The impact of an automated antibiotic stewardship intervention for the management of Staphylococcus aureus bacteraemia utilizing the electronic health record.

BACKGROUND: Staphylococcus aureus bacteraemia (SAB) management bundles have been shown to improve performance measures and clinical outcomes. SAB bundles often require direct intervention by infectious diseases (ID) physicians or antibiotic stewardship programme (ASP) members or pharmacists. The purpose of this study was to evaluate an automated, real-time ASP intervention utilizing clinical decision support (CDS) in the electronic health record (EHR) for the management of SAB. METHODS: A retrospective, single-centre quasi-experimental study of hospitalized patients with known SAB was conducted. The intervention was the implementation of a hard-stop best practice advisory (BPA) alert that would prompt physicians to use an electronic order set, on identification of SAB, with management recommendations, including ID consultation. The primary outcome was overall adherence to six institutional ASP SAB bundle elements. Secondary outcomes included both clinical and process outcomes. RESULTS: A total of 227 patients were included, 111 in the pre-intervention and 116 in the post-intervention period. Completion of all six bundle elements improved by 27.2% in the post-intervention group (29.7% versus 56.9%, P < 0.001). BPA activation and order-set utilization occurred in 95.7% and 57.8% in the post-intervention group, respectively. Composite outcome of 30 day mortality or 90 day readmission with SAB complication decreased in the post-intervention group by 9.6% (24.3% versus 14.7%, P = 0.092). CONCLUSIONS: Optimization of CDS within the EHR, using real-time BPA alert and order set, demonstrated an immediate, sustainable intervention that improved adherence to institutional performance measures for SAB management without direct prospective audit with intervention and feedback.

Cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia.

BACKGROUND: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction. METHODS: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs. RESULTS: Total duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05). CONCLUSION: Preemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.

Identifying the priority infection prevention and control gaps contributing to neonatal healthcare-associated infections in low-and middle-income countries: results from a modified Delphi process.

Background: In low- and middle-income countries (LMIC), neonatal healthcare-associated infections (HAI) are associated with increased morbidity, mortality, hospital stay, and costs. When resources are limited, addressing HAI through infection prevention and control (IPC) requires prioritizing interventions to maximize impact. However, little is known about the gaps in LMIC that contribute most to HAI. Methods: A literature review was conducted to identify the leading IPC gaps contributing to neonatal HAIs in intensive care units and specialty care wards in LMIC. Additionally, a panel of 21 global experts in neonatology and IPC participated in an in-person modified Delphi process to achieve consensus on the relative importance of these gaps as contributors to HAI. Results: Thirteen IPC gaps were identified and summarized into four main categories: facility policies such as prioritizing a patient safety culture and maintaining facility capacity, general healthcare worker behaviors such as hand hygiene and proper device insertion and maintenance, specialty healthcare worker behaviors such as cleaning and reprocessing of medical equipment, and infrastructural considerations such as adequate medical equipment and hand hygiene supplies. Conclusions: Through a modified Delphi process, we identified the leading IPC gaps contributing to neonatal HAIs; this information can assist policymakers, public health officials, researchers, and clinicians to prioritize areas for further study or intervention.

Lack of effect of P-glycoprotein inhibition on renal clearance of dicloxacillin in patients with cystic fibrosis.

STUDY OBJECTIVE: To determine whether upregulation of P-glycoprotein is responsible for the enhanced renal clearance of dicloxacillin in patients with cystic fibrosis. DESIGN: Single-center, prospective, open-label, randomized, three-part crossover pharmacokinetic study. SETTING: General clinical research center. SUBJECTS: Eleven patients with cystic fibrosis and 11 age-matched healthy volunteers. INTERVENTION: All subjects received a single oral dose of dicloxacillin 500 mg alone, dicloxacillin 500 mg plus probenecid (an organic anion transport inhibitor) 1 g, and dicloxacillin 500 mg plus cyclosporine (a P-glycoprotein inhibitor) 5 mg/kg; each treatment was separated by a washout period of 48 hours. A bolus dose of iothalamate meglumine 456 mg was administered on each study day as a marker of glomerular filtration. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were taken serially up to 6 hours after each dose. Pharmacokinetics of dicloxacillin and iothalamate were determined by using compartmental and noncompartmental methods. Quantitative polymerase chain reaction was performed on peripheral blood mononuclear cells to measure expression of multidrug resistance 1 (MDR1) messenger RNA (mRNA). Genotyping for ABCB1 was performed to determine the presence of single nucleotide polymorphisms (exons 21 and 26). In both healthy subjects and patients with cystic fibrosis, compared with dicloxacillin alone, coadministration with probenecid produced a significantly lower renal clearance of dicloxacillin, whereas coadministration with cyclosporine resulted in no significant change; renal clearance was not significantly different between the two study groups. No correlation was found between MDR1 mRNA expression and renal clearance of dicloxacillin. The renal excretion of dicloxacillin was significantly greater in subjects with the ABCB1 exon 26 TT polymorphism when compared with subjects with the CT genotype. CONCLUSION: We found no significant difference in the pharmacokinetics of dicloxacillin between patients with cystic fibrosis and healthy volunteers. Renal clearance of dicloxacillin was significantly reduced in the presence of probenecid but not with cyclosporine, suggesting that the rate-limiting step in tubular secretion of dicloxacillin is uptake mediated by the organic anion transporter, and not P-glycoprotein inhibition.

