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Anthony D Andre,1 John F Mohr,2 Barbara W Cornelius,2 Matthew M Goodwin,2 Carson P Whitaker,1 Bhavini H Patel,2 Jessica A Huckleberry,3 Michael D Hassman2 1Interface Analysis Associates LLC, Saratoga, CA, USA; 2scPharmaceuticals, Inc, Burlington, MA, USA; 3Heart Group of the Eastern Shore, P.C, Fairhope, AL, USACorrespondence: Michael D Hassman, scPharmaceuticals, Inc, 25 Mall Road, Suite 203, Burlington, MA, 01803, USA, Tel +1 781 301 7373, Email mhassman@scpharma.comPurpose: Furoscix® (subcutaneous furosemide) is administered using a wearable On-Body Infusor (OBI) and is approved for the treatment of congestion associated with heart failure (HF). The purpose of this study was to assess the safe and effective use of the OBI and Instructions for Use (IFU) by patients with HF, caregivers, and healthcare practitioners (HCPs).Methods: Sixty participants (patients, n=30; caregivers, n=15; HCPs, n=15) were evaluated on completion of OBI use tasks and IFU knowledge tasks in a simulated use environment. Fifteen of the patients received OBI/IFU training before evaluation.Results: Overall, 893/900 (99.2%) use tasks and 2211/2220 (99.6%) knowledge tasks were completed successfully, without differences due to training. The most common (n=6) use error was failure to wipe skin or cartridge tip with an alcohol wipe. Errors were due to forgetfulness/misinterpretation rather than IFU clarity.Conclusion: The subcutaneous furosemide OBI can be safely and effectively used by patients, caregivers, and HCPs, regardless of training.Keywords: heart failure, furosemide, subcutaneous furosemide, on-body infusor, human factors

Marya D Zilberberg,1 Brian H Nathanson,2 Kate Sulham,3 John F Mohr,3 Matthew Goodwin,3 Andrew F Shorr4 1EviMed Research Group, LLC, Goshen, MA, USA; 2OptiStatim, LLC, Longmeadow, MA, USA; 3scPharmaceuticals, Burlington, MA, USA; 4Washington Hospital Center, Washington, DC, USACorrespondence: Marya D Zilberberg, Department of Health Services Research, EviMed Research Group, LLC, PO Box 303, Goshen, MA, 01032, USA, Email evimedgroup@gmail.comBackground: Two-thirds of the 1 million annual US CHF hospitalizations are for diuresis only; some may be avoidable. We describe a population of low-severity short-stay ( 2. We compared baseline characteristics, processes of care, and outcomes in low-severity (CHF-L) to CHF-H.Results: Among 301,672 short-stay CHF patients, 135,304 (44.8%) were CHF-L. Compared to CHF-H, CHF-L was younger (70.5 ± 14.1 vs 72.1 ± 13.6 years, p < 0.001), more commonly female (48.6% vs 45.8%, p < 0.001), and more likely to receive IV ACE-I/ARB agents (0.5% vs 0.4%, p = 0.003). Most other IV medications were more common in CHF-H, and anticoagulation was the most prevalent non-diuretic IV therapy in both groups (23.8% vs 33.3%, p < 0.001). Hospital mortality (0.2% vs 1.5%, p < 0.001) and CHF-related 30-day readmissions (8.1% vs 10.5%, p < 0.001) were lower in CHF-L than CHF-H.Conclusion: Among short-stay CHF patients, nearly &half; meet criteria for CHF-L, and are mainly admitted for fluid management. Avoiding these admissions could result in substantial savings.Keywords: congestive heart failure, epidemiology, outcomes, hospital, costs

Marya D Zilberberg,1 Brian H Nathanson,2 Katherine Sulham,3 John F Mohr,3 Matthew M Goodwin,3 Andrew F Shorr4 1EviMed Research Group, LLC, Goshen, MA, USA; 2Optistatim, LLC, Longmeadow, MA, USA; 3scPharmaceuticals, Burlington, MA, USA; 4Washington Hospital Center, Washington, DC, USACorrespondence: Marya D Zilberberg, EviMed Research Group, LLC, PO Box 303, Goshen, MA, 01032, USA, Email evimedgroup@gmail.comBackground: Congestive heart failure (CHF) hospitalizations cost the US &dollar;35 billion annually. Two-thirds of these admissions, generally requiring /=65 years: 68.3% vs 71.9%), less likely covered by Medicare (71.9% vs 75.4%), and had a lower comorbidity burden (Charlson: 3.9 [2.1] vs 4.5 [2.2) than patients with LLOS; they less frequently developed acute kidney injury (0.4% vs 2.9%) or a need for mechanical ventilation (0.7% vs 2.8%). A higher proportion with SLOS than with LLOS underwent no procedures (70.4% vs 48.4%). Mean LOS (2.2 [0.8] vs 7.7 [6.5]), direct hospital costs (&dollar;6150 [&dollar;4413]) vs &dollar;17,127 [&dollar;26,936]), and aggregate annual hospital costs &dollar;3,131,560,372 vs &dollar;11,359,002,072) were all lower with SLOS than LLOS. All comparisons reached alpha = 0.001.Conclusion: Among patients admitted for CHF, nearly &half; have LOS

