Combination therapy with IV fosfomycin for adult patients with serious Gram-negative infections: a review of the literature.

Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a ß-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a ß-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of ß-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.

Taurolidine and Heparin as Catheter Lock Solution for Central Venous Catheters in Hemodialysis.

BACKGROUND: Chronic kidney disease can lead to end-stage renal disease, and the prevalence is increasing. Many patients starting hemodialysis require central venous catheters (CVCs). Catheter-related bloodstream infections (CRBSIs) are a common complication and lead to significant morbidity and mortality. Interventions to prevent CRBSI include antimicrobial lock therapy but concern for the development of antimicrobial resistance and adverse effects. Nonantimicrobial antiseptics as catheter lock solutions have also been used. Taurolidine and heparin catheter lock solution is first approved by the Food and Drug Administration for the prevention of CRBSI in patients on hemodialysis. Taurolidine has a unique mechanism of action and favorable safety profile. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Taurolidine and heparin catheter lock solution have both antimicrobial and anticoagulant properties. Taurolidine is derivative of the amino acid taurine, and heparin is derived from porcine intestinal mucosa. Taurolidine not only damages microbial cell walls but also prevents the adherence of microorganisms to biological surfaces, preventing biofilm formation. Taurolidine and heparin catheter lock solution is intended to be used intraluminally within the catheter and should be aspirated. Because it is used locally, limited pharmacokinetic and pharmacodynamic data are available. CLINICAL TRIALS: The LOCK-IT-100 trial is a randomized, double-blind, phase 3 study, which included 795 end-stage renal disease patients on hemodialysis with CVC. Taurolidine and heparin was compared with the control heparin alone. The results of the study showed a 71% risk reduction in CRBSI for taurolidine and heparin arm (95% confident interval, 38%-86%, P = 0.0006). Other studies have also shown that taurolidine lock solution leads to decreased CRBSI episodes. Several systematic reviews and meta-analysis consisted of taurolidine in adult, and pediatric populations also showed reduction in the incidence of CRBSIs. THERAPEUTIC ADVANCE: Taurolidine and heparin lock solution represents a novel preventive strategy for those undergoing hemodialysis through a CVC by reducing the risk of CRBSI. This is significant progress because there are no other similar options available for patients for whom catheters are the only options for their life-saving treatment.

Optimizing aminoglycoside selection for KPC-producing Klebsiella pneumoniae with the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib.

OBJECTIVES: KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates commonly co-harbour the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib, which encodes an AME that can confer resistance to some of the commercially available aminoglycosides. We sought to determine the influence of AAC(6')-Ib in KPC-Kp on the pharmacodynamic activity of aminoglycosides. METHODS: Six KPC-Kp clinical isolates, three with and three without aac(6')-Ib, were analysed. Using these isolates, the bacterial killing of amikacin, gentamicin and tobramycin was assessed in static time-kill experiments. The pharmacodynamic activity of the aminoglycosides was then assessed in a dynamic one-compartment infection model over 72 h using simulated human pharmacokinetics of once-daily dosing with amikacin (15 mg/kg), gentamicin (5 mg/kg) and tobramycin (5 mg/kg). RESULTS: At clinically relevant aminoglycoside concentrations in time-kill experiments and the dynamic one-compartment model, gentamicin was more active than amikacin or tobramycin against the isolates harbouring aac(6')-Ib. Amikacin, gentamicin and tobramycin all showed progressively reduced bacterial killing with exposure to repeated doses against most isolates in the dynamic one-compartment model. MIC values were generally not a good predictor of gentamicin pharmacodynamic activity against KPC-Kp, but were more reliable for amikacin and tobramycin. CONCLUSIONS: Gentamicin may be preferred over amikacin or tobramycin for treatment of KPC-Kp infections. However, gentamicin MICs are not a consistent predictor of its pharmacodynamic activity and unexpected treatment failures are possible.

The NAS-NRC Twin Registry and Duke Twins Study of Memory in Aging: An Update.

The National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the USA. It comprises 15,924 White male twin pairs born in the years 1917-1927 (N = 31.848), both of whom served in the armed forces, chiefly during World War II. This article updates activities in this registry since the most recent report in Twin Research and Human Genetics (Page, 2006). Records-based data include information from enlistment charts and Veterans Administration data linkages. There have been three major epidemiologic questionnaires and an education and earnings survey. Separate data collection efforts with the NAS-NRC registry include the National Heart, Lung, and Blood Institute (NHLBI) subsample, the Duke Twins Study of Memory in Aging and a clinically based study of Parkinson's disease. Progress has been made on consolidating the various data holdings of the NAS-NRC Twin Registry. Data that had been available through the National Academy of Sciences are now freely available through National Archive of Computerized Data on Aging (NACDA).

IGEMS: The Consortium on Interplay of Genes and Environment Across Multiple Studies - An Update.

