"Once more, with feeling": no difference in outcomes between patients discharged on oral versus intravenous antibiotics for orthopedic infections in a propensity score matched cohort at a US medical center.

Objective: To compare outcomes between patients discharged on intravenous (IV) versus oral (PO) antibiotics for the treatment of orthopedic infections, after creation of an IV-to-PO guideline, at a single academic medical center in the United States. Methods: This was a retrospective, propensity score matched, cohort study of adult patients hospitalized for orthopedic infections from September 30, 2020, to April 30, 2022. Patients discharged on PO antibiotics were matched to patients discharged on IV antibiotics. The primary outcome was one-year treatment failure following discharge. Secondary outcomes were incidence of 60-day treatment failure, adverse drug events (ADE), readmissions, infectious disease clinic "no-show" rates, and emergency department (ED) encounters. Results: Ninety PO-treated patients were matched to 90 IV-treated patients. Baseline characteristics were similar in the two groups after matching. There was no significant difference in the proportions of patients on PO versus IV antibiotics experiencing treatment failure at one year (26% vs 31%, P = .47). There were no significant differences for any secondary outcomes: treatment failure within 60 days (13% vs 14%, P = 1.00), ADE (13% vs 11%, P = .82), unplanned readmission (17% vs 21%, P = .57), or ED encounters (9% vs 18%, P = .54). Survival analyses identified no significant differences in time-to-event between PO and IV treatment for any of the outcomes assessed. Conclusions: There were no appreciable differences in outcomes between patients discharged on PO compared to IV regimens. Antimicrobial stewardship interventions to increase prescribing of PO antibiotics for the treatment of orthopedic infections should be encouraged.

In vitro activity of omadacycline against clinical isolates of Nocardia.

Nocardiosis typically requires a prolonged treatment duration of ≥6 months and initial combination therapy with 2-3 antibiotics. First-line regimens for nocardiosis are associated with considerable toxicity; therefore, alternative therapies are needed. Omadacycline is an aminomethylcycline with broad antimicrobial activity whose in vitro activity against Nocardia species has not been formally assessed. The in vitro potency of omadacycline was evaluated against 300 Nocardia clinical isolates by broth microdilution. The most common Nocardia species tested were N. cyriacigeorgica (21%), N. nova (20%), and N. farcinica (12%). The most common specimens were respiratory (178 isolates, 59%) and wound (57 isolates, 19%). Omadacycline minimum inhibitory concentrations (MICs) across all Nocardia species ranged from 0.06 µg/mL to 8 µg/mL, with an MIC50 of 2 µg/mL and MIC90 of 4 µg/mL. The lowest MICs were found among N. paucivorans (MIC50 = 0.25 µg/mL, MIC90 = 0.25 µg/mL), N. asiatica (MIC50 = 0.25 µg/mL, MIC90 = 1 µg/mL), N. abscessus complex (MIC50 = 0.5 µg/mL, MIC90 = 1 µg/mL), N. beijingensis (MIC50 = 0.5 µg/mL, MIC90 = 2 µg/mL), and N. otitidiscaviarum (MIC50 = 1 µg/mL, MIC90 = 2 µg/mL). The highest MICs were found among N. farcinica (MIC50 = 4 µg/mL, MIC90 = 8 µg/mL). In vitro potency differed by species among Nocardia clinical isolates. Further studies are warranted to evaluate the potential clinical utility of omadacycline for nocardiosis.

Switching from intravenous vancomycin to oral antibiotics reduces adverse events in a retrospective cohort of outpatients with orthopedic infections.

