Antimicrobial Stewardship Opportunities in Patients with Bacteremia Not Identified by BioFire FilmArray.

A subset of bacteremia cases are caused by organisms not detected by a rapid-diagnostics platform, BioFire blood culture identification (BCID), with unknown clinical characteristics and outcomes. Patients with ≥1 positive blood culture over a 15-month period were grouped by negative (NB-PC) versus positive (PB-PC) BioFire BCID results and compared with respect to demographics, infection characteristics, antibiotic therapy, and outcomes (length of hospital stay [LOS] and in-hospital mortality). Six percent of 1,044 positive blood cultures were NB-PC. The overall mean age was 65 ± 22 years, 54% of the patients were male, and most were admitted from home; fewer NB-PC had diabetes (19% versus 31%, P = 0.0469), although the intensive care unit admission data were similar. Anaerobes were identified in 57% of the bacteremia cases from the NB-PC group by conventional methods: Bacteroides spp. (30%), Clostridium (11%), and Fusobacterium spp. (8%). Final identification of the NB-PC pathogen was delayed by 2 days (P < 0.01) versus the PB-PC group. The sources of bacteremia were more frequently unknown for the NB-PC group (32% versus 11%, P < 0.01) and of pelvic origin (5% versus 0.1%, P < 0.01) compared to urine (31% versus 9%, P < 0.01) for the PB-PC patients. Fewer NB-PC patients received effective treatment before (68% versus 84%, P = 0.017) and after BCID results (82% versus 96%, P = 0.0048). The median LOS was similar (7 days), but more NB-PC patients died from infection (26% versus 8%, P < 0.01). Our findings affirm the need for the inclusion of anaerobes in BioFire BCID or other rapid diagnostic platforms to facilitate the prompt initiation of effective therapy for bacteremia.

Emergency Department Urinary Antibiograms Differ by Specific Patient Group.

Patients presenting to the emergency department (ED) represent a heterogeneous population comprised of all ages, various backgrounds, such as from the community and skilled-nursing facilities (SNFs), and at various risks for resistant pathogens. The aim of this study was to compare patient group-specific urinary antibiograms in the ED. Adults presented to the ED with an ICD 9/10 code urinary tract infection (UTI) diagnosis during July 2015 to June 2016 were randomly selected (n = 500) to extract relevant demographic, laboratory, and clinical data from the medical record. Urinary Escherichia coli antibiograms were compared between institutional versus ED and among ED patients (male versus female; age of 18 to 64 years versus ≥65 years; female aged 18 to 50 years versus >50 years; home versus SNF; and admitted versus discharged). E. coli grew from 56% (145/259) of the positive urine cultures. Overall ciprofloxacin (CIP), trimethoprim-sulfamethoxazole (SXT), and cefazolin (CFZ) susceptibilities were <71%. Differences in antibiograms were the following: lower CFZ and SXT susceptibilities in ED versus institutional (CFZ, 67% versus 86% [P = 0.001]; SXT, 66% versus 74% [P = 0.02]), lower ampicillin and gentamicin susceptibilities in females aged 18 to 50 years versus >50 years (32% versus 52% [P = 0.04]; 78% versus 93% [P = 0.02]), lower CIP susceptibilities in the elderly (64% versus 81%; P = 0.03), SNF versus home (35% versus 77%; P < 0.001), admitted versus discharged (63% versus 78%; P = 0.04), and lower SXT susceptibilities in patients aged <65 years versus the elderly (58% versus 71%; P = 0.01). Nitrofurantoin showed >80% susceptibility in all groups. Patient group-specific urinary antibiograms revealed distinct differences in E. coli susceptibility and should be developed to better inform empirical UTI therapy selection in the ED.

Comparison of type III secretion system virulence among fluoroquinolone-susceptible and -resistant clinical isolates of Pseudomonas aeruginosa.

Fluoroquinolone resistance and type III secretion system (TTSS) virulence are independently associated in Pseudomonas aeruginosa infections with poor patient outcomes. In the present study, the virulence of fluoroquinolone-susceptible and -resistant isolates of P. aeruginosa was compared, focusing on TTSS virulence. Clinical isolates (n = 45) exhibiting a broad range of susceptibilities to fluoroquinolones, with differing mechanisms of resistance and associated with varying disease sites, were selected for the study. PCR, Southern blot and western immunoblot analyses were performed to determine the presence of TTSS-encoding genes and secretion of gene products. The cytotoxicity of the clinical isolates towards human lung epithelial cells was also determined. Clinical isolates encoding only the exoS cytotoxin gene occurred more frequently than those encoding only exoU (62% vs. 27%; p 0.0007). Compared with exoS(+) isolates, exoU(+) isolates were more likely to be fluoroquinolone-resistant (92% vs. 61%, p 0.05) and to exhibit both a gyrA mutation and the efflux pump over-expressed (EPO) phenotype (91% vs. 59%; p 0.06). Almost all exoU(+) strains secreted ExoU and exhibited increased cytotoxicity compared with ExoS-secreting strains (7% vs. 92.5%, relative to a PA103 reference strain control). These data suggest that exoU(+) and fluoroquinolone resistance may be co-selected traits that result in highly virulent and resistant strains. Adverse outcomes associated with infections caused by fluoroquinolone-resistant strains may, in part, be attributable to this co-association, which warrants further clinical investigation.