Kathryn Fitch,1 Jocelyn Lau,1 Tyler Engel,1 Joseph J Medicis,2 John F Mohr,2 William S Weintraub3 1Milliman Inc., New York, NY, USA; 2scPharmaceuticals Inc., Burlington, MA, USA; 3MedStar Washington Hospital Center, Washington, DC, USA Purpose: The aim of this study was to quantify the potential cost savings to Medicare of shifting the site of treatment for worsening heart failure (HF) from inpatient to outpatient (OP) settings for a subset of worsening HF episodes among the Medicare fee-for-service (FFS) population.Materials and methods: A cross-sectional analysis of a random 5% sample of 2014 FFS Medicare beneficiaries was conducted. Incidence and cost of worsening HF episodes in both inpatient and OP settings were identified. These results were used to calculate cost savings associated with shifting a proportion of worsening HF episodes from the inpatient to OP settings.Results: A total of 151,908 HF beneficiaries were identified. The estimated annual cost for the treatment of worsening HF across both inpatient and OP settings ranged from US$9.3 billion to US$17.0 billion or 2.4%–4.3% of total Medicare FFS spend. The cost saving associated with shifting worsening HF treatment from inpatient hospital setting to OP settings was US$667.5 million or 0.17% of total Medicare spend when 10% of HF admissions were targeted and 60% of targeted HF admissions were successfully shifted. The cost savings increased to US$2.098 billion or 0.53% of total Medicare spend when 20% of HF admissions were targeted and 90% of targeted HF admissions were successfully shifted.Conclusion: Treatment options that can shift costly hospital admissions for worsening HF treatment to less expensive OP settings potentially lead to significant cost savings to Medicare. Pursuit of OP therapy options for treating worsening HF might be considered a viable alternative. Keywords: health care resource utilization, heart failure management, hospital admission burden, administrative claims data, cost impact analysis

The fluoroquinolones are an extremely popular class of antibacterials, owing to their broad spectrum of activity and the convenience of their intravenous and oral dosage formulations. Overall, the currently available fluoroquinolones have a good safety profile; however, certain fluoroquinolones within the class have been associated with severe and life-threatening adverse drug reactions. Dysglycaemic episodes (hyperglycaemia and hypoglycaemia) have been observed in patients taking multiple antibacterials, including the fluoroquinolones. Although gatifloxacin has been associated with dysglycaemias more frequently than other fluoroquinolones, dysglycaemic events have been reported with some of the other currently available fluoroquinolones as well. Hypoglycaemia appears to be related to insulin release and is an early-onset event. However, hyperglycaemia tends to present several days into therapy and the exact mechanism by which it is caused is still unclear. Recent studies point towards the important role of the adenosine triphosphate (ATP)-sensitive K+ channels in the pancreatic beta cell and the importance of anti-insulin hormones. Several retrospective studies have elucidated risk factors associated with fluoroquinolone exposure and subsequent dysglycaemic events. These studies suggest that dysglycaemia is a dose-related adverse effect involving the fluoroquinolone class; however, some drugs within the class appear to have a greater association. This may be related to the affinity of fluoroquinolones to the ATP-sensitive K+ channel or higher concentrations of drugs achieved in certain patients who are already at risk for hyperglycaemia and hypoglycaemia. Understanding these risk factors will allow the fluoroquinolones to be utilized in a way that minimizes the probability of associated dysglycaemic events. [ABSTRACT FROM AUTHOR]

Background: Therapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF)., Objectives: This pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion., Methods: Participants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro-B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life., Results: Thirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was -2.02 kg at day 3 (95% CI: -3.9 to -0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%)., Conclusions: SC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure-A Pilot Study]; NCT04593823)., Competing Interests: Funding Support and Author Disclosures This study was funded by scPharmaceuticals, Inc. Dr M.A. Konstam has received personal fees from Alnylam, Boehringer-Ingelheim, Cardurian, LivaNova, scPharmaceuticals, Fire 1, Vicardia, and Alleviant. Dr Dhingra has received personal fees from scPharmaceuticals, Bristol Myers Squibb, and CareDx. Dr Walsh has received personal fees from scPharmaceuticals. Ms Ordway has received personal fees from scPharmaceuticals. Dr Pursley has received personal fees from scPharmaceuticals. Dr McLean has received personal fees from scPharmaceuticals. Mr Saha is a full-time employee of Cardiovascular Clinical Science Foundation. Dr Close is a full-time employee of EmpiriStat, Inc. Mr J.M. Konstam is a full-time employee of iQVIA. Dr Luepke is a full-time employee of scPharmaceuticals. Dr Mohr is a full-time employee of scPharmaceuticals. Dr Udelson has received personal fees from scPharmaceuticals, Merck, Alleviant, Reprieve CV, and Cardurion., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Compare heart failure (HF) costs of Furoscix use at home compared with inpatient intravenous (IV) diuresis. Patients & methods: Prospective, case control study of chronic HF patients presenting to emergency department (ED) with worsening congestion discharged to receive Furoscix 80 mg/10 ml 5-h subcutaneous infusion for ≤7 days. 30-day HF-related costs in Furoscix group derived from commercial claims database compared with matched historical patients hospitalized for <72 h. Results: Of 24 Furoscix patients, 1 (4.2%) was hospitalized in 30-day period. 66 control patients identified and were well-matched for age, sex, ejection fraction (EF), renal function and other comorbidities. Furoscix patients had reduced mean per patient HF-related healthcare cost of $16,995 (p < 0.001). Conclusion: Furoscix use was associated with significant reductions in 30-day HF-related healthcare costs versus matched hospitalized controls.

Organic matter regulates the availability of important trace elements in aquatic and terrestrial ecosystems by acting as a source and container for microbes. To overcome the limitation of trace elements, nitrogen-fixing bacteria, e.g. release low-molecular-weight chelators (metallophores), which scavenge the essential cofactors of the nitrogenase, iron, and molybdenum (Mo), via complexation and subsequent uptake. The formation of metallophores is triggered by limiting conditions, which must be replicated in the laboratory in order to study metallophores as a mediator in metal cycling. While ethylenediaminetetraacetic acid (EDTA)-based buffer systems for metal cations are well established, there is limited knowledge regarding the buffering of oxoanions such as molybdate in a bacterial growth medium. To mimic the availability of molybdenum in nature under laboratory conditions, this study created a Mo-buffer system for bacterial growth media of the model organisms Azotobacter vinelandii and Frankia sp. CH37. We investigated selected hydroxypyridinones (HPs) as potential molybdenum-chelating agents, determining the amount required for efficient molybdenum complexation by calculating speciation plots of the various candidate complexes in artificial growth media at various pH values. The Mo-maltol system was identified as an ideal, nontoxic molybdenum-buffer system. In the presence of the Mo-maltol system, the growth of Frankia sp. was limited under diazotrophic conditions, whereas A. vinelandii could acquire molybdenum through the release of protochelin and subsequent molybdenum uptake. The study paves the way for unravelling molybdenum recruitment and homeostasis under limiting conditions in bacteria., (© The Author(s) 2022. Published by Oxford University Press.)

