Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Prevalence and risk factors associated with readmission with acute kidney injury in patients receiving vancomycin outpatient parenteral antimicrobial therapy.

INTRODUCTION: Vancomycin is commonly used during outpatient parenteral antimicrobial therapy (OPAT). Therapeutic drug monitoring (TDM) of vancomycin is recommended to ensure effective and safe therapy, as use has been associated with acute kidney injury (AKI). METHODS: The MarketScan® Commercial Database was queried from 2010 to 2016 to identify patients aged 18-64 years discharged from an inpatient hospitalization on vancomycin OPAT. The primary endpoint was hospital readmission with AKI within 6 weeks of index hospital discharge. TDM was defined as at least one vancomycin level obtained during outpatient therapy. Bivariate analysis was used to examine associations with outcomes; significant factors were incorporated into a multivariable logistic regression model. RESULTS: A total of 14,196 patients were included in the study; median age was 54 years and 53.8% were male. Readmission with AKI occurred in 385 (2.7%) and was independently associated with chronic kidney disease (aOR 2.63 [95%CI 1.96-3.52]), congestive heart failure (1.81 [1.34-2.44]), chronic liver disease (1.74 [1.17-2.59]), hypertension (1.73 [1.39-2.17]), septicemia (1.61 [1.30-2.00]), and concomitant OPAT with IV penicillins (1.73 [1.21-2.49]) while skin and soft tissue infection (0.67 [0.54-0.83]) and surgical site infection (0.74 [0.59-0.93]) were associated with lower risk of readmission with AKI. TDM was not associated with lower risk of readmission with AKI. CONCLUSION: Chronic kidney disease, congestive heart failure, hypertension, chronic liver disease, septicemia, and concomitant OPAT with IV penicillins were significantly associated with higher risk of readmission with AKI during vancomycin OPAT.

Experience with Liposomal Amphotericin B in Outpatient Parenteral Antimicrobial Therapy.

Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The most common doses of L-AMB were 3 mg/kg (n = 16, 38%) or 5 mg/kg (n = 14, 33%) based on actual body weight. Twenty-six (62%) patients completed their anticipated course of L-AMB. Twenty-two (52%) patients were readmitted within 30 days of discharge; median time to readmission was 11 days (interquartile range [IQR] 5 to 18). While hypokalemia and acute kidney injury (AKI) were common, occurring in 26 (62%) and 20 (48%) patients, respectively, only 5 (12%) were readmitted to the hospital due to L-AMB-associated AEs. Ninety percent of patients achieved at least partial renal recovery within 30 days after L-AMB discontinuation. Factors significantly associated with AKI include higher L-AMB dose, lower serum potassium levels after therapy initiation, and receipt of potassium supplementation at discharge. L-AMB is associated with significant AEs; however, these results suggest that treatment is feasible in the outpatient setting with close monitoring, as the majority of AEs were managed effectively in an outpatient without long-term sequelae.

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with fub). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.

The role of chronic suppressive antibiotics therapy in superficial drive line infection relapse of left ventricular assist devices: A retrospective cohort from a tertiary care center.

INTRODUCTION: Drive line infections (DLIs) are common complications of left ventricular assist devices (LVADs). Data on use of suppression antibiotic therapy are limited. METHODS: We performed a retrospective review of 451 patients who underwent LVAD placement from January 2009 to May 2015. First superficial DLIs were included for analysis. We examined factors associated with the use of chronic suppressive antibiotics (CSAs) therapy. Cox proportional hazards models were performed to identify factors associated with DLI relapse with the same organism as the initial DLI. RESULTS: A total of 69 patients developed a superficial DLI within a median of 195 (interquartile range [IQR] 98-348) days of LVAD insertion. The median age was 57 years, 87% were males, and 74% were White. Gram positive bacteria caused 61% of infections, with Staphylococcus aureus being the most common (35%). Forty-three (62%) patients received suppressive antibiotic therapy. Relapse DLI occurred in 29 (42%) patients. Independent risk factors for relapse infection in multivariable analysis were sepsis (aHR 5.94 [CI 1.42-24.92]), and MRSA DLI (aHR 4.19 [CI 1.37-12.79]). There was no difference in the proportion of patients with relapse among those who were treated with antibiotic suppression therapy versus not (44% vs. 38%, p = 0.64), although relapse occurred at a later time in those who received suppression (185 vs. 69 days, p < 0.01). CONCLUSION: CSA therapy was associated with delayed time to DLI relapse but no significant difference in the proportion of patients with relapse. A prospective study is needed to examine the effect of suppression on relapse rates.

