Summary Background Antimicrobial stewardship is advocated to improve the quality of antimicrobial use. We did a systematic review and meta-analysis to assess whether antimicrobial stewardship ...objectives had any effects in hospitals and long-term care facilities on four predefined patients' outcomes: clinical outcomes, adverse events, costs, and bacterial resistance rates. Methods We identified 14 stewardship objectives and did a separate systematic search for articles relating to each one in Embase, Ovid MEDLINE, and PubMed. Studies were included if they reported data on any of the four predefined outcomes in patients in whom the specific antimicrobial stewardship objective was assessed and compared the findings in patients in whom the objective was or was not met. We used a random-effects model to calculate relative risk reductions with relative risks and 95% CIs. Findings We identified 145 unique studies with data on nine stewardship objectives. Overall, the quality of evidence was generally low and heterogeneity between studies was mostly moderate to high. For the objectives empirical therapy according to guidelines, de-escalation of therapy, switch from intravenous to oral treatment, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation the overall evidence showed significant benefits for one or more of the four outcomes. Guideline-adherent empirical therapy was associated with a relative risk reduction for mortality of 35% (relative risk 0·65, 95% CI 0·54–0·80, p<0·0001) and for de-escalation of 56% (0·44, 0·30–0·66, p<0·0001). Evidence of effects was less clear for adjusting therapy according to renal function, discontinuing therapy based on lack of clinical or microbiological evidence of infection, and having a local antibiotic guide. We found no reports for the remaining five stewardship objectives or for long-term care facilities. Interpretation Our findings of beneficial effects on outcomes with nine antimicrobial stewardship objectives suggest they can guide stewardship teams in their efforts to improve the quality of antibiotic use in hospitals. Funding Dutch Working Party on Antibiotic Policy and Netherlands National Institute for Public Health and the Environment.
These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on ...the effectiveness of individual antibiotics and on combination versus monotherapy.
An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak).
The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
Summary In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin ...B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.
Summary Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected ...by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.
Although testing of antimicrobial agents for susceptibility has inherent variability like any assay, it is generally held that there are also real differences in susceptibility between strains. In ...the routine laboratory, variability of the MIC measurement may be sufficient to mask real strain differences. We determined which factors contributed to the variability, using linezolid against Staphylococcus aureus as one example.
Twenty-five S. aureus strains were sent to five different laboratories in quadruplicate in a blinded fashion. Laboratories determined MICs of linezolid using Etest. Results of 22 strains corresponding to 440 observations were available for analysis. Sources of variability were explored and quantified using an ANOVA approach.
The overall geometric mean MIC was 1.8 mg/L, comparable to that of the published WT distribution of 1.7 mg/L (www.eucast.org). The total variation amounted to ∼1.3 2-fold dilutions for a one-sided CI of 95% and two 2-fold dilutions for a CI of 99%. Variation between laboratories and variation between strains contributed 10% and 48%, and in a subset analysis averaging 17% and 26%, respectively. Strain-to-strain variation (biological variation) could not be reliably determined, even with four replicates.
This analysis serves as an example of an approach to discerning various sources of MIC variation. Here, at best, a single measurement of an MIC may provide an indication of whether it likely belongs to the WT distribution. Only repeated measurements of MICs for individual strains within one laboratory may provide an indication of differences in susceptibility between strains.
The Minimum Inhibitory Concentration (MIC) is a reference value for susceptibility testing of bacteria. However, the MIC is a net result of growth and killing after a certain duration of exposure ...under standardized favourable in vitro conditions. Killing and growth characteristics of a drug may yield more information on its activity and help to explain discrepancies between efficacy observed in vitro and in vivo.
The MIC of meropenem was determined for P. aeruginosa ATCC 27853 both by microdilution and the E-test in dilutions of Mueller Hinton (MH) broth from 100% to 1%. Time-kill curves were obtained for twofold dilutions of meropenem. Growth rates and kill rates at each concentration and dilution were obtained by linear regression. The Hill equation was fit to the kill rates vs concentrations.
Growths rates decreased log linearly from 0.63/h at 100% to 0.29/h at 6% MH. Over the 100–6% MH dilution range, there was a log-linear decrease of the MIC of meropenem of both the E-test and microdilution. The EC50s decreased from 0.29 mg/L to 0.07 mg/L, which is in agreement with the MIC results. There was a log-linear relationship between MIC and EC50 for the various dilutions MH.
The availability of nutritional factors is related to the MIC, and a lower availability is related to both a lower growth rate and higher kill rate. Since nutritional factors are less abundantly available in vivo as compared to in vitro, this should be taken into account when translating in vitro to in vivo pharmacodynamics.
