurements were done at baseline and after 5 and 10 years of follow-up. Hazard ratios (HR), with 95 % CI, for incident hypertension were obtained in tertiles of energy-adjusted protein, using time-dependent Cox regression models. Models were adjusted for age, sex, BMI, education, smoking, baseline systolic BP, dietary confounders and protein from other sources (if applicable). Mean BP was 118/76 mmHg at baseline. Protein intake was 85 (sd 22) g/d (approximately 15 % of energy) with 62 % originating from animal sources. The main sources of protein were dairy products (28 %), meat (24 %) and grain (19 %). During the follow-up, 1568 new cases of hypertension were identified (44 % of the participants). Energy-adjusted intake of total protein, plant protein and animal protein was not significantly associated with hypertension risk (all HR approximately 1·00, P>0·60). Protein from grain showed a significant inverse association with incident hypertension, with a HR of 0·85 (95 % CI 0·73, 1·00, P trend = 0·04) for the upper tertile ( ≥ 18 g/d) v. the lower tertile ( < 14 g/d), whereas dairy protein and meat protein were not associated with incident hypertension. In conclusion, higher intake of grain protein may contribute to the prevention of hypertension, which warrants confirmation in other population-based studies and randomised controlled trials.

Dietary protein and risk of hypertension in a Dutch older population: the Rotterdam study.

BACKGROUND: Several observational studies suggest an inverse association of protein with blood pressure (BP). However, little is known about the role of dietary protein from specific sources in BP. METHOD: We examined the relation between several types of dietary protein (total, plant, animal, dairy, meat, grain, fish, soy, and nut) and incident hypertension in 2241 participants from the Rotterdam Study, aged at least 55 years, who were free of hypertension at baseline. Hazard ratios, with 95% confidence intervals (CIs), for incident hypertension during 6 years of follow-up were obtained per standard deviation (SD) of energy-adjusted intake of protein. Hazard ratios were adjusted for age, sex, body mass index (BMI), baseline systolic blood pressure (SBP) smoking, educational level, alcohol, intake of carbohydrates, other nutrients, and other types of protein (if applicable). We conducted stratified analyses by age (cut-off 70 years), sex, and BMI (cut-off 25 kg/m). RESULTS: The risk of hypertension in the total cohort (1113 cases) was not related to intake of total protein or types of protein (all hazard ratios ∼1.00 per SD). Sex and BMI did not significantly modify the associations of dietary protein with hypertension. In 559 participants aged at least 70 years, the intake of animal protein was positively related to risk of hypertension (hazard ratio 1.37 per SD, 95% CI 1.09-1.72). For participants aged below 70 years no association was found (hazard ratio 0.92, 95% CI 0.81-1.06). CONCLUSION: Total dietary protein or types of protein are not related to incident hypertension in this older population. In the more aged, however, high intake of animal protein may increase the risk of hypertension, which warrants further investigation.

Dietary protein and blood pressure: a systematic review.

BACKGROUND: Elevated blood pressure (BP), which is a major risk factor for cardiovascular disease, is highly prevalent worldwide. Recently, interest has grown in the role of dietary protein in human BP. We performed a systematic review of all published scientific literature on dietary protein, including protein from various sources, in relation to human BP. METHODOLOGY/PRINCIPAL FINDINGS: We performed a MEDLINE search and a manual search to identify English language studies on the association between protein and blood pressure, published before June 2010. A total of 46 papers met the inclusion criteria. Most observational studies showed no association or an inverse association between total dietary protein and BP or incident hypertension. Results of biomarker studies and randomized controlled trials indicated a beneficial effect of protein on BP. This beneficial effect may be mainly driven by plant protein, according to results in observational studies. Data on protein from specific sources (e.g. from fish, dairy, grain, soy, and nut) were scarce. There was some evidence that BP in people with elevated BP and/or older age could be more sensitive to dietary protein. CONCLUSIONS/SIGNIFICANCE: In conclusion, evidence suggests a small beneficial effect of protein on BP, especially for plant protein. A blood pressure lowering effect of protein may have important public health implications. However, this warrants further investigation in randomized controlled trials. Furthermore, more data are needed on protein from specific sources in relation to BP, and on the protein-BP relation in population subgroups.