Fidaxomicin versus oral vancomycin for severe Clostridium difficile infection: a retrospective cohort study.

OBJECTIVES: This study was conducted to compare clinical outcomes of fidaxomicin versus oral vancomycin in the management of severe Clostridium difficile infection (CDI). METHODS: The investigation was a retrospective, multicentre, propensity score-matched analysis using a national clinical administrative database. Veterans treated for severe CDI from any Veterans Affairs Medical Center between 1 June 2011 and 30 June 2017 were included if they received fidaxomicin or an oral vancomycin regimen for treatment. The two groups were matched by the nearest-neighbour method from a propensity score derived from independent variables associated with the selection of a fidaxomicin course. RESULTS: Propensity score matching resulted in two well-matched cohorts consisting of 213 fidaxomicin and 639 oral vancomycin courses. No statistically-significant difference was found for the primary outcome of combined clinical failure or recurrence (68/213 (31.9%) versus 163/639 (25.5%), respectively, p 0.071). Additionally, no statistically significant differences were found for the secondary outcomes of 30-day (23/213 (10.8%) versus 75/639 (11.7%), respectively, p 0.71), 90-day (48/213 (22.5%) versus 140/639 (21.9%), respectively, p 0.85), and 180-day mortality (62/213 (29.1%) versus 186/639 (29.1%), respectively, p 1.0) between the two treatment groups. CONCLUSIONS: Courses of fidaxomicin or oral vancomycin for severe CDI resulted in similar treatment outcomes. Study findings are consistent with current treatment guideline recommendations for the use of either agent in the management of severe CDI.

Evaluation of fidaxomicin usage patterns and outcomes for Clostridium difficile infection across the United States Veterans Health Administration.

WHAT IS KNOWN AND OBJECTIVE: Fidaxomicin was recently approved for the treatment of Clostridium difficile infection (CDI). Limited data on its use exist outside of the phase 3 trials. The purposes of this study were to assess the compliance with the Veterans Health Administration (VHA) fidaxomicin criteria for use and describe patient characteristics and outcomes following fidaxomicin treatment for CDI using real-world data within the VHA system. METHODS: This was a multicentre, retrospective, observational study including all adult patients who received at least 1 dose of fidaxomicin at any Veterans Affairs Medical Center. RESULTS AND DISCUSSION: A total of 880 unique patients received 1098 courses of fidaxomicin, resulting in an overall usage rate per C. difficile-positive laboratory test of 1.98%. The rate of fidaxomicin courses per 1000 C. difficile-positive diagnostic tests increased steadily from 2011 through 2015 and plateaued from 2015 to 2016. Compliance with the VHA criteria for use was low (9.1%). The majority of courses were given for a first recurrence (25.0%), followed by an initial episode (23.9%) of CDI. The failure and recurrence rates were 6.8% and 24.4%, respectively. WHAT IS NEW AND CONCLUSION: Although overall use of fidaxomicin was low, compliance with the VHA criteria for use was also low, suggesting that the criteria may need to be revised. Further studies are warranted to clarify the role of fidaxomicin in clinical practice.

Prevalence of the Clostridium difficile BI/NAP1/027 strain across the United States Veterans Health Administration.

OBJECTIVES: The increased incidence and severity of Clostridium difficile infection (CDI) are thought to result partly from the emergence of the hypervirulent BI/NAP1/027 strain. Limited recent data are available on the prevalence of BI/NAP1/027 in the United States (US). The objective of this study was to assess the recent prevalence of BI/NAP1/027 within the US Veterans Health Administration (VHA). METHODS: Patients with CDI at any Veterans Affairs Medical Center found to routinely test for the presence of BI/NAP1/027 during the study period were included between 1 June 2011 and 30 June 2016 in this retrospective, observational, nationwide study. RESULTS: In total, 7571 patients had 8224 positive C. difficile tests that had a corresponding BI/NAP1/027 test. Of those, there were 1810 (22.0%) presumptive positive for BI/NAP1/027. The overall prevalence of BI/NAP1/027 decreased from a high of 26.2% in 2013 to 16.9% in 2016. Statistically significant reductions in rates from 2012 to 2016 occurred in seven of nine US Census Bureau regions. CONCLUSIONS: The prevalence of C. difficile with the BI/NAP1/027 strain was 22.0% across the VHA between 2012 and 2016. Further studies are needed to confirm these results and for continued monitoring of the trends in BI/NAP1/027 prevalence.

Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini.

Protein expression after delivery of plasmid DNA to the cell nucleus depends on the processes of transcription and translation. Cytotoxic gene-delivery systems may compromise these processes and limit protein expression. This situation is perhaps most prevalent in current nonviral polycationic gene-delivery systems in which the polycationic nature of the delivery system can lead to cytotoxicity. To approach the problem of creating nontoxic but effective gene-delivery systems, we hypothesized that by optimizing the balance between polymer cationic density with endosomal escape moieties, effective gene transfer with low cytotoxicity could be created. As a model system, we synthesized a series of polymers whose side-chain termini varied with respect to the balance of cationic centers and endosomal escape moieties. Specifically, by polymer-analogous amidation we conjugated imidazole groups to the epsilon-amines of polylysine in varying mole ratios (73.5 mol % imidazole, 82.5 mol % imidazole, and 86.5 mol % imidazole). The primary epsilon-amine terminus of polylysine served as a model for the cationic centers, whereas the imidazole groups served as a model for the endosomal escape moieties. These polymers condensed plasmid DNA into nanostructures <150 nm and possessed little cytotoxicity in vitro. Transfection efficiency, as measured by luciferase protein expression, increased with increasing imidazole content of the polymers in a nonlinear relationship. The polymer with the highest imidazole content (86.5 mol %) mediated the highest protein expression, with levels equal to those mediated by polyethylenimine, but with little to no cytotoxicity.

Increasing antimicrobial resistance in gram-negative bacilli isolated from patients in intensive care units.

BACKGROUND: We investigated gram-negative bacilli from patients in intensive care units to determine whether antimicrobial resistance was increasing. METHODS: Minimal inhibitory concentrations were determined by broth microdilution on 334 gram-negative bacilli collected in 1990, 1995, and 1998. RESULTS: During the 3 study years, the types of gram-negative bacilli encountered in our intensive care units changed with proportional increases of Pseudomonas sp and decreases of inducible enterics. Dramatic increases in resistance for ceftazidime, cefotaxime, and piperacillin were paralleled between respiratory-tract isolates and inducible enterics. By 1998, ticarcillin was more active than piperacillin against most isolates except Escherichia coli and Klebsiella sp, and most isolates became more resistant to gentamicin and tobramycin. CONCLUSIONS: Continuous changes in the types of gram-negative bacilli and antimicrobial resistance complicate empirical selection of antimicrobials in the intensive care units. These complications will place more emphasis on communication and strategy formations among health care workers (nurses, physicians, laboratorians, and pharmacists) in an effort to treat infections in a timely and effective manner.

Outcomes of an antimicrobial control program in a teaching hospital.

The clinical outcomes and cost-effectiveness of an antimicrobial control program (ACP) were studied. The impact of an ACP in a teaching hospital was analyzed by comparing clinical outcomes and intravenous antimicrobial costs over two two-year periods, the two years before the program and the first two years after the program's inception. Admission baseline data, length of stay, mortality, and readmission rates were gathered for each patient. Patients were identified by using the International Classification of Diseases. Multivariate logistic regression models were constructed for mortality and for lengths of stay of 12 or more days. The acquisition costs of intravenous antimicrobial agents for the second baseline year and the entire program period were tabulated and compared. The average daily inpatient census was determined. The ACP was associated with a 2.4-day decrease in length of stay and a reduction in mortality from 8.28% to 6.61%. Rates of readmission for infection within 30 days of discharge remained about the same. Inpatient pharmacy costs other than intravenous antimicrobials decreased an average of only 5.7% over the two program years, but the acquisition cost of intravenous antimicrobials for both program years yielded a total cost saving of $291,885, a reduction of 30.8%. The institution's average daily census fell 19% between the second baseline year and the second program year. An ACP directed by a clinical pharmacist trained in infectious diseases was associated with improvements in inpatient length of stay and mortality. The ACP decreased intravenous antimicrobial costs and facilitated the approval process for restricted and nonformulary antimicrobial agents.

Retrospective evaluation of therapies for Staphylococcus aureus endocarditis.