The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 18 twin studies from 5 different countries (Sweden, Denmark, Finland, United States, and Australia) established to explore the nature of gene-environment (GE) interplay in functioning across the adult lifespan. Fifteen of the studies are longitudinal, with follow-up as long as 59 years after baseline. The combined data from over 76,000 participants aged 14-103 at intake (including over 10,000 monozygotic and over 17,000 dizygotic twin pairs) support two primary research emphases: (1) investigation of models of GE interplay of early life adversity, and social factors at micro and macro environmental levels and with diverse outcomes, including mortality, physical functioning and psychological functioning; and (2) improved understanding of risk and protective factors for dementia by incorporating unmeasured and measured genetic factors with a wide range of exposures measured in young adulthood, midlife and later life.

The CODATwins Project: The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits.

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project.

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.

Compatibility of Omadacycline With Select Parenteral Products in Simulated Y-site Administration.

PURPOSE: Omadacycline is a broad-spectrum intravenous and oral tetracycline antibiotic approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Available information on the compatibility of intravenous omadacycline is limited to sterile water, 0.9% sodium chloride, and 5% dextrose via a dedicated line. The objective of this work was to determine the intravenous compatibility of omadacycline with commonly used intravenous fluids and medications using simulated Y-site administration. METHODS: Omadacycline was prepared at concentrations consistent with a maintenance dose (1 mg/mL) and a loading dose (2 mg/mL) with 0.9% sodium chloride according to the prescribing information. Compatibility via simulated Y-site administration was assessed with selected crystalloids (lactated Ringer's solution, magnesium sulfate, and normal saline with potassium chloride) and intravenous medications (bumetanide, furosemide, heparin, and insulin). Y-site administration was simulated by mixing 5 mL of omadacycline with 5 mL of each parenteral product prepared at standard concentrations for infusion. Compatibility was assessed by using visual, Tyndall beam, microscopy, and spectrophotometry methods at 0, 30, and 60 minutes. FINDINGS: Omadacycline appeared physically compatible with lactated Ringer's solution, magnesium sulfate, normal saline with potassium chloride, bumetanide, heparin, and insulin at standard infusion concentrations. However, although the lower concentrations of omadacycline 1 mg/mL and furosemide 2 mg/mL showed compatibility, higher concentrations of either agent in combination resulted in incompatibility. IMPLICATIONS: Omadacycline appeared physically compatible with all products tested and incompatible with furosemide. Simultaneous administration of omadacycline with tested intravenous medications, except furosemide, is suggested to be safe.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Development of a 51-hospital Chicagoland regional antibiogram and comparison to local hospital and national surveillance data.

OBJECTIVE: To develop a regional antibiogram within the Chicagoland metropolitan area and to compare regional susceptibilities against individual hospitals within the area and national surveillance data. DESIGN: Multicenter retrospective analysis of antimicrobial susceptibility data from 2017 and comparison to local institutions and national surveillance data. SETTING AND PARTICIPANTS: The analysis included 51 hospitals from the Chicago-Naperville-Elgin Metropolitan Statistical Area within the state of Illinois. Overall, 18 individual collaborator hospitals provided antibiograms for analysis, and data from 33 hospitals were provided in aggregate by the Becton Dickinson Insights Research Database. METHODS: All available antibiogram data from calendar year 2017 were combined to generate the regional antibiogram. The final Chicagoland antibiogram was then compared internally to collaborators and externally to national surveillance data to assess its applicability and utility. RESULTS: In total, 167,394 gram-positive, gram-negative, fungal, and mycobacterial isolates were collated to create a composite regional antibiogram. The regional data represented the local institutions well, with 96% of the collaborating institutions falling within ±2 standard deviations of the regional mean. The regional antibiogram was able to include 4-5-fold more gram-positive and -negative species with ≥30 isolates than the median reported by local institutions. Against national surveillance data, 18.6% of assessed pathogen-antibiotic combinations crossed prespecified clinical thresholds for disparity in susceptibility rates, with notable trends for resistant gram-positive and gram-negative bacteria. CONCLUSIONS: Developing an accurate, reliable regional antibiogram is feasible, even in one of the largest metropolitan areas in the United States. The biogram is useful in assessing susceptibilities to less commonly encountered organisms and providing clinicians a more accurate representation of local antimicrobial resistance rates compared to national surveillance databases.

Multidrug Resistant Acinetobacter baumannii: Resistance by Any Other Name Would Still be Hard to Treat.