Implementing a program for switching from i.v. to oral antimicrobial therapy.

Management Case Studies describe approaches to real-life management problems in health systems. Each installment is a brief description of a problem and how it was dealt with. The cases are intended to help readers deal with similar experiences in their own work sites. Problem solving, not hypothesis testing, is emphasized. Successful resolution of the management issue is not a criterion for publication--important lessons can be learned from failures, too.

Therapeutic challenges associated with extended-spectrum, beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

The emergence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae, presents significant diagnostic and therapeutic challenges to the management of infections due to these organisms. Detection of resistant isolates is difficult based on routine susceptibility testing performed by a clinical microbiology laboratory. In addition, the utility of penicillins, cephalosporins, and aztreonam in treating serious infections due to these organisms is uncertain due to reports of treatment failure despite apparent in vitro susceptibility. A critical evaluation of the English literature was performed on treatment outcomes associated with ESBL-producing Enterobacteriaceae. Imipenem and extended-spectrum cephalosporins were commonly administered. Discordant outcomes in relation to in vitro susceptibility of the agent did not occur exclusively with cephalosporins but with all drugs including imipenem. Until more outcome data are available, drug selection must take into consideration whether or not an outbreak is occurring and whether therapy is empirical or definitive.

Fluconazole-induced agranulocytosis with eosinophilia.

Fluconazole is a commonly prescribed antifungal agent with a favorable safety profile. A patient experienced agranulocytosis and eosinophilia associated with the drug. Similar bone marrow-suppressive effect due to the azoles is rarely described in the English-language literature.

Lipid formulations of amphotericin B: clinical efficacy and toxicities.

Commercially available lipid formulations of amphotericin B (Abelcet, Amphotec, and AmBisome) represent a significant advance in drug delivery technology. Differences in biochemical, pharmacokinetic, and pharmacodynamic properties among the lipid products have been shown in in vitro and in vivo models. Clinical experience with these products has been primarily in patients either refractory to or intolerant of conventional amphotericin B deoxycholate (AmBd). None of the lipid-based products demonstrates superior efficacy when prospectively compared with AmBd in the treatment of documented infections. When used for the empirical treatment of febrile neutropenia, AmBisome significantly reduced the incidence of proven emergent fungal infections but did not improve short-term survival rates, in comparison with AmBd. Acute infusion-related adverse events vary, whereas nephrotoxicity is reduced with all three lipid formulations. Until superior efficacy is clearly shown (for documented infections) or pharmacoeconomic analyses document the value of these drugs, use of such expensive agents should be highly restricted to those who are intolerant of or refractory to AmBd.

Predictive performance of a vancomycin-aminoglycoside population model.

OBJECTIVE: To evaluate the Wragge-Cooper method of predicting vancomycin serum concentrations utilizing knowledge of aminoglycoside pharmacokinetic parameters in general medicine and intensive care unit populations, and to develop a revised model if necessary. DESIGN: This study consists of two phases evaluating 50 adults receiving concurrent vancomycin and aminoglycoside therapy. Patients were identified by a retrospective review of medical records. Bayesian analysis of measured serum aminoglycoside and vancomycin concentrations was performed to determine the individualized pharmacokinetic parameters. Phase I of the study tested the predictive performance of a published model incorporating aminoglycoside elimination (Wragge-Cooper) in 25 patients (group 1), and a revised model was developed. Phase II determined the predictive performance of the revised model (revised) and its performance relative to the Wragge-Cooper model and a traditional model incorporating estimated creatinine clearance (traditional) in an additional 25 patients (group 2). SETTING: Two tertiary care university teaching hospitals. MAIN OUTCOME MEASURES: The predictive performance of the models was determined by comparing predicted with measured vancomycin serum concentrations. Bias and precision were evaluated by calculating the mean prediction error (ME) and mean absolute error (MAE), respectively. Linear regression was performed to determine relationships between parameters. RESULTS: The Wragge-Cooper model consistently underpredicts vancomycin serum concentrations in general medicine and intensive care unit populations (ME = -5.18, MAE = 6.63). Relative predictive performance analysis indicates no significant difference in bias or precision between the traditional and Wragge-Cooper models (delta ME 1.17, delta MAE -0.80). Regression analysis of individualized aminoglycoside and vancomycin elimination derived from patients in group 1 reveals the following relationship: vancomycin k10 (1/h) = 0.081 + 1.037ke,amg, r = 0.73. The revised model is significantly less biased and more precise compared with the traditional model (delta ME -4.48; delta MAE 1.22), and is significantly less biased (delta ME 4.29) but no more precise than the Wragge-Cooper model (delta MAE -0.58), using patients from group 2. CONCLUSIONS: The revised model is an accurate method of predicting vancomycin serum concentrations in both general medicine and intensive care unit populations. Use of this model enables individualization of vancomycin dosage in patients receiving concurrent aminoglycoside therapy and minimizes vancomycin serum concentration monitoring.