The steadily rising prevalence of heart failure (HF) and the associated increase in health care expenditures represent a significant burden for patients, caregivers, and society. Ambulatory management of worsening congestion is a complex undertaking that requires diuretic escalation, yet clinical success is often hindered by the progressively declining bioavailability of oral agents. Once beyond a threshold, patients with acute on chronic HF often require hospital admission for intravenous diuresis. A novel, pH neutral formulation of furosemide that is administered by a biphasic drug delivery profile (80 mg total over 5 ​hours) via an automated, on-body infusor was designed to overcome these limitations. Early studies have shown that it has equivalent bioavailability with comparable diuresis and natriuresis to the intravenous formulation, leads to significant decongestion, and improvement in quality of life. It was shown to be safe and is well tolerated by patients. Although there is one ongoing clinical trial, available data have demonstrated the potential to shift hospital-administered, intravenous diuresis to the outpatient setting. Reduction in the need for recurrent hospital admissions would be highly desirable by most patients with chronic HF and would lead to a significant reduction in health care expenditures. In this article, we describe the rationale and evolution of this novel PH neutral formulation of furosemide administered subcutaneously, summarize its pharmacokinetic and pharmacodynamic profiles, and review emerging clinical trials demonstrating its clinical safety, efficacy, and potential to reduce health care expenditures., Competing Interests: D. Bensimhon is a consultant at scPharmaceuticals. M.M. Goodwin and J.F. Mohr are employees at scPharmaceuticals. G. Dahiya and T. Alexy had no conflicts to declare., (© 2022 The Authors.)

A series of new metallophores, referred to as frankobactins, were extracted from cultures of the symbiotic and nitrogen-fixing actinobacterium Frankia sp. CH37. Structure elucidation revealed a 2-hydroxyphenyl-substituted oxazoline core and a chain composed of five proteinogenic and nonproteinogenic amino acids, suggesting nonribosomal peptide synthesis as the biosynthetic origin. By whole-genome sequencing, bioinformatic analysis, and comparison with other Frankia strains, the genetic locus responsible for the biosynthesis was detected. Spectrophotometric titration of frankobactin with Fe(III) and Cu(II) and mass spectrometry established the 1:1 (metal:frankobactin) coordination. Uptake experiments suggested that frankobactin A 1 ( 1 ) did not serve to recruit iron, but to detoxify Cu(II). As frankobactin A 1 prevents the cellular entry of Cu(II), it could play a crucial role in the symbiosis of Frankia sp. and its host in the reclamation of copper-contaminated soil.

Since the 1970s, outpatient parenteral antimicrobial therapy (OPAT) has been a viable option for patients who require intravenous antibiotics when hospitalization is not warranted. While the benefits of OPAT as a measure to improve the efficiency of healthcare delivery (i.e., reduced hospital days) and patient satisfaction are well-documented, OPAT is associated with a number of challenges, including line complications and reliance on daily healthcare interactions in some cases at home or in a clinic. To minimize the continued need for intensive healthcare services in the outpatient setting, there is trend toward patients self-administering antibiotics at home without the presence of healthcare workers, after adequate training. In most cases, patients administer the antibiotics through an established intravenous catheter. While this OPAT practice is becoming more accepted as a standard of care, the potential for line complications still exists. Outpatient subcutaneous antimicrobial therapy (OSCAT) has become an increasingly accepted alternative route of administration of antibiotics to IV by French infectious diseases physicians and geriatricians; however, currently, no antibiotics are approved to be administered subcutaneously. Antibiotics with longer half-lives that are completely absorbed and have a favorable local tolerability profile are ideal candidates for OSCAT and have the potential to maximize the quality and efficiency of parenteral antibiotic delivery in the outpatient setting. The increasing development of wearable, on-body subcutaneous delivery systems make OSCAT even more viable as they increase patient independence while avoiding line complications and potentially removing the need for direct healthcare professional observation., Competing Interests: TF received speaker honorarium from scPharmaceuticals. TL served as a consultant for scPharmaceuticals. JG served as an advisory board member for scPharmaceuticals. VT received honoraria and research grants from scPharmaceuticals. JM was SVP of Clinical Development and Medical Affairs for scPharmaceuticals who was developing antibiotics for subcutaneous administration. CR-B received research grant from the French Health authorities (Agence Nationale de Sécurité du Médicament et des produits de santé, ANSM) and SG from the Foundation Innovations en Infectiologie (FINOVI) to perform a prospective study about the pharmacokinetic and safety of subcutaneous antimicrobial therapy in France (Pharmacocinétique et tolérance des antibiotiques administrés par voie sous-cutanée chez le patient âgé de plus de 65 ans; PHASAGE study). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ferry, Lodise, Gallagher, Forestier, Goutelle, Tam, Mohr and Roubaud-Baudron.)

We report the genome sequence of Frankia sp. strain CH37, a filamentous nitrogen-fixing soil-dwelling Gram-positive bacterium and hyperproducer of metal-complexing organic ligands (metallophores) isolated from the sea buckthorn ( Hippophae rhamnoides ). The 9.7-Mbp sequence, obtained using PacBio technology, harbors 7,766 predicted coding sequences, including gene clusters for metallophore production., (Copyright © 2020 Mohr et al.)