PURPOSE OF REVIEW: Acinetobacter baumannii (AB) is an infamous nosocomial pathogen with a seemingly limitless capacity for antimicrobial resistance, leading to few treatment options and poor clinical outcomes. The debatably low pathogenicity and virulence of AB are juxtaposed by its exceptionally high rate of infection-related mortality, likely due to delays in time to effective antimicrobial therapy secondary to its predilection for resistance to first-line agents. Recent studies of AB and its infections have led to a burgeoning understanding of this critical microbial threat and provided clinicians with new ammunition for which to target this elusive pathogen. This review will provide an update on the virulence, resistance, diagnosis, and treatment of multidrug resistant (MDR) AB. RECENT FINDINGS: Advances in bacterial genomics have led to a deeper understanding of the unique mechanisms of resistance often present in MDR AB and how they may be exploited by new antimicrobials or optimized combinations of existing agents. Further, improvements in rapid diagnostic tests (RDTs) and their more pervasive use in combination with antimicrobial stewardship interventions have allowed for more rapid diagnosis of AB and decreases in time to effective therapy. Unfortunately, there remains a paucity of high-quality clinical data for which to inform the optimal treatment of MDR AB infections. In fact, recently completed studies have failed to identify a combination regimen that is consistently superior to monotherapy, despite the benefits demonstrated in vitro. Encouragingly, new and updated guidelines offer strategies for the treatment of MDR AB and may help to harmonize the use of high toxicity agents such as the polymyxins. Finally, new antimicrobial agents such as eravacycline and cefiderocol have promising in vitro activity against MDR AB but their place in therapy for these infections remains to be determined. Notwithstanding available clinical trial data, polymyxin-based combination therapies with either a carbapenem, minocycline, or eravacycline remain the treatment of choice for MDR, particularly carbapenem-resistant, AB. Incorporating antimicrobial stewardship intervention with RDTs relevant to MDR AB can help avoid potentially toxic combination therapies and catalyze the most important modifiable risk factor for mortality-time to effective therapy. Further research efforts into pharmacokinetic/pharmacodynamic-based dose optimization and clinical outcomes data for MDR AB continue to be desperately needed.

Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

BACKGROUND: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.

Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts.

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m2)], but factors modifying these variance components are poorly understood.Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity.Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs).Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI.Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population.

Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994.

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

The DoD Joint Pathology Center as a Resource for Researchers.

The Department of Defense's Joint Pathology Center (JPC) is the world's largest collection of human pathology specimens, comprising some 7.4 million accessions. The biorepository, which began during the Civil War as a collection of materials obtained from medical and surgical procedures performed by Army physicians, houses specimens and associated data obtained for diagnostic purposes. It also holds several collections of specimens from military personnel who shared a common, service-related exposure or medical condition. This article, which is excerpted and adapted from the 2012 Institute of Medicine report "Future Uses of the Department of Defense JPC Biorepository,"1 summarizes information on the repository, its past uses, and the future operational issues and challenges that the JPC faces as it develops a concept of operations that will allow it to move forward as a resource for researchers.

The Air Force Health Study Data and Specimens as a Resource for Researchers.

The Air Force Health Study (AFHS) is perhaps the most thorough longitudinal examination of both the health of military personnel and the health effects of herbicide exposure ever conducted. Data were collected through comprehensive physical examinations, questionnaires, and other records at six time points over a 20-year period; 2,758 subjects participated in at least one examination cycle. Data collected during physical examinations included indices of health status overall and specific endpoints for each organ system. Questionnaire data included sociodemographic information, marital and fertility history, health habits, recreation activities, toxic substances exposure, and military experience. Biospecimens were collected at each examination cycle; serum was collected at all six examinations while other biospecimens, such as semen and whole blood, were collected at one time. More than 200 clinical laboratory tests and measures were performed, with more than 60 of these measured at all six cycles. The vast amount of electronic data and the more than 91,000 unaliquoted biospecimens contained in the repository offer unique opportunities for new research on understanding determinants of health. The Institute of Medicine is the custodian of the AFHS materials and conducted a pilot research program to facilitate new research using the materials. An expert committee issued requests for proposals, created a Web-based form for submissions, reviewed and evaluated potential research studies, and made data and biospecimens available to qualified researchers. This article summarizes the experience of this initiative.

Cohort Profile: The National Academy of Sciences-National Research Council Twin Registry (NAS-NRC Twin Registry).

The National Academy of Sciences-National Research Council Twin Registry (NAS-NRC Twin Registry) is a comprehensive registry of White male twin pairs born in the USA between 1917 and 1927, both of the twins having served in the military. The purpose was medical research and ultimately improved clinical care. The cohort was assembled in the early 1960s with identification of approximately 16,000 twin pairs, review of service records, a brief mailed questionnaire assessing zygosity, and a health survey largely comparable to questionnaires used at that time with Scandinavian twin registries. Subsequent large-scale data collection occurred in 1974, 1985 and 1998, repeating the health survey and including information on education, employment history and earnings. Self-reported data have been supplemented with mortality, disability and medical data through record linkage. Potential collaborators should access the study website [http://www.iom.edu/Activities/Veterans/TwinsStudy.aspx] or e-mail the Medical Follow-up Agency at [Twins@nas.edu]. Questionnaire data are being prepared for future archiving with the National Archive of Computerized Data on Aging (NACDA) at the Inter-University Consortium for Political and Social Research (ICPSR), University of Michigan, MI.

Ingestion of lead and nontoxic shot by Green-winged Teal (Anas crecca) and Northern Shovelers (Anas clypeata) from the mid-Gulf Coast of Texas, USA.

Ninety-eight Green-winged Teal (Anas crecca) and 84 Northern Shoveler (Anas clypeata) gizzards were examined for ingested shot. One Northern Shoveler had lead and three had steel shot; 24 teal and 17 shovelers had composite nontoxic shot or nonlead metal fragments. Prevalence of ingested lead appears minimal and consistent with other studies conducted after lead-shot bans.