Systemic antifungal therapy: new options, new challenges.

The frequency of invasive fungal infections has increased dramatically in recent decades because of an expanding population at risk. Until now, treatment options for invasive mycoses have been primarily amphotericin B and the azoles, fluconazole and itraconazole. Traditional agents are limited by an inadequate spectrum of activity, drug resistance, toxicities, and drug-drug interactions. The recent approval of caspofungin and voriconazole clearly has expanded the number of existing antifungal drugs available. However, the enthusiasm that accompanies their availability is counterbalanced by limited clinical experience, high drug acquisition costs, and distinctive toxicities. The pharmacologic characteristics, extent of clinical experience (efficacy and toxicity), and drug acquisition costs among available systemic antifungal agents are compared, with emphasis on the new agents. Also, recommendations on the role of each agent are provided according to the most common indications for systemic antifungal therapy: invasive candidiasis, invasive aspergillosis, and febrile neutropenia.

Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.

STUDY OBJECTIVE: To evaluate the relationship between voriconazole dose and corresponding serum concentrations in obese and overweight immunocompromised patients. DESIGN: Retrospective medical record review. SETTING: National Cancer Institute-designated comprehensive cancer center. PATIENTS: A total of 92 patients with hematologic malignancies and/or hematopoietic stem cell transplants who received voriconazole and had reported steady-state serum concentrations (peak, random, or trough) during 2005-2010; 124 serum concentrations were available for analysis. MEASUREMENTS AND MAIN RESULTS: Data on patient demographics, voriconazole concentrations, and other clinical and safety data were collected. Patients were stratified based on body mass index (BMI). Patients with higher BMIs tended to have significantly higher median random voriconazole concentrations with intravenous administration (6.4 mg/L for BMI ≥ 25 kg/m(2) vs 2.8 mg/L for BMI < 25 kg/m(2), p=0.04). This trend was more notable with the intravenous than the oral formulations. With the oral formulation, patients with a BMI of 25 kg/m(2) or greater had a median random concentration of 2.8 mg/L compared with 2.0 mg/L in patients with a BMI less than 25 kg/m(2) (p=0.18). Patients with a BMI of 25 kg/m(2) or greater also had a higher median daily voriconazole dose (640 vs 400 mg, p<0.001). No significant differences were noted in factors that would affect oral absorption of voriconazole (e.g., graft-versus-host disease) among BMI groups. When comparing all voriconazole concentrations, higher concentrations were associated with a greater percentage of patients who had alanine aminotransferase levels of more than 3 times the upper limit of normal. Patients with voriconazole random concentrations of 2 mg/L or greater had higher response rates (50%) than patients with concentrations lower than 2 mg/L (33%). CONCLUSION: Standard voriconazole dosing using actual body weight in obese and overweight patients resulted in higher associated serum concentrations. Dosing using adjusted body weight may be necessary in this population in order to achieve optimal concentrations while preventing the potential for increased toxicity.

Epidemiology and treatment approaches in management of invasive fungal infections.