Macroalgal microbiomes have core functions related to biofilm formation, growth, and morphogenesis of seaweeds. In particular, the growth and development of the sea lettuce Ulva spp. (Chlorophyta) depend on bacteria releasing morphogenetic compounds. Under axenic conditions, the macroalga Ulva mutabilis develops a callus-like phenotype with cell wall protrusions. However, co-culturing with Roseovarius sp. (MS2) and Maribacter sp. (MS6), which produce various stimulatory chemical mediators, completely recovers morphogenesis. This ecological reconstruction forms a tripartite community which can be further studied for its role in cross-kingdom interactions. Hence, our study sought to identify algal growth- and morphogenesis-promoting factors (AGMPFs) capable of phenocopying the activity of Maribacter spp. We performed bioassay-guided solid-phase extraction in water samples collected from U. mutabilis aquaculture systems. We uncovered novel ecophysiological functions of thallusin, a sesquiterpenoid morphogen, identified for the first time in algal aquaculture. Thallusin, released by Maribacter sp., induced rhizoid and cell wall formation at a concentration of 11 pmol l-1. We demonstrated that gametes acquired the iron complex of thallusin, thereby linking morphogenetic processes with intracellular iron homeostasis. Understanding macroalgae-bacteria interactions permits further elucidation of the evolution of multicellularity and cellular differentiation, and development of new applications in microbiome-mediated aquaculture systems., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Frankia spp. are widespread nitrogen-fixing soil bacteria, which often live in symbiosis with a broad range of hosts. Metal homeostasis plays a crucial role in the success of the symbiosis regarding the acquisition of essential trace metals and detoxification of potentially toxic elements. We have hypothesised that Frankia releases many organic ligands with a broad spectrum of affinity for essential and toxic metals. We coined the term 'ligandosphere' to describe the entirety of excreted metal complexing agents and ligands derived from the dissolved organic matter. Using metal isotope-coded profiling (MICP); metallophores of physiological important and toxic trace metals were identified by the addition of stable metal isotope pairs such as 54Fe/58Fe, 63Cu/65Cu, 66Zn/68Zn or 95Mo/98Mo. Liquid chromatography coupled to a mass spectrometer revealed strong variations of the metallophore profile in between the 14 test-strains. In total, about 83 organic ligands were identified as binding to one of the tested metals. The predicted sum formula of the major Fe binding ligands and MS/MS experiments suggested that several metallophore candidates have a similar molecular backbone. Growth experiments with a hyper-producer of metallophores revealed a positive relationship between metallophore production and the concentration of Cu in the growth medium. The present study provides the first comprehensive overview of the complexity of Frankia's ligandosphere. It opens a path to a deeper understanding of mechanisms that regulate metal homeostasis in frankiae. Deciphering these mechanisms is important since the fitness of actinorhizal plants and their potential in ecological restoration relies heavily on their symbiosis with frankiae.

The accessibility of iron (Fe) species for microbial processes is dependent on solubility and redox state, which are influenced by complexation with dissolved organic matter (DOM) and water-extractable organic matter (WEOM). We evaluated the complexation of these pools of organic matter to soluble Fe(II) and Fe(III) in the slightly acidic Schlöppnerbrunnen fen and subsequent effects on Fe(II) oxidation and Fe(III) reduction. We found the majority of soluble Fe(II) and Fe(III) is complexed to DOM. High-resolution mass spectrometry identified potential complexing partners in peat-derived water extracts (PWE), including compound classes known to function as ligands or electron shuttles, like tannins and sulfur-containing compounds. Furthermore, we observed clear differences in the stability of Fe(II)- and Fe(III)-DOM, with more labile complexes dominating the upper, oxic layers (0-10 cm) and more stable complexes in lower, anoxic layers (15-30 cm). Metal isotope-coded profiling identified a single potential chemical formula (C 42 H 57 O 13 N 9 Fe 2 ) associated with a stable Fe-DOM complex. Fe(III) reduction and Fe(II) oxidation incubations with Geobacter sulfurreducens PCA and Shewanella oneidensis MR-1 or Sideroxydans CL-21, respectively, were used to determine the influence of Fe-DOM complexes on Fe cycling rates. The addition of PWE led to a 2.3-fold increase in Fe(III) reduction rates and 0.5-fold increase in Fe(II) oxidation rates, indicating Fe-DOM complexes greatly influence microbial Fe cycling by potentially serving as electron shuttles. Molecular analyses revealed Fe(III)-reducing and Fe(II)-oxidizing bacteria co-exist across all depths, in approximately equal proportions (representing 0.1-1.0% of the total microbial community), despite observed changes in redox potential. The activity of Fe(III)-reducing bacteria might explain the presence of the detected Fe(II) stabilized via complexation with DOM even under oxic conditions in upper peat layers. Therefore, these Fe(II)-DOM complexes can be recycled by microaerophilic Fe(II)-oxidizers. Taken together, these results suggest Fe-DOM complexation in the fen accelerates microbial-mediated redox processes across the entire redox continuum., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Genome mining and chemical analyses revealed that rhizosphere bacteria (Paraburkholderia graminis) produce a new type of siderophore, gramibactin, a lipodepsipeptide that efficiently binds iron with a logβ value of 27.6. Complexation-induced proton NMR chemical shifts show that the unusual N-nitrosohydroxylamine (diazeniumdiolate) moieties participate in metal binding. Gramibactin biosynthesis genes are conserved in numerous plant-associated bacteria associated with rice, wheat, and maize, which may utilize iron from the complex.

Introduction: Stable isotopic labeling experiments are powerful tools to study metabolic pathways, to follow tracers and fluxes in biotic and abiotic transformations and to elucidate molecules involved in metal complexing., Objective: To introduce a software tool for the identification of isotopologues from mass spectrometry data., Methods: DeltaMS relies on XCMS peak detection and X 13 CMS isotopologue grouping and then analyses data for specific isotope ratios and the relative error of these ratios. It provides pipelines for recognition of isotope patterns in three experiment types commonly used in isotopic labeling studies: (1) search for isotope signatures with a specific mass shift and intensity ratio in one sample set, (2) analyze two sample sets for a specific mass shift and, optionally, the isotope ratio, whereby one sample set is isotope-labeled, and one is not, (3) analyze isotope-guided perturbation experiments with a setup described in X 13 CMS., Results: To illustrate the versatility of DeltaMS, we analyze data sets from case-studies that commonly pose challenges in evaluation of natural isotopes or isotopic signatures in labeling experiment. In these examples, the untargeted detection of sulfur, bromine and artificial metal isotopic patterns is enabled by the automated search for specific isotopes or isotope signatures., Conclusion: DeltaMS provides a platform for the identification of (pre-defined) isotopologues in MS data from single samples or comparative metabolomics data sets.