A Cluster of Cefepime-induced Neutropenia During Outpatient Parenteral Antimicrobial Therapy.

A cluster of cefepime-induced neutropenia (CIN) was identified from June 2017 to May 2018 in a regional outpatient parenteral antimicrobial therapy population. Our data suggest prolonged courses of cefepime (≥2 weeks), administered by rapid intravenous push, were associated with a higher risk of CIN.

Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services' SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the "all-or-nothing" measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. DESIGN: Retrospective cohort study. SETTING: Seven U.S. hospitals. PATIENTS: Adult patients included in SEP-1 reporting between October 2015 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19-2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85-2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04-3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70-1.72; p = 0.674). CONCLUSIONS: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Outcomes of Ceftriaxone Compared With Cefazolin or Nafcillin/Oxacillin for Outpatient Therapy for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infections: Results From a Large United States Claims Database.

Background: Ceftriaxone is a convenient option for methicillin-sensitive Staphylococcus aureus (MSSA) outpatient parenteral antimicrobial therapy (OPAT), but population-based studies for its effectiveness are lacking. Methods: In this retrospective cohort, a large insurance claims database was queried from 2010 to 2018 for adults with MSSA bloodstream infection (BSI). Patients discharged on OPAT on cefazolin or oxacillin/nafcillin were compared with ceftriaxone with respect to 90-day hospital readmission with the same infection category and 90-day all-cause readmission using logistic regression models. Results: Of 1895 patients with MSSA BSI, 1435 (75.7%) patients received cefazolin, oxacillin, or nafcillin and 460 (24.3%) ceftriaxone. Readmission due to the same infection category occurred in 366 (19.3%), and all-cause readmission occurred in 535 (28.3%) within 90 days. Risk factors significantly associated with readmission with the same infection category were the oldest sampled age group (61-64 years: adjusted odds ratio [aOR], 1.47 [95% confidence interval {CI}, 1.01-2.14]), intensive care unit stay during index admission (aOR, 2.33 [95% CI, 1.81-3.01]), prosthetic joint infection (aOR, 1.96 [95% CI, 1.18-2.23]), central line-associated BSI (aOR, 1.72 [95% CI, 1.33-2.94]), and endocarditis (aOR, 1.63 [95% CI, 1.18-2.23]). Ceftriaxone was not associated with increased risk of readmission with the same infection category (aOR, 0.89 [95% CI, .67-1.18]), or 90-day all-cause readmission (aOR, 0.86 [95% CI, .66-1.10]) when compared with oxacillin/nafcillin/cefazolin. Conclusions: In this cohort of MSSA BSI patients discharged on OPAT, there were no differences in outcomes of readmission with the same infection and 90-day all-cause readmission in patients treated with ceftriaxone compared to oxacillin/nafcillin or cefazolin. Patients with complicated BSIs such as endocarditis and epidural abscess were more likely to be prescribed cefazolin or oxacillin/nafcillin.

Outcomes of Outpatient Parenteral Antimicrobial Therapy With Ceftriaxone for Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections-A Single-Center Observational Study.

BACKGROUND: Staphylococcus aureus bloodstream infections (BSIs) are associated with significant morbidity and mortality. Ceftriaxone is convenient for outpatient parenteral antimicrobial therapy (OPAT), but data for this indication are limited. METHODS: Adult patients with methicillin-susceptible Staphylococcus aureus (MSSA) BSI discharged on OPAT with cefazolin, oxacillin, or ceftriaxone for at least 7 days were included. We compared outcomes of ceftriaxone vs either oxacillin or cefazolin. Ninety-day all-cause mortality, readmission due to MSSA infection, and microbiological failure were examined as a composite outcome and compared among groups. Rates of antibiotic switches due to intolerance were assessed. RESULTS: Of 243 patients included, 148 (61%) were discharged on ceftriaxone and 95 (39%) were discharged on either oxacillin or cefazolin. The ceftriaxone group had lower rates of intensive care unit care, endocarditis, and shorter duration of bacteremia, but higher rates of cancer diagnoses. There was no significant difference in the composite adverse outcome in the oxacillin or cefazolin group vs the ceftriaxone group (18 [19%] vs 31 [21%]; P = .70), comprising microbiological failure (6 [6.3%] vs 9 [6.1%]; P = .94), 90-day all-cause mortality (7 [7.4%] vs 15 [10.1%]; P = .46), and readmission due to MSSA infection (10 [10.5%] vs 13 [8.8%]; P = .65). Antibiotic intolerance necessitating a change was similar between the 2 groups (4 [4.2%] vs 6 [4.1%]; P = .95). CONCLUSIONS: For patients with MSSA BSI discharged on OPAT, within the limitations of the small numbers and retrospective design we did not find a significant difference in outcomes for ceftriaxone therapy when compared with oxacillin or cefazolin therapy.