Economic aspects of antibacterial adverse effects.

The economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking. The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug's potential for causing and adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge. Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately $US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the beta-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

Safety and efficacy of Intralipid emulsions of amphotericin B.

To evaluate the clinical role of amphotericin/20% Intralipid emulsions (ILA), we conducted a Medline search of the English literature to locate the relevant case reports and clinical studies involving the use of this formulation. Due to differences in study design and definitions, we applied a set of treatment outcome definitions to determine the clinical efficacy of this treatment modality. Only 37 patients received ILA for the treatment of documented fungal infections. Using our definitions, four were considered successfully treated, one improved, two failed, and 30 were unevaluable. While infusion-related adverse events and nephrotoxicity were reportedly reduced with ILA, use of adjunctive therapies and concomitant nephrotoxic agents, and comparisons with high infusion concentrations complicate evaluation. Furthermore, incomplete and conflicting data exist regarding the physiochemical stability of ILA. The currently available data do not support recommendations for the use of this formulation for the treatment of systemic fungal infections.

Influence of timing of antibiotic administration on tissue concentrations during surgery.

BACKGROUND: Prophylactic antibiotics must be administered so as to achieve adequate tissue levels before the initial surgical incision. We characterized antimicrobial tissue concentrations following intravenous administration at various times prior to surgical incision. PATIENTS AND METHODS: Twelve patients scheduled for elective colorectal surgery were randomized to receive cefmetazole 2 g by intravenous push either immediately prior to incision or 15 to 60 minutes prior. Blood and wound-muscle samples were obtained at predetermined intervals and assayed by high-performance liquid chromatography. RESULTS: Tissue distribution of the study drug was extremely rapid. All patients had theoretically adequate tissue levels at the time of incision. Levels above MIC90 of the common pathogens were sustained throughout the surgical procedure regardless of the timing of administration. CONCLUSIONS: Administration of cefmetazole immediately prior to surgical incision should be effective prophylaxis for surgical wound infections.

Immune globulin therapy in allogeneic bone marrow transplant: a critical review.

Various immune globulin products have been utilized in allogeneic bone marrow transplant (BMT) in an effort to decrease the incidence of cytomegalovirus (CMV) infection, infection due to other pathogens and graft versus host disease (GVHD). Controlled trials regarding the use of prophylactic immune globulin have been reviewed. Differences among products and use of various dosing regimens complicates the comparison of the results of one trial to another. Risk factors, such as donor and recipient CMV serology, GVHD prophylaxis, the use of white blood cell transfusions and conditioning regimens, vary significantly, further complicating the analysis. Autologous BMT patients do not appear to benefit from prophylactic globulin therapy. The effectiveness of immune globulin in the prevention of CMV disease in allogeneic BMT is questionable; other measures, including prophylactic ganciclovir and screening of blood products appear to be of greater value. Immune globulin inconsistently decreases the incidence of infection due to pathogens other than CMV. The best established role for prophylactic immune globulin in allogeneic BMT is in the prevention of GVHD.

Treatment of funguria.

We evaluated the use of antifungal agents in the treatment of uncomplicated funguria by reviewing all case reports and studies regarding the treatment of funguria published in the English language from 1960 to 1991 (MEDLINE). Adult patients treated for uncomplicated funguria were included. Patients with fungal pyelonephritis and/or other systemic fungal manifestations were excluded from our analysis. All investigations were assessed for study design, sample size, definition of significant funguria, treatment regimen, inclusion of predisposing risk factors in outcome analysis, end points of therapy, and patient follow-up. Direct comparison of the studies on the use of antifungals in the treatment of uncomplicated funguria was not possible given the differing definitions of significant funguria, inconsistent reporting of risk factors, varying treatment regimens, end points of therapy, and duration of follow-up. Case reports and studies involving antifungals such as amphotericin B bladder irrigation, miconazole nitrate bladder irrigation, ketoconazole, and flucytosine were reviewed. Amphotericin B bladder irrigation appeared to be most effective and ketoconazole the least effective treatment of uncomplicated funguria. Predisposing risk factors, such as the presence of an indwelling urinary catheter, appear to play an important role in the persistence of positive cultures and failure of pharmacologic interventions. Until prospective, well-controlled studies are performed, no recommendation can be made for the treatment of uncomplicated funguria. In symptomatic patients therapy is indicated; however, the best regimen is unknown.