Introduction: With the worldwide increase in the rates of antimicrobial resistance, antimicrobials with novel mechanisms of action are needed to fill a void in the antimicrobial armamentarium. Areas covered: Intravenous fosfomycin has been studied extensively in a wide variety of infections including cUTI, lower respiratory tract infection, bone and joint infections, endocarditis, meningitis, and bacteremia outside of the United States. This paper reviews the in vitro activity, pharmacokinetic properties, and clinical experience of intravenous fosfomycin in hospitalized patients with serious infections. Expert commentary: Drug resistant infections in hospitalized and critically ill patients are associated with high morbidity and mortality. Fosfomycin is an epoxide antimicrobial that acts by inhibiting cell wall synthesis earlier in the process compared to other classes of antimicrobial agents. Fosfomycin exerts bactericidal activity against a broad range of gram-negative and gram-positive pathogens, including extended-spectrum beta-lactamase- and carbapenemase-producing bacteria. Although an oral formulation of fosfomycin is approved by the United States (US) Food and Drug Administration for uncomplicated urinary tract infections, intravenous fosfomycin at a dose of 18 g/day is currently under clinical development for the treatment of complicated urinary tract infection (cUTI), including pyelonephritis in the US.

Introduction: The combination of growing antimicrobial resistance with a dry pipeline has resulted in infections that can no longer be treated. Specific reasons have led to companies' exit from the antibacterial space, however recent incentives are spurring interest to reinvigorate the pipeline. Areas covered: This article summarizes the available information on the discovery, developmental, and regulatory challenges in antibacterial development that have led to disinterest in the space, as well as ongoing incentives such as public-private partnerships and streamlined pathways to mend these challenges and bring new antibiotics to patients in need. Expert commentary: Clinicians should not only understand the reasons for the decline in antibiotic development that have resulted in the dry pipeline, but also the ongoing initiatives in place to build an appropriate supply. Doing so will result in greater appreciation and prudent use of these life-saving drugs when they become available.

Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies., (© 2016 Pharmacotherapy Publications, Inc.)

Metal isotope coded profiling (MICP) introduces a universal discovery platform for metal chelating natural products that act as metallophores, ion buffers or sequestering agents. The detection of cation and oxoanion complexing ligands is facilitated by the identification of unique isotopic signatures created by the application of isotopically pure metals.

Objective: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL., Data Sources: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013)., Study Selection and Data Extraction: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included., Data Synthesis: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d)., Conclusions: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Purpose: Important articles on topics pertinent to infectious diseases (ID) pharmacotherapy published in prominent peer-reviewed journals in 2010 are summarized., Summary: At the end of 2010, pharmacists, physicians, and researchers in the Houston Infectious Diseases Network were asked to nominate articles published from January through December 2010 that they perceived as having a significant impact in the field of ID pharmacotherapy. The resulting list, comprising 27 articles relating to human immunodeficiency virus (HIV) disease or acquired immune deficiency syndrome (AIDS) and 52 articles on a broad range of other ID-related topics, was sent to members of the Society of Infectious Diseases Pharmacists (SIDP) for evaluation via an Internet survey. The survey participants were asked to select from the list 10 articles unrelated to HIV or AIDS and 1 HIV- or AIDS-related article that in their view had the most significant impact in the field. Of the 380 SIDP members surveyed, 105 (27.6%) ranked the non-HIV-related papers and 45 (11.8%) ranked the HIV-related papers. The 11 highest-ranked publications-including 2 articles presenting updated practice guidelines-are summarized here., Conclusion: Due to the increasing number of articles published each year, it is difficult to maintain a current knowledge of significant publications in the field of ID pharmacotherapy. This review of key publications in 2010 may be helpful to the nonspecialist clinician by lessening this burden.

The risk factors for relapse of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin treatment are unknown. Diversilab typing was used to classify recurrent bacteremia as relapse or reinfection. Bacteremia for >7 days and staphylococcal cassette chromosome mec element (SCCmec) type II were independently associated with relapse of MRSA bacteremia after vancomycin treatment.

Vancomycin and daptomycin MICs from 161 isolates of methicillin-resistant Staphylococcus aureus (MRSA) were compared using commercial and in-house broth microdilution, Etest, and common automated methods. Vancomycin Etest MICs were higher than those of other methods, whereas the MICs for daptomycin testing were comparable. Vancomycin MICs vary depending on the testing methodology.

Non-culture-based diagnostic strategies are needed for diagnosing invasive candidiasis (IC). We evaluated serial serum (1→3)-β-d-glucan (BG) levels in patients in the surgical trauma intensive care unit (SICU) patients with clinical evidence of IC. Serum samples from patients admitted to the SICU for a minimum of 3 days were collected twice weekly and analyzed for BG by using a Fungitell kit with a positive cutoff of ≥ 80 pg/ml. Diagnosis of IC was done using a set of predefined and validated clinical practice-based criteria. A total of 57 patients consented to participate and were enrolled. The median ICU stay was 16 days (range, 3 to 51). A total of 14 of 57 (25%) false positives were observed in the first sample (ICU day 3) and, overall, 73% of the day 3 samples had higher BG levels than subsequent samples. On the date of clinical diagnosis of IC, the sensitivity of a positive BG for identifying invasive candidiasis was 87%, with a 73% specificity. In patients with evidence of IC, the median BG value was significantly higher than those without evidence of IC (171 versus 48 pg/ml, P = 0.02), respectively. In the three patients with proven IC, BG was detected 4 to 8 days prior to diagnosis. BG serum detection may be a useful tool to aid in the early diagnosis of IC in SICU patients, particularly after day 3 and in patients with at least two positive samples drawn several days apart. Elevated BG levels within the first 3 days need to be further characterized.

