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A comparison of microbial dose-response models fitted to human data.

A study of eight mathematical dose-response models for microbial risk assessment was conducted using infectivity and illness data on a variety of microbial pathogens from published studies with human volunteers. The purpose was to evaluate variability among the models for human microbial dose-response data in order to determine whether two-parameter models might suffice for most microbial dose-response data or whether three-parameter models should generally be fitted. Model variability was measured in terms of estimated ED01s and ED10s, with the view that these effective dose levels correspond to the lower and upper limits of the 1-10% risk range generally recommended for establishing benchmark doses in risk assessment. An investigation of the ranks of the ED01 and ED10 values among the models led to the conclusion that the two-parameter models captured at least as much uncertainty as the three-parameter models for the data examined. A further evaluation of the two-parameter models did not result in the selection of one "best" model, but it did provide some insights into the models' relative behavior. The model uncertainty analysis proposed by Kang et al. [Regulat. Toxicol. Pharmacol. 32 (2000) 68] using four two-parameter models was reinforced.

Algorithms↗

A CT-based Monte Carlo simulation tool for dosimetry planning and analysis.

The Los Alamos code MCNP4A (Monte Carlo N-Particle version 4A) is currently used to simulate a variety of problems ranging from nuclear reactor analysis to boron neutron capture therapy. A graphical user interface has been developed that automatically sets up the MCNP4A geometry and radiation source requirements for a three-dimensional Monte Carlo simulation using computed tomography data. The major drawback for this dosimetry system is the amount of time to obtain a statistically significant answer. A specialized patch file has been developed that optimizes photon particle transport and dose scoring within the standard MCNP4A lattice geometry. The transport modifications produce a performance increase (number of histories per minute) of approximately 4.7 based upon a 6 MV point source centered within a 30 x 30 x 30 cm3 lattice water phantom and 1 x 1 x 1 mm3 voxels. The dose scoring modifications produce a performance increase of approximately 470 based upon a tally section of greater than 1 x 10(4) lattice elements and a voxel size of 5 mm3. Homogeneous and heterogeneous benchmark calculations produce good agreement with measurements using a standard water phantom and a high- and low-density heterogeneity phantom. The dose distribution from a typical mediastinum treatment planning setup is presented for qualitative analysis and comparison versus a conventional treatment planning system.

Algorithms↗

A multi-port low-fluence alpha-particle irradiator: fabrication, testing and benchmark radiobiological studies.

A new multi-port irradiator, designed to facilitate the study of the effects of low fluences of alpha particles on monolayer cultures, has been developed. The irradiator consists of four individual planar (241)Am alpha-particle sources that are housed inside a helium-filled Lucite chamber. Three of the radioactive sources consist of 20 MBq of (241)Am dioxide foil. The fourth source, used to produce higher dose rates, has an activity of 500 MBq. The four sources are mounted on rotating turntables parallel to their respective 1.5-microm-thick Mylar exit windows. A stainless steel honeycomb collimator is placed between the four sources and their exit windows by a cantilever attachment to the platform of an orbital shaker that moves its table in an orbit of 2 cm. Each exit window is equipped with a beam delimiter to optimize the uniformity of the beam and with a high-precision electronic shutter. Opening and closing of the shutters is controlled with a high-precision timer. Custom-designed stainless steel Mylar-bottomed culture dishes are placed on an adapter on the shutter. The alpha particles that strike the cells have a mean energy of 2.9 MeV. The corresponding LET distribution of the particles has a mean value of 132 keV/microm. Clonogenic cell survival experiments with AG1522 human fibroblasts indicate that the RBE of the alpha particles compared to (137)Cs gamma rays is about 7.6 for this biological end point.

Alpha Particles↗

Impact of physiologically based pharmacokinetic modeling on benchmark dose calculations for TCDD-induced biochemical responses.

In risk assessment, noncancer risk is currently estimated using a no observed adverse effect level (NOAEL) from an experimental dose-response study, divided by uncertainty factors, to estimate a presumably safe level of human exposure. A benchmark dose approach, in which an effective dose (ED) resulting in a specified percentage increase over background for effects is estimated by empirical modeling, has been proposed as a replacement for the NOAEL methodology. The aim of this analysis is to compare methods for estimation of body burden resulting in a 1 or 10% maximum increase over background (BB(01) or BB(10)) for biochemical responses following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female Sprague-Dawley rats. In one method, an ED resulting in a prespecified increase in response over background was estimated using average daily doses and an empirical Hill model. The ED was then converted to an equivalent body burden by a simple kinetic model assuming steady-state conditions, half-life of TCDD in the rat, and 100% absorption of TCDD. Alternatively, a mechanistic physiologically based pharmacokinetic (PBPK) model of TCDD in the rat was used to predict body burdens for administered doses. These PBPK-modeled body burdens were then used directly by the Hill model to calculate a BB(01) or BB(10). In general, the body burden values derived from EDs were within five-fold of BB(01) or BB(10) calculated from the PBPK model. BB(01) and BB(10) values from both methods were within two orders of magnitude of current human general population exposure to all dioxin-like compounds.