We retrospectively evaluated antiinfective therapy for methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) endocarditis in 54 patients who had 57 treatment courses for the disease. Three treatments were assessed: 27 nafcillin-treated courses of MSSA endocarditis, 18 vancomycin-treated courses of MSSA endocarditis, and 11 vancomycin-treated courses of MRSA endocarditis. At baseline, patients with MSSA treated with vancomycin had more chronic conditions (p<0.01), a lower frequency of intravenous drug use (p<0.01), a lower hematocrit concentration (p<0.05), and a higher serum creatinine concentration (p<0.05) than the nafcillin group. Vancomycin-treated patients had a higher complication rate during therapy (p<0.05) and a longer duration in an intensive care unit (p<0.01) than the nafcillin group. The trend was for a higher complete response rate in the nafcillin group (74% vs 50%, p=0.12), but no difference in mortality (22% vs 28%, p=0.73). Patients with MRSA infection treated with vancomycin had higher mortality than those with MSSA who received that drug (55% vs 28%, p=0.24). Patients with vancomycin-treated MSSA endocarditis may have a poorer outcome than those who receive nafcillin, but this may be influenced by different or more severe clinical features.

Is there a therapeutic or pharmacokinetic rationale for amphotericin B dosing in systemic Candida infections?

OBJECTIVE: To review the literature regarding the dosage of amphotericin B in Candida infections. The correlation or rationale of current dosing practices is assessed in light of the literature. DATA SOURCES: A MEDLINE search encompassing the years 1968-1995 was used to identify pertinent literature. Additional references were obtained from the articles retrieved from MEDLINE. STUDY SELECTION: Studies that directly assessed amphotericin B dosage and/or duration, pharmacokinetic literature dealing with plasma concentrations and amphotericin B disposition, and literature dealing with dose and/or concentration as well as clinical outcome were selected for inclusion. Additional relevant citations were used in the introductory material and discussion. DATA EXTRACTION: Although there was a large number of articles related to amphotericin B, surprisingly few large studies were designed to address the issues in question. The description of the methods and results of these heterogeneous articles are the basis of this review. Although additional controlled studies with more subjects need to be performed, the results to date provide a foundation from which to make some inferences regarding optimal use of this therapeutic modality until more definitive data become available. DATA SYNTHESIS: Despite numerous articles addressing the pharmacokinetics of amphotericin B, little is known about its tissue distribution, the rate of transfer of the drug from vascular to peripheral sites, or its terminal disposition. Less information is available regarding the relevance of pharmacokinetic parameters or serum concentrations to clinical outcome. Most of the articles mentioning dosing provide little or no justification for the doses employed. The variety of the dosages used and the heterogeneity of the populations studied make determination of dose-outcome relationships difficult. CONCLUSIONS: From the available clinical data, it appears that early initiation of amphotericin B therapy is crucial to a favorable outcome. Daily dosing initially followed by every-other-day administration of twice the daily dose is better tolerated by the patient than daily dosing and produces a similar therapeutic outcome. The drug should be continued until therapeutic endpoints have been achieved, rather than until a specific total dosage has been administered. The nephrotoxicity that occurs with amphotericin B administration is apparently reversible and should not be used as an endpoint for therapy if total dosages do not exceed 4 g. Additional well-designed, controlled trials evaluating standardized dosing methods of amphotericin B with predetermined dosing regimens and/or definitive therapeutic endpoints are needed to determine the optimal dosing approach for this agent.

Bayesian forecasting of serum vancomycin concentrations in neonates and infants.

A dynamic pharmacokinetic model for i.v. vancomycin administration was developed and tested in 47 neonates and infants. Twenty-nine patients (Group 1), having two or more concentrations, were used to estimate population parameters by nonlinear least-squares analysis. Multiple stepwise linear regression techniques showed that estimated creatinine clearance, Clcr, and postnatal age were significant demographic factors related to vancomycin clearance (CL). No strong associations were found for the apparent volume of distribution. A one-compartment model was constructed using the associations of CLcr and postnatal age with vancomycin CL. Eighteen patients (Group 2), receiving 35 courses of vancomycin therapy, with both initial and subsequent sets of peak and trough concentrations, were used to test the predictive performance of the model with and without the use of Bayesian forecasting. Using only population-based parameters, the respective mean error (ME) (bias) and mean absolute error (MAE) (precision) for predicting subsequent peak concentrations were -1.20 and 3.89 mg/L and for trough concentrations, 0.83 and 2.23 mg/L, respectively. For the Bayesian method, these values were, respectively, 0.45 and 4.13 mg/L for peak concentrations and 1.55 and 2.40 mg/L for trough concentrations. When predicted concentrations occurred within 30 days of feedback concentrations, the Bayesian method tended to be slightly less biased and more precise than the population-based parameters. The opposite was true > 30 days of the initial set of feedback concentrations. The use of population-specific pharmacokinetic parameters and Bayesian forecasting should allow accurate dosage regimen design as well as minimize the need for monitoring serum vancomycin concentrations in neonates and young infants.