Over the past 20 years, the number of invasive fungal infections has continued to persist, due primarily to the increased numbers of patients subjected to severe immunosuppression. Despite the development of more active, less toxic antifungal agents and the standard use of antifungal prophylaxis, invasive fungal infections (especially invasive mold infections) continue to be a significant factor in hematopoietic cell and solid organ transplantation outcomes, resulting in high mortality rates. Since the use of fluconazole as standard prophylaxis in the hematopoietic cell transplantation setting, invasive candidiasis has come under control, but no mold-active antifungal agent (except for posaconazole in the setting of acute myelogenous leukemia and myelodysplastic syndrome) has been shown to improve the survival rate over fluconazole. With the advent of new azole and echinocandin agents, we have seen the emergence of more azole-resistant and echinocandin-resistant fungi. The recent increase in zygomycosis seen in the hematopoietic cell transplantation setting may be due to the increased use of voriconazole. This has implications for the empiric approach to pulmonary invasive mold infections when zygomycosis cannot be ruled out. It is imperative that an amphotericin B product, an antifungal that has never developed resistance in over 50 years, be initiated. The clinical presentations of invasive mold infections and invasive candidiasis can be nonspecific and the diagnostic tests insensitive, so a high index of suspicion and immediate initiation of empiric therapy is required. Unfortunately, our currently available serologic tests do not predict infection ahead of disease, and, therefore cannot be used to initiate "preemptive" therapy. Also, the Aspergillus galactomannan test gives a false negative result in patients receiving antimold prophylaxis, ie, virtually all of our patients with hematologic malignancy and hematopoietic cell transplant recipients. We may eventually be able to select patients at highest risk for invasive fungal infections for prophylaxis by genetic testing. However, with our current armamentarium of antifungal agents and widespread use of prophylaxis in high-risk groups (hematologic malignancy, hematopoietic cell transplantation), we continue to see high incidence and mortality rates, and our future hope lies in reversing the immunosuppression or augmenting the immune system of these severely immunocompromised hosts by developing and utilizing immunotherapy, immunoprophylaxis, and vaccines.

Approaches to the early treatment of invasive fungal infection.

Invasive fungal infections account for significant morbidity and mortality in the seriously immunocompromised host, especially those suffering from hematologic malignancies and the recipients of hematopoietic cell transplant. One of the reasons for the continuing high mortality rates due to invasive fungal infection is the delay in administering appropriate therapy. As preemptive antifungal therapy is not feasible for lack of a predictive test, early empiric therapy is currently the only approach likely to result in improvement in survival. Here, we present our approach to both invasive candidiasis and invasive mold infection. Therapy should be initiated at the first signs and symptoms of disease, utilizing knowledge of local fungal epidemiology, the patient's recent antifungal agent exposure, and the diagnostic tests immediately available, to select an appropriate antifungal agent most likely to be effective against the suspected fungal species.

Use of an efflux pump inhibitor to determine the prevalence of efflux pump-mediated fluoroquinolone resistance and multidrug resistance in Pseudomonas aeruginosa.

Fluoroquinolone-resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression (EPO) and/or target mutations. EPO can result in multidrug resistance (MDR) due to broad substrate specificity of the pumps. MC-04,124, an efflux pump inhibitor (EPI) shown to significantly potentiate activity of levofloxacin in P. aeruginosa, was used to examine the prevalence of EPO in clinical isolates. MICs were determined for ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin with or without EPI and for other antipseudomonal agents by using broth microdilution against P. aeruginosa isolates from adults (n = 119) and children (n = 24). The prevalence of the EPO phenotype (>/=8-fold MIC decrease when tested with EPI) was compared among subgroups with different resistance profiles. The EPO phenotype was more prevalent among levofloxacin-resistant than levofloxacin-sensitive strains (61%, 48/79 versus 9%, 6/64). EPO was present in 60% of fluoroquinolone-resistant strains without cross-resistance, while it was present at variable frequencies among strains with cross-resistance to other agents: piperacillin-tazobactam (86%), ceftazidime (76%), cefepime (65%), imipenem (56%), gentamicin (55%), tobramycin (48%), and amikacin (27%). The magnitude of MIC decrease with an EPI paralleled the frequency of which the EPO phenotype was observed in different subgroups. EPI reduced the levofloxacin MIC by as much as 16-fold in eight strains for which MICs were 128 microg/ml. Efflux-mediated resistance appears to contribute significantly to fluoroquinolone resistance and MDR in P. aeruginosa. Our data support the fact that increased fluoroquinolone usage can negatively impact susceptibility of P. aeruginosa to multiple classes of antipseudomonal agents.

Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis.

Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h(-1); P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h(-1); P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 +/- 6.0 mg/liter) far exceeded the maximum serum drug concentration ( approximately 50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.