Animals↗

Dose-response modeling of in vivo genotoxicity data for use in risk assessment: some approaches illustrated by an analysis of acrylamide.

Methods for dose-response modeling of in vivo genotoxicity data are introduced and applied to a case study of acrylamide. Genetic toxicity results are typically summarized as being either positive or negative, with no further consideration of the dose-response patterns that can be estimated from such studies. This analysis explores the use of three modeling approaches: Poisson regression of counts of genetic effects per cell; dynamic modeling of the time-course of micronucleus production and loss as a function of exposure; and categorical regression of sets of genetic toxicity experiments, the results of which are recoded in terms of severities of response. Estimates derived from these models (benchmark doses and predictions of response rates for predetermined doses of interest) are then used to assess the relevance and role of the genetic toxicity results in a risk assessment. With respect to the acrylamide data base, the results suggest that the genetic damage studies do not appear to be consistent or congruent with the thyroid tumor endpoints observed in two long-term bioassays in rats. This suggests that acrylamide's mechanism of action with respect to production of such tumors may not be genotoxic, and that a cancer risk assessment that applied a linear, no-threshold approach to such endpoints might be inappropriate. Benchmark doses derived from the genetic toxicity data base do not appear to be the critical ones for acrylamide risk assessment. Dose metric and modeling issues associated with the proposed dose-response approach to evaluation of genetic toxicity data are explored, and it is recommended that further advancements of the methodology be developed and employed for optimal use of such data for risk assessment purposes.

Acrylamide↗

Benchmarking of Monte Carlo based shutdown dose rate calculations for applications to JET.

The calculation of dose rates after shutdown is an important issue for operating nuclear reactors. A validated computational tool is needed for reliable dose rate calculations. In fusion reactors neutrons induce high levels of radioactivity and presumably high doses. The complex geometries of the devices require the use of sophisticated geometry modelling and computational tools for transport calculations. Simple rule of thumb laws do not always apply well. Two computational procedures have been developed recently and applied to fusion machines. Comparisons between the two methods showed some inherent discrepancies when applied to calculation for the ITER while good agreement was found for a 14 MeV point source neutron benchmark experiment. Further benchmarks were considered necessary to investigate in more detail the reasons for the different results in different cases. In this frame the application to the Joint European Torus JET machine has been considered as a useful benchmark exercise. In a first calculational benchmark with a representative D-T irradiation history of JET the two methods differed by no more than 25%. In another, more realistic benchmark exercise, which is the subject of this paper, the real irradiation history of D-T and D-D campaigns conducted at JET in 1997-98 were used to calculate the shut-down doses at different locations, irradiation and decay times. Experimental dose data recorded at JET for the same conditions offer the possibility to check the prediction capability of the calculations and thus show the applicability (and the constraints) of the procedures and data to the rather complex shutdown dose rate analysis of real fusion devices. Calculation results obtained by the two methods are reported below, comparison with experimental results give discrepancies ranging between 2 and 10. The reasons of that can be ascribed to the high uncertainty on the experimental data and the unsatisfactory JET model used in the calculation. A new dedicated JET benchmark experiment will be performed trying to solve these issues.

Algorithms↗

Estimation of a chromium inhalation reference concentration using the benchmark dose method: a case study.

The benchmark dose (BD) method has been proposed as an alternative to the NOAEL/UF method for setting reference levels. The BD is the 95% lower confidence limit on a dose corresponding to a 10% increase (or relative change) in an adverse effect. A case study exploring the suitability of the current Cr(III) and Cr(VI) inhalation toxicity data bases to the BD approach is presented. Because chromic acid mists, typical of many occupational Cr(VI) exposures, present a toxicological profile different from that of Cr(VI) particulates, representative of environmental exposures, Cr(VI) particulate data were evaluated separately from Cr(VI) acidic mist data. The current Cr(III) and Cr(VI) acidic mist data bases proved inadequate for BD analysis due to data and/or study quality limitations. Benchmark reference concentrations (RfCs) for particulate Cr(VI) ranging from 0.34 microgram/m3 (for lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF)) to 1.4 micrograms/m3 (for increased lung weights) are derived from data taken from U. Glaser et al. (Arch. Toxicol. 57, 250-256, 1985) and U. Glaser et al. (Environmental Hygiene II, Springer-Verlag, Berlin/New York, 1990). A Cr(VI) particulate RfC of 0.34 microgram/m3 based upon LDH in BALF as the critical effect is proposed. This value may be viewed as conservative since it represents the 95% lower confidence limit on the dose associated with a 10% increase in response for a sensitive endpoint and has appropriate dosimetric adjustments and uncertainty factors incorporated.