INTRODUCTION: Vancomycin is frequently used for prolonged courses in treating osteoarticular infections despite a high rate of adverse drug events (ADE). The objective of this study was to evaluate the safety and effectiveness of transitioning to oral therapy compared to continuing parenteral vancomycin in patients with orthopedic infections. METHODS: We conducted a single-center, retrospective cohort study of patients with orthopedic infections discharged on parenteral vancomycin with a planned duration of at least 4 weeks. We compared rates of ADE while on vancomycin to rates of ADE after switching to an oral regimen. As a secondary analysis, we compared unplanned hospital readmission within 60 days and treatment failure at 1 year between patients who were transitioned to oral antibiotics within 4 weeks of vancomycin initiation and those that were not. RESULTS: Two hundred twenty-eight patients met the inclusion criteria. Vancomycin was associated with significantly greater toxicity compared to oral regimens. Fifty-one patients had an adverse event while on vancomycin (5.87 ADE per 1000 patient-days) while 9 patients had an adverse event on oral therapy (1.49 ADE per 1000 patient-days) (Rate difference 4.39 per 1000 patient days, 95% CI: 2.52 to 6.26 events per 1000 patient-days). In proportional hazards analysis, transition to an oral antibiotic regimen was independently associated with a lower rate of ADE (aHR 0.12, 95% CI: 0.02-0.86). Forty-one patients (18%) were transitioned to oral therapy within 4 weeks; these patients did not have an increased rate of unplanned readmission (12.2% vs 17.1%) or treatment failure (17.1% vs 21.9%). CONCLUSIONS: Patients transitioned to oral therapy within 4 weeks of discharge had significantly fewer adverse events and similar incidences of 1-year treatment failure compared to patients maintained on parenteral vancomycin. Substituting oral antibiotics for parenteral vancomycin is a potential strategy to minimize vancomycin toxicity during the treatment of orthopedic infections.

Patient safety outcomes for continuous infusion vancomycin as outpatient parenteral antimicrobial therapy.

BACKGROUND: Administration of vancomycin as a continuous infusion has been associated with reduced nephrotoxicity. Given limited published experience with continuous infusion vancomycin in outpatient parenteral antimicrobial therapy (OPAT) programs, we reviewed outcomes from our center. METHODS: This was a retrospective, single-center study of adult patients receiving vancomycin OPAT as continuous or intermittent infusion for an intended treatment duration of at least 7 days. The primary outcome was time to nephrotoxicity with continuous versus intermittent infusion vancomycin while on OPAT; additional outcomes included time to any vancomycin-associated adverse event, time to 60-day death or readmission, and time to 60-day emergency department encounter. Proportional hazards modeling was used to identify variables independently associated with outcomes, as well as assess the strength of association of continuous infusion with each outcome. RESULTS: Four-hundred ninety-two patients were included: 118 treated with continuous and 374 with intermittent vancomycin infusion. Continuous infusion was not associated with lower rates of nephrotoxicity compared to intermittent infusion (adjusted hazard ratio (aHR) 0.72, 95% CI: 0.35-1.50). There were no advantages of continuous over intermittent infusion in the rates of any adverse event (aHR 0.93, 95% CI: 0.56-1.53), 60-day death or readmission (aHR 1.04, 95% CI: 0.68-1.61), or 60-day emergency department encounter (aHR 1.17, 95% CI: 0.68-1.99). Vancomycin area under the concentration-time curve (AUC) at discharge was the only modifiable factor identified that was independently associated with patient safety outcomes. CONCLUSION: There was no appreciable benefit of continuous infusion vancomycin on outpatient safety outcomes. AUC-centered dosing approaches warrant further investigation as strategies to improve vancomycin safety in OPAT programs.

A Quality Initiative to Improve Postdischarge Care for Patients on Outpatient Parenteral Antimicrobial Therapy.

Background: Patients discharged from the hospital on outpatient parenteral antimicrobial therapy (OPAT) require close monitoring, including weekly blood tests and an early posthospital follow-up visit. However, because patients often receive OPAT in a separate healthcare system from where they received inpatient care, the OPAT plan often fails, with less than 75% of OPAT patients receiving the recommended laboratory monitoring. We sought to determine whether changing our inpatient OPAT documentation method would improve postdischarge care. Methods: As a quality improvement initiative, we conducted 2 Plan-Do-Study-Act interventions on our OPAT documentation. Our first intervention was to create a standardized OPAT Progress Note, and our second was to turn that note into a SmartForm (Epic) with discrete fields for the key information. We examined the effects of these changes on the rate of completion of recommended laboratory monitoring, attendance at outpatient follow-up visits, and 30-day readmission rates. Results: Changing our documentation to a standardized Progress Note and then to a SmartForm with discrete fields led to an increase in the proportion of patients with a serum creatinine checked within 10 days of discharge (from 63% to 71% to 73%) and who attended an infectious disease clinic visit within 3 weeks of discharge (from 21% to 36% to 47%). However, the rate of readmissions for OPAT-related problems did not change, nor did a composite outcome of 30-day mortality/unplanned readmission. Conclusions: Changes in how and where care plans are documented in the inpatient medical record can have significant effects on patient care outcomes after discharge.