Objectives: To quantify influenza vaccination rates and determine perceived barriers to influenza vaccination among U.S. pharmacists from various practice settings., Design: Prospective study., Setting: United States in 2008., Participants: 1,028 respondents, including 895 pharmacists., Intervention: A survey request was distributed manually at the 2008 National Community Pharmacists Association annual meeting, and an initial e-mail was sent with two follow-up e-mails to all pharmacists who receive e-mails via Pharmacist e-link., Main Outcome Measures: Vaccination rates and barriers to vaccination among pharmacists., Results: Pharmacists reported an influenza vaccination rate of 78%, with coverage varying across practice settings: hospital (88%), academia (86%), clinic (83%), and community (75%). Employers infrequently required the influenza vaccine as a condition of employment (7%), and slightly more than one-half (58%) compensated pharmacists for being vaccinated; both of these were significantly associated with higher influenza vaccination rates (P < 0.001 for both). One-quarter of pharmacists (26%) expressed at least one issue regarding the influenza vaccine. Pharmacists were significantly less likely to be vaccinated if they expressed a concern (91% vs. 43%, P < 0.0001). Community pharmacists were significantly less likely to be compensated for receiving the influenza vaccination and significantly more likely to express one or more concerns than pharmacists from any other practice setting., Conclusion: Pharmacists reported high influenza vaccination rates overall, with slight variability among practice settings. Although employers infrequently required influenza vaccination, approximately one-half of employers compensated their pharmacists for being vaccinated. Employer incentives and pharmacist attitudes were highly correlated with influenza vaccination.

Vancomycin is the first-line therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, but its efficacy in adult patients has been questioned. Less is known about the outcomes of MRSA bacteremia treated with vancomycin in pediatric patients. This study reviews the outcomes and clinical characteristics of MRSA bacteremia in children treated with vancomycin and characterizes the microbiologic and molecular features of the bloodstream isolates. A retrospective cohort study was conducted among pediatric patients with MRSA bacteremia treated with vancomycin for >5 days from 1 August 2005 to 31 May 2007 in a large tertiary care center. MRSA bloodstream isolates were characterized by antimicrobial susceptibility testing, PCR analysis of virulence genes, and Diversilab typing. Clinical records were reviewed for outcomes and comorbidities. A total of 22 pediatric patients with MRSA bacteremia were identified. Eleven cases (50.0%) were considered vancomycin treatment failures. Features significantly associated with vancomycin treatment failure were prematurity (P = 0.02) and isolates positive for Panton-Valentine leukocidin (PVL) (P = 0.008). Features typically associated with community-associated MRSA strains were identified in hospital-associated isolates. A dominant clone was not responsible for the high number of treatment failures. Further studies are needed to determine if vancomycin should be the first-line treatment for MRSA bacteremia in premature infants and for PVL-positive isolates.

This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly. Overall, additive or indifferent effects with daptomycin combinations were observed; however, synergy was observed for certain isolates of vancomycin-resistant enterococci when exposed to daptomycin and rifampicin. Unexpected synergy was demonstrated against methicillin-resistant Staphylococcus aureus by daptomycin and beta-lactams. Most importantly, no in vitro antagonism of daptomycin with any other agent tested was confirmed in these studies. The most striking in vivo effects were noted in two different complicated infection models; i.e. osteomyelitis and implant infections, where rifampicin combinations with daptomycin increased efficacy and reduced the incidence of rifampicin resistance.

Appropriate use of antimicrobials in health care continues to be a challenge. Reliable and reproducible antimicrobial susceptibility testing methods are necessary to provide the clinician with valuable information that can be translated into positive clinical outcomes at the bedside. However, there are nuances with these testing methods that, if unrecognized, could lead to misinterpretation of results and inappropriate antibiotic selection. This primer describes the common antimicrobial susceptibility tests used in the clinical microbiology laboratory and reviews how subtle differences in testing methods and technique can influence reported results. Clinicians who have a thorough understanding of qualitative and quantitative methods, automated susceptibility testing systems, and commonly used screening and confirmatory tests for antibiotic-resistant organisms can strengthen institutional antibiotic stewardship programs and improve patient outcomes.

Enterococcal infections are a common cause of nosocomial bloodstream infections. Vancomycin resistance and the emergence of linezolid resistance necessitate alternative therapies. Studies in vitro as well as animal and case studies suggest that daptomycin may be effective in enterococcal infections. Patients with positive blood cultures for enterococci in the Cubicin((R)) Outcomes Registry and Experience (CORE) 2005-2006 were identified. Patients with endocarditis, intracardiac foreign body infections or non-speciated enterococci were excluded. Outcome was assessed using protocol-defined criteria. Of 159 patients included in the efficacy population, Enterococcus faecium and Enterococcus faecalis were isolated in 120 (75.5%) and 39 (24.5%) patients, respectively. Vancomycin resistance was detected in 91% and 23% of patients with E. faecium and E. faecalis infections, respectively. Prior to daptomycin, 94/159 (59.1%) and 35/159 (22.0%) patients had received vancomycin and linezolid, respectively. Daptomycin was first-line therapy in 27/159 cases (17%). Success was observed in 139/159 patients (87%) and in 104/120 (87%) and 35/39 (90%) patients with E. faecium and E. faecalis infections, respectively. Among the safety population (n=211), 20 (9.5%) experienced 28 adverse events possibly related to daptomycin, 8 of which were considered serious. Daptomycin may be a useful agent for treating enterococcal bacteraemia caused by E. faecium or E. faecalis. Further studies are warranted.