Administration, Inhalation↗

Quantitative risk analyses for RCF: survey and synthesis.

Refractory ceramic fiber (RCF) is a high-temperature insulating fiber used principally in industrial applications. Epidemiological studies on occupationally exposed cohorts have not indicated that exposure leads to fibrosis, increased lung cancer, or mesothelioma. However, inhalation bioassays with rats and hamsters have shown that these animals can develop each of these endpoints when exposed to high levels of RCF-particle mixtures. This work summarizes relevant quantitative risk analyses based upon analysis of the rat bioassay studies, which lead to predicted unit risks that range nearly three orders of magnitude. Additionally, we identify key assumptions that affect the risk estimates and provide additional estimates using the benchmark dose methodology favored by the U.S. EPA in cases where mechanistic models are inadequate or not available. We show that a key determinant of risk is how lung burdens are normalized (e.g., in terms of the number of fibers per square centimeter of lung surface or the number of fibers per milligram dry lung) for species conversion. Plausible values of unit potency/risk range from 1.4x10(-4) to 7.2x10(-4), neglecting any allowance for the effects of particulate material in the RCF tested in the bioassay experiments.

Administration, Inhalation↗

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers.

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.

Adult↗

Investigation of the potential impact of benchmark dose and pharmacokinetic modeling in noncancer risk assessment.

There has been relatively little attention given to incorporating knowledge of mode of action or of dosimetry of active toxic chemical to target tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference concentration (RfC) process on delivered dose adjustments for inhaled materials. The studies reported here attempt to continue in the spirit of the new RfC guidelines by incorporating both mechanistic and delivered dose information using a physiologically based pharmacokinetic (PBPK) model, along with quantitative dose-response information using the benchmark dose (BMD) method, into the noncancer risk assessment paradigm. Two examples of the use of PBPK and BMD techniques in noncancer risk assessment are described: methylene chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK analysis of these chemicals were generally similar to those based on the traditional process, but individual MRLs ranged from roughly 10-fold higher to more than 10-fold lower than existing MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modeling, and in these two cases the BMD models were unable to provide an acceptable fit to the overall dose-response of the data, even using pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequate to support BMD modeling. Three general observations regarding the use of PBPK and BMD modeling in noncancer risk assessment were noted. First, a full PBPK model may not be necessary to support a more accurate risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Second, pharmacokinetic and mode of action considerations are a crucial factor in conducting noncancer risk assessments that involve animal-to-human extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the toxicological literature should include both means and standard deviations for each dose group in the case of quantitative endpoints, such as relative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.

Animals↗

[Regional clinical audit, guideline targets, and local and regional benchmarks].

Regional clinical Audit, guideline Targets and local and regional Benchmarks In order to improve the quality of dialysis treatment, we have devised some routines, particularly suitable for electronic data management systems. First, we suggest a systematic monthly analysis of 10 common clinical performance measures (CPM), with the following guideline based targets: predialysis systolic blood pressure (SBP) < 140 mmHg; session length >/= 240 min; dialysis dose (spKt/V) >/=1.3; normalized protein catabolic rate (NPCR) >/=1.2 g/kg/d; hemoglobin (Hb) >/=11 g/dL; serum calcium (Ca) 8.4-9.5 mg/dL; serum phosphorus (P) 3.5-5.5 mg/dL; Ca x P </=55 mg 2 /dL 2 ; serum bicarbonate (HCO3) >/=20 mmol/L; serum potassium (K) 3.5-6.0 mmol/L. The Hb target should be reached in at least 85% of all maintenance hemodialysis (HD) patients in the unit; for all other targets, an arbitrary >/=80% is proposed. Since the above percentages are quite difficult to reach on a short-term basis, an intermediate local or regional standard (benchmark) could be devised as an average of the percentage of patients who actually reach the targets for each CPM at any dialysis unit in a given regional area; and therefore, from truly comparable patients. As an example, we simulated a regional audit by using the above targets with available data from 398 patients from southern Italy. A further step in this process was to find the cause(s) of failure in each patient who did not reach the targets. To this end, we suggest a systematic search of the well-known factors that could affect each CPM, for each failed patient. As an example, we screened all patients with Hb < 11 g/dL at a single unit, to establish the presence/absence of any common cause associated with inadequate response to epoetin treatment. Moreover, by using criteria for prescribing iron therapy or increasing epoetin dose, we found that some patients did not receive the appropriate therapy after blood sampling results. To avoid this possible common problem, we suggest the need for a monthly report of failure cases for any particular CPM and a check that the appropriate treatment has been delivered to all patients at the dialysis unit. This should also favor guideline implementation.