Perspectives of Patients on Outpatient Parenteral Antimicrobial Therapy: Experiences and Adherence.

BACKGROUND: Nonadherence to medication is a burden to the US health care system and is associated with poor clinical outcomes. Data on outpatient parenteral antimicrobial therapy (OPAT) treatment plan adherence are lacking. The purpose of this study is to determine the rate of nonadherence and factors associated with it. METHODS: We surveyed patients discharged from a tertiary hospital on OPAT between February and August 2019 about their baseline characteristics, OPAT regimen, adherence, and experience with OPAT. RESULTS: Sixty-five patients responded to the survey. The median age was 62 years, and 56% were male. The rate of reported nonadherence to intravenous (IV) antibiotics was 10%. Factors associated with nonadherence to IV antibiotics included younger age, household income of <$20 000, and lack of time for administering IV antibiotics (30 vs 64 years, P < .01; 83% vs 20%, P < .01, and 33% vs 4%, P = .04, in the nonadherent vs adherent groups, respectively), while less frequent administration (once or twice daily) and having friend or family support during IV antibiotic administration were associated with better adherence (17% vs 76%, P < .01, and 17% vs 66%, P = .03, in the nonadherent vs adherent groups, respectively). Most patients attended their infectious diseases clinic visits (n = 44, 71%), and the most commonly cited reasons for missing an appointment were lacking transportation (n = 12, 60%), not feeling well (n = 8, 40%), and being unaware of the appointment (n = 6, 30%). CONCLUSIONS: Less frequent antibiotic dosing and better social support were associated with improved adherence to OPAT. In contrast, younger age, lower income, and lack of time were associated with nonadherence.

Perspectives of United States-based Infectious Diseases Physicians on Outpatient Parenteral Antimicrobial Therapy Practice.

BACKGROUND: While outpatient parenteral antimicrobial therapy (OPAT) is generally considered safe, patients are at risk for complications and thus require close monitoring. The purpose of this study is to determine how OPAT programs are structured and how United States-based infectious diseases (ID) physicians perceive barriers to safe OPAT care. METHODS: We queried members of the Emerging Infections Network (EIN) between November and December 2018 about practice patterns and barriers to providing OPAT. RESULTS: 672 members of the EIN (50%) responded to the survey. Seventy-five percent of respondents were actively involved in OPAT, although only 37% of respondents reported ID consultation was mandatory for OPAT. The most common location for OPAT care was at home with home-health support, followed by post-acute-care facilities. Outpatient and inpatient ID physicians were identified as being responsible for monitoring laboratory results (73% and 54% of respondents, respectively), but only 36% had a formal OPAT program. The majority of respondents reported a lack of support in data analysis (80%), information technology (66%), financial assistance (65%), and administrative assistance (60%). Perceived amount of support did not differ significantly across employment models. Inability to access laboratory results in a timely manner, lack of leadership awareness of OPAT value, and failure to communicate with other providers administering OPAT were reported as the most challenging aspects of OPAT care. CONCLUSION: ID providers are highly involved in OPAT, but only a third of respondents have a dedicated OPAT program. Lack of financial and institutional support are perceived as significant barriers to providing safe OPAT care.

Outcomes in Lung Transplant Recipients With Mycobacterium abscessus Infection: A 15-Year Experience From a Large Tertiary Care Center.