Purpose: Significant publications on infectious diseases (ID) pharmacotherapy in 2007 were compiled and summarized., Summary: On January 2, 2008, the 21 members of the Houston Infectious Disease Network (HIDN) were asked to select an article that was published in a peer-reviewed journal between January 1 and December 31, 2007, and write a summary highlighting why the article was significant to the diagnosis or treatment of ID. Articles were selected based on prior "top 10" presentations at major ID and pharmacy meetings or were listed as major articles in prominent ID journals. Priority was given to peer-reviewed publications and nationally recognized clinical treatment guidelines. Nineteen articles and summaries were submitted by HIDN members. The publication listing was distributed to Society of Infectious Diseases Pharmacists members via an Internet survey in early February 2008. Members were asked to select the 10 most significant articles relating to ID pharmacotherapy from the list of 19 and were allowed to add an additional article that was not already listed. A total of 102 individuals participated in the survey. A listing of the top 10 articles published in 2007 and one honorable mention was compiled, and the significance of each article was summarized., Conclusion: The increased number of articles in the peer-reviewed medical literature related to the diagnosis and treatment of ID has made it challenging to maintain a contemporary knowledge base of key publications. This summary of significant ID articles published in 2007 can help to alleviate the burden of knowledge management.

Meropenem is a carbapenem antibiotic approved by the US Food and Drug Administration for the treatment of complicated skin and skin-structure infections, complicated intra-abdominal infections, and pediatric bacterial meningitis (in patients >or=3 months of age). In clinical trials, it also has shown efficacy as initial empirical therapy for the treatment of nosocomial pneumonia. Unlike other beta-lactam antibiotics, including third-generation cephalosporins, carbapenems have shown activity against extended-spectrum beta-lactamase-producing and AmpC chromosomal beta-lactamase-producing bacteria. Compared with imipenem, meropenem is more active against gram-negative pathogens and somewhat less active against gram-positive pathogens, and it does not require coadministration of a renal dehydropeptidase inhibitor. In most comparative trials, clinical and bacteriological response rates with imipenem and meropenem were similar. Compared with clindamycin/tobramycin, meropenem is associated with a reduced length of hospital stay and a shorter duration of therapy among patients with complicated intra-abdominal infections. Meropenem is well tolerated by children and adults and has an acceptable safety profile. Alternative meropenem dosing strategies for the optimization of outcomes are under investigation.

Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg.

Background: The prevalence of glucose abnormalities has been reported to be greater in hospitalized patients receiving gatifloxacin than in patients receiving ceftriaxone., Objective: The purpose of the current study was to identify risk factors for hyperglycemia in hospitalized patients receiving gatifloxacin., Methods: This retrospective, nested case-controlled study was conducted in 69 patients and 69 controls in 2 nonteaching hospitals in Houston, Texas. Classification and regression tree (CART) analysis was conducted to identify break points in continuous variables. Univariate and multivariate logistic regression analyses were also performed., Results: A total of 138 patients (mean [SD] age, 68.3 [17.3] years; weight, 77.4 [21.1] kg; sex, women/ men, 69.6%/30.4%; race [Hispanic, 58.3%; white, 28.5%; black, 9.2%; other, 4.0%]) were identified. Patients who developed hyperglycemia (blood glucose level > 200 mg/dL) within 72 hours of gatifloxacin administration (cases) were matched 1:1 with patients who received gatifloxacin for > or = 5 days and did not experience hyperglycemia during treatment and for 3 days after the end of treatment (controls). In univariate analysis, cases were more likely than controls to have diabetes (89.9% vs 13.0%; P < 0.001), have a decreased mean (SD) creatinine clearance (CrCl) (53.8 [36.8] vs 69.2 [45.3] mL/min; P = 0.025), be located in the intensive care unit at the time of the event (20.3% vs 7.2%; P = 0.02), have received gatifloxacin doses higher than recommended based on renal function (> 200 mg/d when CrCl < 40 mL/min) (25/69 [36.2%] vs 9/69 [13.0%]), have leukocytosis (mean [SD] white blood cell [WBC] count, 15.5 [7.4] vs 12.8 [6.2] cells/mm3), and have received concomitant total parenteral nutrition (7/69 [10.1%] vs 0 [0%]; P = 0.02) and/or steroids (22/69 [31.9%] vs 8/69 [11.6%]; P = 0.008). CART analysis identified age > 65 years, albumin < 3.2 g/dL, WBC count > 14.5 cells/mm3, and CrCl < 40 mL/min to be more common in hyperglycemic patients. In logistic regression, diabetes (odds ratio [OR] = 233; 95% CI, 19-2784) and excessive dose for renal function (OR = 42; 95% CI, 2-770) were identified as independent predictors for hyperglycemia in patients receiving gatifloxacin. After controlling for diabetes, concomitant steroids (OR = 5.7; 95% CI, 1.5-21.1) and excessive dose for renal function (OR = 4.9; 95% CI, 1.2-20.4) were associated with hyperglycemia in patients receiving gatifloxacin., Conclusions: This retrospective, nested case-controlled study found that the risk of hyperglycemia increased in diabetic patients who received concomitant steroids or higher gatifloxacin doses than recommended by the manufacturer's prescribing information. The application of these data should be assessed for other fluoroquinolones used at higher doses.

Study Objectives: To compare rates of hypoglycemia and hyperglycemia among elderly hospitalized patients with normal blood glucose concentrations at baseline who were receiving either gatifloxacin or levofloxacin, and to determine if appropriateness of their doses, according to their package inserts, was associated with hypoglycemia or hyperglycemia., Design: Retrospective cohort study., Setting: Integrated Veterans Administration (VA) health care system., Patients: Nine hundred thirty-seven elderly (>or= 65 yrs) patients with documented blood glucose levels of 65-140 mg/dl before receiving a fluoroquinolone., Measurements and Main Results: Between January 2003 and April 2004, 405 patients receiving levofloxacin met study criteria. In April 2004, gatifloxacin was substituted for levofloxacin on the formulary of this VA system. Thus, between April 2004 and December 2004, 532 patients received gatifloxacin. All blood glucose concentrations during hospitalization that were measured during fluoroquinolone therapy or within 72 hours of completion of therapy were reviewed. Demographic characteristics, comorbidities, insulin and oral hypoglycemic therapies, disease severity, blood glucose levels, and outcomes were recorded and compared between groups. The two groups were similar at baseline for all characteristics examined except previous hospitalization. In the logistic regression, gatifloxacin was independently associated with both hypoglycemia (adjusted odds ratio [AOR] 2.5, 95% confidence interval [CI] 1.2-5.7, p=0.04) and hyperglycemia (AOR 2.4, 95% CI 1.5-3.6, p<0.001). Improper dosage adjustment based on renal function was not associated with higher rates of hypoglycemia and hyperglycemia for either drug. Of the 532 patients receiving gatifloxacin, 465 (87.4%) received appropriate doses, yet gatifloxacin was associated with higher rates of hypoglycemia and hyperglycemia compared with patients receiving levofloxacin., Conclusions: Higher rates of both hypoglycemia and hyperglycemia were noted among elderly hospitalized patients who received gatifloxacin compared with those receiving levofloxacin, irrespective of dosing.