Benchmarking↗

Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials.

BACKGROUND: Unfractionated heparin has been the primary anticoagulant therapy for percutaneous coronary intervention for >20 years. Despite the availability of rapid "point of care" testing, little clinical data defining the optimal level of anticoagulation are available. Furthermore, recent reports have advocated the use of low-dose heparin regimens in the absence of large-scale, well-conducted studies to support this practice. METHODS AND RESULTS: We pooled the data from 6 randomized, controlled trials of novel adjunctive antithrombotic regimens for percutaneous coronary interventions in which unfractionated heparin constituted the control arm. Patients were divided into 25-s intervals of activated clotting times (ACTs), from <275 s to >476 s. In a total of 5216 patients, the incidence of death, myocardial infarction, or any revascularization and major or minor bleeding at 7 days were calculated for each group and compared. An ACT in the range of 350 to 375 s provided the lowest composite ischemic event rate of 6.6%, or a 34% relative risk reduction in 7-day ischemic events compared with rates observed between 171 and 295 s by quartile analysis (P=0.001). CONCLUSIONS: Contrary to recent reports, the optimal suppression of ischemic events with unfractionated heparin therapy in patients undergoing percutaneous coronary intervention demands treatment to ACT levels that are substantially higher than currently appreciated. These data define a goal for heparin dosing within coronary interventions and establish a benchmark of optimal unfractionated heparin therapy against which future trials of novel antithrombotic regimens in percutaneous interventions can be compared.

Abciximab↗

Use of benchmark dose-volume histograms for selection of the optimal technique between three-dimensional conformal radiation therapy and intensity-modulated radiation therapy in prostate cancer.

PURPOSE: The aim of this study was to develop and validate our own benchmark dose-volume histograms (DVHs) of bladder and rectum for both conventional three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT), and to evaluate quantitatively the benefits of using IMRT vs. 3D-CRT in treating localized prostate cancer. METHODS AND MATERIALS: During the implementation of IMRT for prostate cancer, our policy was to plan each patient with both 3D-CRT and IMRT. This study included 31 patients with T1b to T2c localized prostate cancer, for whom we completed double-planning using both 3D-CRT and IMRT techniques. The target volumes included prostate, either with or without proximal seminal vesicles. Bladder and rectum DVH data were summarized to obtain an average DVH for each technique and then compared using two-tailed paired t test analysis. RESULTS: For 3D-CRT our bladder doses were as follows: mean 28.8 Gy, v60 16.4%, v70 10.9%; rectal doses were: mean 39.3 Gy, v60 21.8%, v70 13.6%. IMRT plans resulted in similar mean dose values: bladder 26.4 Gy, rectum 34.9 Gy, but lower values of v70 for the bladder (7.8%) and rectum (9.3%). These benchmark DVHs have resulted in a critical evaluation of our 3D-CRT techniques over time. CONCLUSION: Our institution has developed benchmark DVHs for bladder and rectum based on our clinical experience with 3D-CRT and IMRT. We use these standards as well as differences in individual cases to make decisions on whether patients may benefit from IMRT treatment rather than 3D-CRT.

Adult↗

Performance analysis of a film dosimetric quality assurance procedure for IMRT with regard to the employment of quantitative evaluation methods.

A system for dosimetric verification of intensity-modulated radiotherapy (IMRT) treatment plans using absolute calibrated radiographic films is presented. At our institution this verification procedure is performed for all IMRT treatment plans prior to patient irradiation. Therefore clinical treatment plans are transferred to a phantom and recalculated. Composite treatment plans are irradiated to a single film. Film density to absolute dose conversion is performed automatically based on a single calibration film. A software application encompassing film calibration, 2D registration of measurement and calculated distributions, image fusion, and a number of visual and quantitative evaluation utilities was developed. The main topic of this paper is a performance analysis for this quality assurance procedure, with regard to the specification of tolerance levels for quantitative evaluations. Spatial and dosimetric precision and accuracy were determined for the entire procedure, comprising all possible sources of error. The overall dosimetric and spatial measurement uncertainties obtained thereby were 1.9% and 0.8 mm respectively. Based on these results, we specified 5% dose difference and 3 mm distance-to-agreement as our tolerance levels for patient-specific quality assurance for IMRT treatments.

