Step-down [BEST]

Patients in the exposed group (ie, those whose treatment was converted to oral therapy; hereafter referred to as the oral step-down group) had to be transitioned from IV to oral therapy by day 5 of therapy (Figure 1). Day 1 was defined as the first day of in vitro active antibiotic therapy, and antibiotics had to be administered within 24 hours of the time that the first positive blood culture was collected. Because data suggest that 7 days of antibiotics may be sufficient treatment for uncomplicated gram-negative bacteremia,10 transitioning to oral therapy on day 7 or later may not be meaningful because it is possible that sufficient antibiotic therapy was already administered. Therefore, 5 days was selected as the cut-off for the transition to oral step-down therapy for patients to be included in the oral step-down group. Patients for whom oral antibiotic therapy was initiated on day 1 of bacteremia and those who transitioned to oral therapy after day 5 of therapy were excluded from the study.

step-down

Patients were excluded if they met any of the following criteria: at least 1 in vitro active antibiotic was not initiated within 24 hours of initial collection of a blood sample for culture; receipt of fewer than 7 or more than 16 days of total antibiotic therapy, because durations greater than 16 days generally imply a complicated infection in which source control may not have been obtained (ie, osteomyelitis, endocarditis or endovascular infection, and meningitis); the bacteria recovered were not susceptible to the prescribed antibiotic regimen for the full duration of therapy (ie, day 1 until completion of therapy regardless of route of administration); receipt of a second in vitro active agent beyond 5 days (eg, for the oral step-down group, transitioning cefepime hydrochloride to oral ciprofloxacin but the continuation of gentamicin sulfate); or death within the first 5 days of treatment, because this may have precluded the opportunity to convert to oral therapy.

Propensity scores were calculated using a multivariable logistic regression model in which the dependent variable was a binary indicator of receipt of oral step-down therapy within the first 5 days (the exposed group). Covariates included in generating the propensity score included age, race/ethnicity, preexisting medical conditions (each included separately: end-stage liver disease, end-stage renal disease requiring dialysis, structural lung disease, congestive heart failure with an ejection fraction of

Patient and microbial characteristics of the 2161 patients meeting eligibility criteria are presented in Table 1. There were several notable differences between the 2 groups. Patients who were transitioned to oral step-down therapy were less likely than patients who continued to receive IV therapy to be severely neutropenic (59 patients [6.7%] vs 181 patients [14.1%]) or have received a hematopoietic stem cell transplant in the previous 12 months (30 patients [3.4%] vs 97 patients [7.5%]). Moreover, patients in the oral step-down group were less likely to be severely ill at the onset of their bloodstream infection; as they had a decreased likelihood of requiring care in an intensive care unit (161 patients [18.4%] vs 415 patients [32.3%]) and had lower median Pitt bacteremia scores on day 1 of antibiotic therapy (1 [IQR, 1-3] vs 2 [IQR, 2-4]) than patients who continued to receive IV therapy. Patients in the oral step-down group were less likely to receive combination antibiotic therapy (ie, addition of a fluoroquinolone or aminoglycoside) for greater than 48 hours (54 patients [6.2%] vs 154 patients [12.0%]). There were also differences in the likelihood of transitioning to oral step-down therapy based on the source of bacteremia. Patients with urinary tract sources for bacteremia were significantly more likely to be converted to oral step-down therapy (405 patients [46.2%] vs 383 patients [29.8%]), whereas patients with gastrointestinal tract (160 patients [18.3%] vs 290 patients [22.6%]), pulmonary (29 patients [3.3%] vs 117 patients [9.1%]), or catheter-associated (137 patients [15.6%] vs 282 patients [22.0%]) sources were more likely to continue to receive IV therapy.

One-to-one propensity-score matching yielded 1478 patients, with 739 in each study arm. Patient characteristics were well balanced between the 2 treatment groups (Table 1). Standardized biases for all variables were 0.05 or less (Figure 2). Patients received a median of 3 days (IQR, 2-4 days) of IV therapy in the oral step-down group and 14 days (IQR, 11-15 days) of IV therapy in the IV group.