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is the second most common etiological agent of invasive aspergillosis (IA) after
. However, most literature describes IA in relation to
or together with other
species. Certain differences exist in IA ...caused by
and
and studies on
infections are increasing. Hence, we performed a comprehensive updated review on IA due to
.
is the cause of a broad spectrum of human diseases predominantly in Asia, the Middle East, and Africa possibly due to its ability to survive better in hot and arid climatic conditions compared to other
spp. Worldwide, ~10% of cases of bronchopulmonary aspergillosis are caused by
Outbreaks have usually been associated with construction activities as invasive pulmonary aspergillosis in immunocompromised patients and cutaneous, subcutaneous, and mucosal forms in immunocompetent individuals. Multilocus microsatellite typing is well standardized to differentiate
isolates into different clades.
is intrinsically resistant to polyenes. In contrast to
, triazole resistance infrequently occurs in
and is associated with mutations in the
gene. Overexpression of efflux pumps in non-wildtype strains lacking mutations in the
gene can also lead to high voriconazole minimum inhibitory concentrations. Voriconazole remains the drug of choice for treatment, and amphotericin B should be avoided. Primary therapy with echinocandins is not the first choice but the combination with voriconazole or as monotherapy may be used when the azoles and amphotericin B are contraindicated.
MIC-based dose adjustment: facts and fables Mouton, Johan W; Muller, Anouk E; Canton, Rafael ...
Journal of antimicrobial chemotherapy,
03/2018, Letnik:
73, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Over recent decades, several publications have described optimization procedures for antibiotic therapy in the individual patient based on antimicrobial MIC values. Most methods include therapeutic ...drug monitoring and use a single MIC determination plus the relevant pharmacokinetics/pharmacodynamics to adjust the dose to optimize antimicrobial drug exposure and antibacterial effects. However, the use of an MIC obtained by a single MIC determination is inappropriate. First, routine clinical laboratories cannot determine MICs with sufficient accuracy to guide dosage owing to the inherent assay variation in the MIC test. Second, the variation in any MIC determination, whatever method is used, must be accounted for. If dose adjustments are made based on therapeutic drug monitoring and include MIC determinations, MIC variation must be considered to prevent potential underdosing of patients. We present the problems and some approaches that could be used in clinical practice.
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Because of increasing antimicrobial resistance and the shortage of new antibiotics, there is a growing need to optimize the use of old and new antibiotics. Modelling of the ...pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antibiotics can support the optimization of dosing regimens. Antimicrobial efficacy is determined by susceptibility of the drug to the microorganism and exposure to the drug, which relies on the PK and the dose. Population PK models describe relationships between patients characteristics and drug exposure. This article highlights three clinical applications of these models applied to antibiotics: 1) dosing evaluation of old antibiotics, 2) setting clinical breakpoints and 3) dosing individualization using therapeutic drug monitoring (TDM). For each clinical application, challenges regarding interpretation are discussed. An important challenge is to improve the understanding of the interpretation of modelling results for good implementation of the dosing recommendations, clinical breakpoints and TDM advices. Therefore, also background information on PK/PD principles and approaches to analyse PK/PD data are provided.
In 2011, Dutch animal production sectors started recording veterinary antimicrobial consumption. These data are used by the Netherlands Veterinary Medicines Authority to create transparency in and ...define benchmark indicators for veterinary consumption of antimicrobials. This paper presents the results of sector wide consumption of antimicrobials, in the form of prescriptions or deliveries, for all pig, veal calf, and broiler farms. Data were used to calculate animal defined daily dosages per year (ADDD/Y) per pig or veal calf farm. For broiler farms, number of animal treatment days per year was calculated. Furthermore, data were used to calculate the consumption of specific antimicrobial classes per administration route per pig or veal calf farm. The distribution of antimicrobial consumption per farm varied greatly within and between farm categories. All categories, except for rosé starter farms, showed a highly right skewed distribution with a long tail. Median ADDD/Y values varied from 1.2 ADDD/Y for rosé finisher farms to 83.2 ADDD/Y for rosé starter farms, with 28.6 ADDD/Y for white veal calf farms. Median consumption in pig farms was 9.3 ADDD/Y for production pig farms and 3.0 ADDD/Y for slaughter pig farms. Median consumption in broiler farms was 20.9 ATD/Y. Regarding specific antimicrobial classes, fluoroquinolones were mainly used on veal calf farms, but in low quantities: P75 range was 0 - 0.99 ADDD/Y, and 0 - 0.04 ADDD/Y in pig farms. The P75 range for 3(rd)/4(th)-generation cephalosporins was 0 - 0.07 ADDD/Y for veal calf farms, and 0 - 0.1 ADDD/Y for pig farms. The insights obtained from these results, and the full transparency obtained by monitoring antimicrobial consumption per farm, will help reduce antimicrobial consumption and endorse antimicrobial stewardship. The wide and skewed distribution in consumption has important practical and methodological implications for benchmarking, surveillance and future analysis of trends.
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