A Pathway for Community-Acquired Pneumonia With Rapid Conversion to Oral Therapy Improves Health Care Value.

BACKGROUND: Evidence supports streamlined approaches for inpatients with community-acquired pneumonia (CAP) including early transition to oral antibiotics and shorter therapy. Uptake of these approaches is variable, and the best approaches to local implementation of infection-specific guidelines are unknown. Our objective was to evaluate the impact of a clinical decision support (CDS) tool linked with a clinical pathway on CAP care. METHODS: This is a retrospective, observational pre-post intervention study of inpatients with pneumonia admitted to a single academic medical center. Interventions were introduced in 3 sequential 6-month phases; Phase 1: education alone; Phase 2: education and a CDS-driven CAP pathway coupled with active antimicrobial stewardship and provider feedback; and Phase 3: education and a CDS-driven CAP pathway without active stewardship. The 12 months preceding the intervention were used as a baseline. Primary outcomes were length of intravenous antibiotic therapy and total length of antibiotic therapy. Clinical, process, and cost outcomes were also measured. RESULTS: The study included 1021 visits. Phase 2 was associated with significantly lower length of intravenous and total antibiotic therapy, higher procalcitonin lab utilization, and a 20% cost reduction compared with baseline. Phase 3 was associated with significantly lower length of intravenous antibiotic therapy and higher procalcitonin lab utilization compared with baseline. CONCLUSIONS: A CDS-driven CAP pathway supplemented by active antimicrobial stewardship review led to the most robust improvements in antibiotic use and decreased costs with similar clinical outcomes.

Obesity is not strongly associated with increased risk for febrile neutropenia during levofloxacin prophylaxis in patients with hematological malignancies receiving intermediate-risk myelosuppressive chemotherapy.

Levofloxacin given at a standard dose of 500 mg daily is recommended for antibacterial prophylaxis in patients receiving myelosuppressive chemotherapy. Obese patients have been shown to exhibit enhanced clearance of levofloxacin and may be at risk for prophylactic failure. This single center, retrospective cohort study from June 2014 to May 2017 evaluated adult patients with estimated creatinine clearance ≥50 mL/min receiving their first cycle of a National Comprehensive Cancer Network defined intermediate-risk regimen. Primary endpoint was incidence of febrile neutropenia. Secondary endpoints included 30-day mortality and the correlation between estimated levofloxacin area under the concentration-time curve and rates of febrile neutropenia. Febrile neutropenia occurred in 26 patients: 12 (35.3%) obese and 14 (21.9%) non-obese (P = 0.16). Six (23.1%) of these patients required intensive care, but there were no deaths within 30 days of a febrile neutropenia event. Estimated creatinine clearance was similar between obese and non-obese patients (median 97.5 vs. 91.8 mL/min, P = 0.39), as was estimated levofloxacin area under the concentration-time curve (median 85.6 vs. 90.8 mg×h/L, P = 0.39). There were no significant associations between body weight-related variables - total body weight (median 83.4 vs. 80.6 kg, P = 0.51), body mass index (mean 29.6 vs. 26.8 kg/m2, P = 0.35), or body surface area (1.98 vs. 1.99 m2, P = 0.68) - and febrile neutropenia in this cohort of patients with similar renal function. Obesity should not be a justification for more aggressive levofloxacin dosing schemes when used for febrile neutropenia prophylaxis.

Impact of a Multiplex PCR Assay for Bloodstream Infections With and Without Antimicrobial Stewardship Intervention at a Cancer Hospital.

Implementation of Biofire FilmArray Blood Culture Identification Multiplex PCR panel (BCID) at a cancer hospital was associated with reduced time to appropriate antimicrobial therapy. Additional reductions were not observed when BCID was coupled with antimicrobial stewardship intervention.

Potentially Serious Drug Interactions Resulting From the Pretravel Health Encounter.

Travelers seen for pretravel health encounters are frequently prescribed new travel-related medications, which may interact with their previously prescribed medications. In a cohort of 76 324 travelers seen at 23 US clinics, we found that 2650 (3.5%) travelers were prescribed travel-related medications with potential for serious drug interactions.