Study Objectives: To compare rates of blood glucose abnormalities in hospitalized patients receiving fluoroquinolones or ceftriaxone, and to describe the characteristics of patients who develop blood glucose abnormalities while receiving these agents., Design: Retrospective chart review., Setting: Two community-based hospitals in the Houston, Texas, region., Patients: Seventeen thousand one hundred eight patients who received fluoroquinolones or ceftriaxone; of those, 101 received levofloxacin, gatifloxacin, or ceftriaxone and also had serum glucose concentrations above 200 or below 50 mg/dl within 72 hours of receiving the drug., Measurements and Main Results: Baseline demographics of patients with glucose abnormalities while receiving gatifloxacin, levofloxacin, or ceftriaxone were similar. Mean +/- SD patient age, weight, and estimated creatinine clearance were 67 +/- 17 years, 79 +/- 21 kg, and 52 +/- 32 ml/minute, respectively. Dysglycemia rates relative to treatment were as follows: gatifloxacin 76 (1.01%) of 7540 patients, levofloxacin 11 (0.93%) of 1179, ceftriaxone 14 (0.18%) of 7844, ciprofloxacin 0 (0%) of 545, and any fluoroquinolone 87 (0.94%) of 9264. Dysglycemia was more likely to occur in patients receiving any fluoroquinolone than in those receiving ceftriaxone (relative risk [RR] 3.32, 95% confidence interval (CI) 2.31-4.78, p < 0.05). The rate of dysglycemia did not differ with gatifloxacin and levofloxacin (RR 1.07, 95% CI 0.62-1.86, p = 0.8). Of the 101 patients with dysglycemias, hypoglycemia occurred in nine (9%) and hyperglycemia in 92 (91%). In a multivariate analysis of patients receiving fluoroquinolones, only concomitant sulfonylurea therapy was identified as an independent risk factor for development of hypoglycemia compared with patients who experienced hyperglycemia., Conclusion: In the 17,108 patients receiving a fluoroquinolone or ceftriaxone, the rate of dysglycemia was greater in those receiving levofloxacin or gatifloxacin than in those receiving ceftriaxone. However, no difference was noted in the rate of glucose abnormalities with levofloxacin versus gatifloxacin. Clinicians should be aware of dysglycemic events that may occur in patients receiving fluoroquinolones, especially in those with diabetes mellitus or those receiving sulfonylureas.

The toxicity of amphotericin B deoxycholate has led to increased preference for lipid formulations with more favorable safety profiles. However, the primary use of lipid formulations is cost prohibitive, and many hospital formularies list both lipid and nonlipid formulations. A dispensing and administration error that caused amphotericin B deoxycholate to be given instead of liposomal amphotericin B related in a fatality. Measures to prevent confusion and aid in understanding the differences between lipid and nonlipid formulations of amphotericin B should be implemented.

Increasing resistance in Pseudomonas aeruginosa to multiple antibiotics has been observed and is posing therapeutic dilemmas. Antibiotic utilization is one factor that has been associated with the emergence of antimicrobial resistance. We examined the overall and specific antimicrobial use in relation to changes in susceptibility patterns in P. aeruginosa. Regression analysis was performed to explore the relationships between annual antibiotic use and the incidence of resistant P. aeruginosa. There were statistically significant relationships between increasing anti-pseudomonal cephalosporin and levofloxacin use and the increasing incidence of ciprofloxacin resistant P. aeruginosa. However, there was not an association between other fluoroquinolone or overall fluoroquinolone use and this change. In addition, there was no association between increasing anti-pseudomonal cephalosporin use and cefepime resistant P. aeruginosa. No statistical relationship was seen with overall antibiotic use and the development of resistance in P. aeruginosa, suggesting that the development of resistance is associated with the use of individual agents, rather than overall antibiotic consumption.

The pharmacokinetics of intravenous itraconazole (ITC) was studied in dialysis patients. Dialysis had no effect on the half-life and clearance of ITC or OH-ITC. However, dialysis allowed the clearance of hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The area under the concentration-time curve from time zero to infinity (AUC(0- infinity)) for HP-beta-CD administered before dialysis was lower than the AUC(0- infinity) when it was administered after dialysis (P < 0.01). Administration of ITC intravenously just prior to hemodialysis appears to produce adequate systemic exposures of ITC and OH-ITC while allowing dialysis clearance of HP-beta-CD. Studies of multiple administrations are warranted.

Critically ill patients have altered pharmacokinetics (PK) that need to be considered when choosing and dosing antibiotics. We conducted a prospective, observational study to assess clinical and microbiologic response rates in 19 critically ill patients with nosocomial Gram-negative infections. Antibiotics were dosed based on a mathematical pharmacodynamic (PD) model accounting for these altered kinetic parameters. The average APACHE II score +/- SE on intensive care unit admission and at the time of infection was 13.6 +/- 1.2 and 14.6 +/- 1.1, respectively. With targeted antimicrobial therapy adjusted to achieve an optimal PD profile, 17/19 (89%) patients had a clinical cure or improvement and 16/19 (84%) had either microbiologic eradication or presumed eradication. Modeling PD in these critically ill patients resulted in good clinical and microbiologic outcomes.