Molecular dynamics of the anti-fluorescein 4-4-20 antigen-binding fragment. 2. Time-resolved fluorescence spectroscopy.

Time-resolved fluorescence experiments were performed to investigate the dynamic aspects of the antigen-binding fragment (Fab) of a high-affinity monoclonal antibody (4-4-20) which binds the fluorescent hapten fluorescein. Both the unliganded Fab and a complex of the Fab with a nonfluorescent analog of fluorescein (fluoresceinamine, FLM) were examined. A fluorescence polarization probe [5-[[2-[(iodoacetyl)amino]ethyl]amino]naphthalene-1-sulfonic acid, AEDANS] was covalently attached to the C-terminus of the Fab. Experiments were performed at three different temperatures (10, 25, and 35 degrees C), and phase-modulation data sets were collected for five different molar ratios of FLM to Fab at each temperature. Global analyses were then used to extract values for fluorescence lifetime and rotational correlation time from these data. In the lifetime analysis the best fit was obtained when the emission of AEDANS was described by a Lorentzian distribution of lifetimes (tau = 15.6 ns, distribution width = 3.4 ns, both at 25 degrees C), which suggested that the probe experienced a heterogeneous environment. Anisotropy analyses suggested that two different rotational components were present. The first was attributed to the global motion of the Fab and exhibited a rotational correlation time (theta 1) of ca. 33 ns at 25 degrees C. This component was relatively unaffected by antigen binding. The second rotational component was attributed to the local or segmental motion within the Fab and exhibited a rotational correlation time (theta 2) of 1.1 ns at 25 degrees C. This value increased by more than 50% upon antigen binding, a result which was consistent with molecular dynamics simulations of the same Fab--fluorescein system [Lim & Herron (1995) Biochemistry 34, 6962-6974]. Furthermore, statistical analysis showed that this increase was significant at the 95% confidence level.

Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity.

The hypothetical model is built explaining the molecular mechanism of protective action of poly(ethylene glycol) on liposomes in vivo. The protective layer of the polymer on the liposome surface is considered as a statistical 'cloud' of polymer possible conformations in solution. Computer simulation was used to demonstrate that relatively a small number of liposome-grafted molecules of hydrophilic and flexible polymer can create a dense protective conformational cloud over the liposome surface preventing opsonizing protein molecules from contacting liposome. A more rigid polymer fails to form this dense protective cloud, even when hydrophilic. Computer simulation was also used to reveal possible heterogeneity of reactive sites on a polymer-coated liposome surface, and to estimate the optimal polymer-to-lipid ratio for efficient liposome protection. Experiments have been performed with the quenching of liposome-associated fluorescent label (nitrobenzoxadiazole or fluorescein) with protein (rhodamine-ovalbumin or anti-fluorescein antibody) from solution. It was shown that poly(ethylene glycol) grafting to liposomes hinders protein interaction with the liposome surface, whereas liposome-grafted dextran (more rigid polymer) in similar quantities does not affect protein-liposome interaction. Highly-reactive and low-reactive populations of chemically identical reactive sites have been found on polymer-coated liposomes. Experimental data satisfactory confirm the suggested mechanism for the longevity of polymer-modified liposome.

Investigation of specific binding of antifluorescyl antibody and Fab to fluorescein lipids in Langmuir-Blodgett deposited films using quartz crystal microbalance methodology.

Antifluorescyl IgG antibody and Fab binding to two fluorescein-conjugated lipids was measured using the quartz crystal microbalance methodology. By use of the Langmuir-Blodgett technique, the fluorescein lipids, which were diluted to 5% in a L-alpha-dipalmitoyl phosphatidylethanolamine (DPPE) matrix, were deposited directly onto one gold electrode of the quartz crystal. Binding to films containing the fluorescein hapten was significantly enhanced compared to films of the pure DPPE matrix lipid, indicating that binding occurred primarily through a specific interaction. Association constants were 40-300 times less than for binding to haptens free in solution. Binding of IgG to the lipid in which the hydrocarbon chains and the fluorescein hapten were linked via a hydrophilic spacer was approximately 7 times as great as to the lipid containing no spacer. IgG binding to the lipid containing the spacer was increased 1.5-4.4 times compared to Fab binding for the same lipid. Equilibrium binding curves and kinetic measurements are analyzed quantitatively and compared.