Comparison of the Drug-Drug Interaction Potential of Daptomycin in Combination with Rifampin in Healthy Adult Volunteers.

We evaluated the effects of rifampin coadministration and MDR1 single nucleotide polymorphisms on the disposition of daptomycin in twelve healthy adults. There were no significant changes from baseline in the clearance (0.53 versus 0.55 liters/h, P = 1.00), volume of distribution (7.0 versus 7.2 liter, P = 0.62), or half-life (9.7 versus 9.6 h, P = 0.89) of daptomycin after exposure to rifampin. The tested MDR1 polymorphisms were not associated with significant differences in daptomycin disposition.

Patient Variables Associated with Nafcillin Plasma Concentrations and Toxicity.

PRIMARY OBJECTIVE: To retrospectively review nafcillin plasma concentrations (CNAF ) and determine nafcillin clearance (CLNAF ) in a diverse sample of patients treated with nafcillin administered as a continuous infusion. SECONDARY OBJECTIVE: To identify clinical variables associated with CLNAF and nafcillin-related adverse drug reactions (ADRs). METHODS: Retrospective chart review of patients receiving nafcillin via continuous infusion at University of Utah Health Care from 2006 to 2013 who had at least one steady-state CNAF measured. CLNAF was determined by dividing the nafcillin rate of infusion by CNAF . Adverse drug reactions (ADRs) were defined using the National Institutes of Health, Division of Microbiology and Infectious Diseases criteria and scored for probability of association with nafcillin by using Naranjo criteria. Multivariate models were constructed to identify independent variables associated with CLNAF and ADRs. MAIN RESULTS: Seventy-six CNAF from 54 patients were included. Median CLNAF was 13.9 L/hour (range ≤ 4.2 to 36.9 L/hr). Congestive heart failure (p=0.007), hyperbilirubinemia (p<0.0001), and serum creatinine (p<0.0001) were associated with reduced CLNAF , and Hispanic race (p=0.002) was associated with increased CLNAF by multivariate analysis. Twenty patients (37.0%) experienced an ADR. CNAF were significantly higher between patients that experienced an ADR and those that did not (66.0 vs 25.5 mg/L, p<0.001). Individual ADRs associated with CNAF included hepatotoxicity (62.8 vs 27.0 mg/L, p=0.001), nausea/vomiting (80.0 vs 28.5 mg/L, p=0.01), and diarrhea (66.5 vs 26.5 mg/L, p<0.001). Multivariate analysis identified CNAF as being independently associated with ADRs. A putative toxicity relationship between CNAF and predicted probability of ADR was established. CONCLUSIONS: Several patient variables were associated with impaired CLNAF , and elevated CNAF were associated with ADRs. Additional studies assessing the utility of nafcillin therapeutic drug monitoring to minimize toxicity are warranted.

Utilization of posaconazole oral suspension or delayed-released tablet salvage treatment for invasive fungal infection.

Posaconazole may be useful for salvage treatment (ST) for invasive fungal infections (IFIs). The aim of this study was to evaluate the efficacy of posaconazole ST with either posaconazole oral suspension (SUS) or delayed-released tablet (TAB) in patients with IFI. A retrospective review of patients who received posaconazole ST for IFI at the University of Utah Health Sciences Center between December 2007 and March 2014 was conducted. A total of 14 episodes of posaconazole ST for proven (9 episodes) and probable (5 episodes) IFI were identified in 14 patients. The median age was 54 years and the majority of patients (64.3%) had underlying haematological diseases. Posaconazole SUS and TAB were used in 11 episodes and 3 episodes respectively. The duration of posaconazole ST ranged from 28 to 370 days with a median of 65 days. Posaconazole ST with TAB achieved favourable serum posaconazole trough concentrations (median 1.4 µg mL-1 ) compared to posaconazole SUS (median 1.0 µg mL-1 ). The overall clinical success rate with posaconazole ST was 71.4% (10 of 14 episodes). One patient died of progression of IFI. Adverse events were noted in two patients. Posaconazole SUS or TAB may be used effectively for IFI ST.

Risk of Fungal Endophthalmitis Associated with Cataract Surgery: A Mini-Review.