To our knowledge, there have been no randomized clinical trials designed to specifically address the role of oral step-down therapy for the treatment of Enterobacteriaceae bacteremia. However, the effectiveness of early oral step-down therapy for Enterobacteriaceae bacteremia was previously investigated in an observational study conducted at the Medical University of South Carolina by Rieger and colleagues.3 These investigators limited their evaluation to patients with Enterobacteriaceae bloodstream infections from urinary tract sources. They compared proportions of treatment failure between 135 patients transitioned to oral step-down therapy (at a median of 4 days) vs 106 patients who continued to receive IV therapy. Owing to their relatively small sample size, the investigators were unable to adjust for the notable differences in severity of illness between the 2 groups. Although the proportion of treatment failure was similar between patients transitioned to oral step-down therapy and those continuing with IV therapy, as with our study, these investigators found that patients transitioned to oral step-down therapy were discharged from the hospital approximately 2 days earlier than those who continued to receive IV therapy.

We presumed that patients converted to oral fluoroquinolones or trimethoprim-sulfamethoxazole would be less likely to experience treatment failure than patients transitioned to oral β-lactam agents because of both the high bioavailability and the favorable pharmacokinetic and pharmacodynamic profile of the former agents.12,13 However, we found no differences in clinical outcomes between patients converted to high-bioavailability vs low-bioavailability agents. Others have found similar results. Kutob and colleagues16 conducted a retrospective cohort study including 362 patients with gram-negative bloodstream infection to define the role of the bioavailability of oral agents for the treatment of gram-negative bacteremia predominantly from urinary tract sources. As with our study, treatment failures were no different between patients receiving fluoroquinolones or trimethoprim-sulfamethoxazole and patients receiving oral β-lactams. Similarly, Mercuro and colleagues17 compared 140 adult patients at the Maine Medical Center receiving fluoroquinolones with 84 patients receiving oral β-lactams as step-down therapy for Enterobacteriaceae bacteremia and found no difference in clinical outcomes. Reported success with oral step-down therapy exceeded 85% in both of these studies, as well as in the study by Rieger and colleagues described above.3 We conducted a post hoc power calculation comparing 30-day mortality between the high-bioavailability and low-bioavailability groups in our cohort but had only 11% power to detect the difference that we observed with our study sample size. All studies to date, including ours, remain underpowered to determine whether the bioavailability of oral agents is less important for uncomplicated Enterobacteriaceae bacteremia after an appropriate clinical response has been observed and source control has been achieved. Therefore, it remains unclear whether no difference exists in clinical outcomes between high-bioavailability and low-bioavailability agents because we had insufficient power to detect a difference if one exists; after the bacterial burden is sufficiently reduced, the bioavailability of the agent becomes less important, or the duration of therapy typically prescribed for gram-negative bloodstream infection is simply too long.

Office of Mental Health Commissioner Dr. Ann Sullivan said, "This new step-down residential program will help people living with mental illness who had been homeless transition to safe and stable long-term housing. The program is an important transitional step between inpatient care and the independent living provided by supportive housing and other community-based housing options."

Individuals utilizing the new residential step-down programs will also receive assistance from other OMH-supported services, including the Safe Options Support teams, Assertive Community Treatment teams or Intensive Mobile Treatment teams. These teams also provide services and support to unhoused individuals living on the street, in transportation hubs, safe havens, drop-in centers and homeless shelters.

Meaning Oral step-down therapy appears to be a potential treatment approach for adults with Enterobacteriaceae bacteremia after the source is controlled and clinical improvement is observed.

Objective To compare the association of 30-day mortality with early oral step-down therapy vs continued parenteral therapy for the treatment of Enterobacteriaceae bloodstream infections.

Conclusions and Relevance In this study, 30-day mortality was not different among hospitalized patients who received oral step-down vs continued parenteral therapy for the treatment of Enterobacteriaceae bloodstream infections. The findings suggest that transitioning to oral step-down therapy may be an effective treatment approach for patients with Enterobacteriaceae bacteremia who have received source control and demonstrated an appropriate clinical response. Early transition to oral step-down therapy may be associated with a decrease in the duration of hospital stay for patients with Enterobacteriaceae bloodstream infections. 041b061a72