Benchmarking↗

Benchmarking the MCNP code for Monte Carlo modelling of an in vivo neutron activation analysis system.

The Monte Carlo computer code MCNP (version 4A) has been used to develop a personal computer-based model of the Swansea in vivo neutron activation analysis (IVNAA) system. The model included specification of the neutron source (252Cf), collimators, reflectors and shielding. The MCNP model was 'benchmarked' against fast neutron and thermal neutron fluence data obtained experimentally from the IVNAA system. The Swansea system allows two irradiation geometries using 'short' and 'long' collimators, which provide alternative dose rates for IVNAA. The data presented here relate to the short collimator, although results of similar accuracy were obtained using the long collimator. The fast neutron fluence was measured in air at a series of depths inside the collimator. The measurements agreed with the MCNP simulation within the statistical uncertainty (5-10%) of the calculations. The thermal neutron fluence was measured and calculated inside the cuboidal water phantom. The depth of maximum thermal fluence was 3.2 cm (measured) and 3.0 cm (calculated). The width of the 50% thermal fluence level across the phantom at its mid-depth was found to be the same by both MCNP and experiment. This benchmarking exercise has given us a high degree of confidence in MCNP as a tool for the design of IVNAA systems.

Body Composition↗

Reconstructive neurosurgery for Parkinson's disease: a systematic review and preliminary meta-analysis.

This systematic review and meta-analysis aimed to identify the determinants for best practice and establish current benchmarks for recovery following reconstructive neurosurgery for people with Parkinson's disease. Eleven studies reporting results for 95 grafted patients were selected on the grounds of using optimal surgical techniques and the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol for data collection. Consistent trends demonstrating high levels of recovery were identified on most outcome measures. Determinants for best practice were identified as selecting younger patients; using low dose immunosuppression; bilateral grafting; and employing strategies to ensure the quantity and viability of the grafted cells. Secondary analysis of data demonstrated a correlation of rho=0.666 (P<0.05) between increases in striatal dopaminergic activity and UPDRS Motor (off) scores. Overall effect size 'd' was found to be 1.129 UPDRS Motor (off) condition and 0.719 for UPDRS Total (off) condition. The design of the studies and the variable standards for reporting the data precluded the use of more powerful and accurate meta-analyses. It was recommended that the creation of a collaborative database would improve the extraction of data and allow for more powerful statistical analyses for evaluating the overall harm and benefits associated with reconstructive neurosurgery.

Brain Tissue Transplantation↗

Alternatives for a risk assessment on chronic noncancer effects from oral exposure to trichloroethylene.

Changes in methodologies are presently occurring for dose-response assessment in noncancer and cancer risk assessments. The benchmark dose (BMD) method is an alternative to the no-observed-adverse-effect level (NOAEL)/uncertainty factor (UF) approach for development of toxicity values. A comparison of these two methods was undertaken using trichloroethylene, an important industrial chemical and environmental contaminant. This analysis considered liver effects, kidney toxicity, and developmental defects. A range of toxicity values was obtained using the two methods from which acceptable drinking water concentrations were estimated: 1000-10,000 ppb for liver effects, 1750 ppb from kidney toxicity, and 1000-10,000 ppb from developmental defects of the eye. These values are all higher than those based upon cancer as the critical endpoint. This analysis highlighted the strengths of the BMD approach in the presence of adequate dose-response data, but it also suggested that guidance is required for addressing inadequate dose-response data. The selection of UF and critical studies were identified as areas that have a large impact upon the final dose-response values, sometimes greater than the variations arising from using the BMD rather than the NOAEL.

Administration, Oral↗

Surveillance of antibiotic use in hospitals: methods, trends and targets.

A standardised antibiotic surveillance system is an essential requirement of all antibiotic control strategies. Antibiotic use can be quantified accurately using patient-level surveillance, although this is not feasible for most hospitals. Instead, population-level surveillance is a more realistic alternative for ongoing and systematic monitoring of antibiotic use. Monitoring of aggregate, ward-supply data on a monthly basis, stratification by patient care area, and analysis by the anatomical therapeutic chemical/defined daily dose (ATC/DDD) system, adjusting for bed-occupancy, provides a clear picture of antibiotic consumption density and time-trends within a hospital. When usage rates are supplemented and interpreted according to changes in hospital resource indicators, benchmarking is facilitated. This provides an efficient tool for triggering and targeting antibiotic control interventions.

Anti-Bacterial Agents↗