Fungal endophthalmitis is a rare complication after cataract surgery and is associated with significant morbidity including vision loss. The common causative fungal pathogens implicated in fungal endophthalmitis after cataract surgery include Candida species (spp.) and molds such as Aspergillus spp. and Fusarium spp. Early diagnosis and effective antifungal treatment after a high index of clinical suspicion are required to reduce unfavorable complications and to preserve eye function. This review discusses epidemiology, pathogenesis, clinical features, diagnosis, management, and outcomes associated with fungal endophthalmitis after cataract surgery.

An international, multicentre survey of ß-lactam antibiotic therapeutic drug monitoring practice in intensive care units.

OBJECTIVES: Emerging evidence supports the use of therapeutic drug monitoring (TDM) of ß-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for ß-lactam TDM in ICUs. METHODS: A questionnaire survey was developed to describe various aspects relating to the conduct of ß-lactam TDM in an ICU setting. Data sought included: ß-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. RESULTS: Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the ß-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of ß-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT>MIC up to 100% fT>4×MIC) and dose adjustment strategies used by each of the sites. CONCLUSIONS: Large variations were found in the type of ß-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing ß-lactam dosing with TDM.

A multicenter evaluation of the safety of drotrecogin alfa (activated) in patients with baseline bleeding precautions.

PURPOSE: We recently reported an increased incidence of serious bleeding events and mortality in patients with baseline bleeding precautions treated with drotrecogin alfa (activated) compared to patients without such precautions. Whether these observations were specific to our single medical campus is unclear. METHODS: All patients who received drotrecogin alfa (activated) for the treatment of severe sepsis from January 2006 through September 2009 within the South Central Veterans Affairs Health Care Network were retrospectively reviewed using a regional clinical database. Demographic information, bleeding precautions that were exclusion criteria of the PROWESS trial, and 30-day post-discharge incidences of serious bleeding events and mortality were collected. RESULTS: Seventy-nine patients from 5 medical centers were included. Serious bleeding events occurred in 4 of 24 patients (16.7%) with any bleeding precaution vs 1 of 55 patients (1.8%) without a bleeding precaution (P=0.03). All patients (5) who experienced a serious bleeding event died compared to 39 of 74 patients (52.7%) who did not (P=0.06). Seventeen of 24 patients (70.8%) with bleeding precautions died vs 27 of 55 patients (49.1%) without bleeding precautions (P=0.07). The number of serious bleeding events did not allow meaningful multivariate analyses. The mean number of failing organs was an independent predictor of 30-day post-discharge mortality (OR 1.63 for each organ failed, 95% CI 1.05- 2.6). CONCLUSIONS: The findings of this study were consistent with our prior observations and suggest the risk for serious bleeding events with drotrecogin alfa (activated) may outweigh any potential benefit in patients with baseline bleeding precautions.

Alpha2-receptor agonists for treatment and prevention of iatrogenic opioid abstinence syndrome in critically ill patients.

OBJECTIVE: To review the literature regarding the use of alpha(2)-agonists in the treatment and prevention of iatrogenic opioid abstinence syndrome (IOAS) in critically ill patients. DATA SOURCES: Primary literature was identified through a search of MEDLINE (1950-June 2009), EMBASE (1988-June 2009), International Pharmaceutical Abstracts (1970-June 2009), and the Cochrane Library (1996-June 2009), using the names of individual alpha(2)-agonists and the following key words: children, opioid withdrawal, opioid, and adult. Relevant abstracts from the Society of Critical Care Medicine, reference citations from selected articles, and manufacturers' product information were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. Three retrospective studies and 6 case reports/series representing 44 patients were included for analysis. DATA SYNTHESIS: Central alpha(2)-agonists are thought to minimize symptoms of IOAS by decreasing presynaptic outflow of catecholamines. Successful use of clonidine and dexmedetomidine for management of IOAS has been reported. Lofexidine, an alpha(2)-agonist not yet approved in the US, may offer similar withdrawal symptom relief but has yet to be studied in the intensive care setting. Although the quality of studies identified was limited, preliminary evidence does provide some support for the use of transdermal clonidine and injectable dexmedetomidine in the treatment and prevention of IOAS. These agents were shown to facilitate discontinuation of opioids and to minimize withdrawal symptoms with few reported adverse events. CONCLUSIONS: Central alpha(2)-agonists appear to be effective and safe second-line agents for treatment and prevention of IOAS. Further studies should be conducted to determine their role in the therapy of patients with IOAS.