Prediction of acetaminophen concentrations in overdose patients using a Bayesian pharmacokinetic model.

A pharmacokinetic program using population-based parameter estimates and a Bayesian forecasting model was retrospectively evaluated for predicting acetaminophen serum concentrations in overdose patients. Dynamic disposition factors known to affect acetaminophen disposition (emesis, activated charcoal, N-acetylcysteine, etc.) were included in the program. Twenty six patients who reported an acetaminophen ingestion of at least 70 mg/kg within 24 h of presentation to the hospital and had at least one measured acetaminophen concentration were included. Prediction of initial acetaminophen concentrations using only population-based parameter estimates resulted in a percent mean error (%ME) and percent mean absolute error (%MAE) of 9.3 and 42.2, respectively. Using only the initial concentration as feedback, the Bayesian forecasting model accurately predicted the second acetaminophen concentration (%ME = 4.0, %MAE = 23.6). The Bayesian model also accurately predicted all concentrations within 8 h of the ingestion (%ME = 10.6, %MAE = 24.0). The prediction of concentrations between 2 to 4 h and 4 to 4.5 h after ingestion with only population-based parameter estimates resulted in %ME of 17.0 and 13.2, respectively, and %MAE of 36.5 and 35.1, respectively. Our data suggests that acetaminophen serum concentrations occurring within the first 4.5 h after ingestion can be reliably predicted by the set of population-based parameter estimates evaluated. Once a single acetaminophen concentration is available, the Bayesian forecasting model can accurately predict subsequent concentrations within the first 8 h after an acetaminophen ingestion.

Methods of minimising the cost of aminoglycoside therapy to hospitals.

Aminoglycoside agents are used for a wide variety of systemic infections and can profoundly affect hospital expenditures depending upon the amounts used, acquisition costs, and costs incurred during therapy. Significant cost advantages can be gained through selection and proper use of the appropriate aminoglycoside. Institutions can improve the selections by using inservice training and other educational methods, drug-use audits, and therapeutic substitution. Institutions may also restrict or delete certain aminoglycosides from the drug formularies to help minimise costs. Therapeutic drug monitoring can reduce the incidence of aminoglycoside adverse effects. However, some methods of monitoring, such as certain clinical pharmacokinetic services, can be time consuming and require additional manpower. These measures can be shown to be cost effective if they can decrease the length of therapy, minimise toxicity, decrease the length of hospitalisation, or affect mortality. Experimental data and preliminary clinical evidence suggest that once-daily regimens of aminoglycoside agents have some possible advantages over the standard regimens. If this regimen can be widely used, cost savings secondary to decreased use of aminoglycosides can be realised in the future. Potent, broad spectrum beta-lactam monotherapy has threatened to replace conventional combination therapies that include aminoglycosides in some infectious processes and a few studies have found certain single-drug therapies to be cost effective.

Prediction of gentamicin concentrations in neonates and infants using a Bayesian pharmacokinetic model.

This study retrospectively characterized population-based pharmacokinetic parameters for gentamicin in neonates and young infants, and evaluated the predictive performance of these parameters in a Bayesian forecasting program. Population parameter estimates were determined from the serum concentration-time data of 19 neonates and infants using a one-compartment open infusion model and nonlinear least-squares regression analysis. Univariate and multiple stepwise linear regression analyses were used to determine significant relationships between demographic characteristics and gentamicin pharmacokinetic parameters. Creatinine clearance and postnatal age were the most significant predictors of weight-standardized gentamicin clearance (model r2 = 0.86). The relationships between patient characteristics and population-based parameters were incorporated into the one-compartment Bayesian forecasting model. A second group of 17 neonates and infants receiving 35 courses of gentamicin therapy were used to evaluate the predictive performance of the population-based parameters and a Bayesian forecasting model. The population parameters provided accurate prediction of steady state gentamicin concentrations throughout multiple courses of therapy within the same patient. Bayesian forecasting further minimized the mean prediction error (bias) once a set of steady state peak and trough serum gentamicin concentrations became available (peak concentrations: -0.062 vs. -0.273 mg/l; trough concentrations: -0.006 vs. -0.161 mg/l). The mean absolute error (accuracy) was similar for the two sets of parameters. The observed accuracy of both the population parameters and Bayesian forecasting suggests that monitoring of serum gentamicin concentrations can be kept to minimum in neonates and infants.