BACKGROUND: Mycobacterium abscessus (M abscessus) infection is a serious complication post-lung transplant (LTx). We examined determinants of outcomes in LTx recipients infected with M abscessus. METHODS: Electronic records of all patients who underwent LTx in a single transplant center between 2000 and 2015 were screened for isolation of M abscessus before or after LTx. RESULTS: Twenty-six cases of M abscessus isolation were identified. Twenty-four had M abscessus isolation post-LTx. Two had M abscessus isolated from a surgical site, while the others were pulmonary isolates. Out of these 22 with pulmonary isolates, 12 had clinical disease. In 73% of patients, treatment had to be temporarily held or switched due to intolerance and toxicity. There was a statistically significant worsening in survival in those who developed clinical disease compared to matched controls. Among the 12 patients with clinical pulmonary disease, use of clofazimine was significantly associated with a favorable outcome. Six patients had M abscessus isolation pretransplant. Four developed M abscessus recurrence at a median of 2 months post-LTx. Two recurrences were surgical site infections, and 2 were pulmonary infections. CONCLUSION: M abscessus infection is difficult to treat as tolerance to medications used is poor. M abscessus pneumonia is associated with worse survival post-LTx. Use of clofazimine is associated with 1-year infection-free survival.

Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals.

Importance: Sepsis is present in many hospitalizations that culminate in death. The contribution of sepsis to these deaths, and the extent to which they are preventable, is unknown. Objective: To estimate the prevalence, underlying causes, and preventability of sepsis-associated mortality in acute care hospitals. Design, Setting, and Participants: Cohort study in which a retrospective medical record review was conducted of 568 randomly selected adults admitted to 6 US academic and community hospitals from January 1, 2014, to December 31, 2015, who died in the hospital or were discharged to hospice and not readmitted. Medical records were reviewed from January 1, 2017, to March 31, 2018. Main Outcomes and Measures: Clinicians reviewed cases for sepsis during hospitalization using Sepsis-3 criteria, hospice-qualifying criteria on admission, immediate and underlying causes of death, and suboptimal sepsis-related care such as inappropriate or delayed antibiotics, inadequate source control, or other medical errors. The preventability of each sepsis-associated death was rated on a 6-point Likert scale. Results: The study cohort included 568 patients (289 [50.9%] men; mean [SD] age, 70.5 [16.1] years) who died in the hospital or were discharged to hospice. Sepsis was present in 300 hospitalizations (52.8%; 95% CI, 48.6%-57.0%) and was the immediate cause of death in 198 cases (34.9%; 95% CI, 30.9%-38.9%). The next most common immediate causes of death were progressive cancer (92 [16.2%]) and heart failure (39 [6.9%]). The most common underlying causes of death in patients with sepsis were solid cancer (63 of 300 [21.0%]), chronic heart disease (46 of 300 [15.3%]), hematologic cancer (31 of 300 [10.3%]), dementia (29 of 300 [9.7%]), and chronic lung disease (27 of 300 [9.0%]). Hospice-qualifying conditions were present on admission in 121 of 300 sepsis-associated deaths (40.3%; 95% CI 34.7%-46.1%), most commonly end-stage cancer. Suboptimal care, most commonly delays in antibiotics, was identified in 68 of 300 sepsis-associated deaths (22.7%). However, only 11 sepsis-associated deaths (3.7%) were judged definitely or moderately likely preventable; another 25 sepsis-associated deaths (8.3%) were considered possibly preventable. Conclusions and Relevance: In this cohort from 6 US hospitals, sepsis was the most common immediate cause of death. However, most underlying causes of death were related to severe chronic comorbidities and most sepsis-associated deaths were unlikely to be preventable through better hospital-based care. Further innovations in the prevention and care of underlying conditions may be necessary before a major reduction in sepsis-associated deaths can be achieved.

Variability in determining sepsis time zero and bundle compliance rates for the centers for medicare and medicaid services SEP-1 measure.

We compared sepsis "time zero" and Centers for Medicare and Medicaid Services (CMS) SEP-1 pass rates among 3 abstractors in 3 hospitals. Abstractors agreed on time zero in 29 of 80 (36%) cases. Perceived pass rates ranged from 9 of 80 cases (11%) to 19 of 80 cases (23%). Variability in time zero and perceived pass rates limits the utility of SEP-1 for measuring quality.