Variability in Oral Antibiotic Step-Down Therapy in the Management of Gram-Negative Bloodstream Infections

Abstract

Objectives.

There are important gaps in the literature regarding the role and timing of oral therapy for treatment of gram-negative bloodstream infections (GN-BSI). To better understand contemporary management practices involving oral step-down in GN-BSI, we conducted an international survey of infectious diseases (ID) specialists.

Methods.

We developed and disseminated an online survey to ID specialists to assess practice patterns involving oral step-down in GN-BSI, including providers from six continents and 28 countries. Chi square tests and generalized estimating equations were used to identify factors associated with oral step-down.

Results.

In total, 277 ID specialists completed the survey (64% physicians, 31% pharmacists). Relative to a line source, oral step-down was more common in abdominal (odds ratio [OR] 1.96; 95% CI 1.48–2.61; p<0.001), pneumonia (2.24; 1.67–2.99; p<0.001), skin (7.26; 4.71–11.20; p<0.001), and urinary (9.15; 5.73–14.60; p<0.001) sources of GN-BSI. U.S. providers were more likely to practice oral step-down than those outside the U.S. (OR 4.35; 95% CI 2.57–7.36; p<0.001). Forty percent of providers practice oral step-down for some, but not all, sources of GN-BSI. Among all providers, 23–53% (depending on GN-BSI source) recommend extended (≥5 days) IV therapy before oral step-down or ongoing IV therapy. Most respondents (76% of all providers; 80% of ID physicians) expressed interest in enrolling patients in a trial of full IV versus early oral step-down for GN-BSI.

Conclusions.

There is extensive heterogeneity in oral step-down practices for GN-BSI. The optimal role of oral step-down in managing GN-BSI is ripe for further investigation.

1. INTRODUCTION

Gram-negative bloodstream infections (GN-BSI) are common and associated with high morbidity and mortality [1–4]. Despite this, there is often little evidence to guide clinicians on key management decisions such as step-down from intravenous (IV) to oral antibiotics. No randomized controlled trials (RCTs) have compared the clinical outcomes of patients with GN-BSI remaining on IV therapy to those who transition to oral therapy, and existing evidence is limited to observational studies [5–9]. There are many potential benefits of treating GN-BSI with oral step-down therapy, including decreased length of hospital stay and decreased complications from a vascular catheter such as catheter occlusion, venous thrombosis, phlebitis, extravasation, and catheter-associated BSIs [10, 11]. RCTs that examine the safety and efficacy of oral step-down therapy are needed, though enrolling patients in such trials may be challenging due to concerns over equipoise in trial arms. For example, providers who typically practice oral step-down might be hesitant to have a peripherally inserted central catheter (PICC) placed in patients who are randomized to full IV therapy. In contrast, providers that typically prescribe a full course of IV therapy may believe insufficient data exists to justify transitioning to oral antibiotics. Through the development and dissemination of an international survey of infectious diseases (ID) specialists, we sought to describe contemporary practices surrounding the management of GN-BSI and to understand the residual heterogeneity in treatment recommendations.

2. METHODS

2.1. Survey development and content.

A 41-question multiple choice and open-ended question online survey was developed by the authors, with pilot and sensibility testing by ID physicians and pharmacists with expertise in managing GN-BSI. Participants were requested to enter demographic data (e.g., professional title, country of practice, years of experience). The majority of the survey questions focused on management decisions for each of five scenarios of GN-BSI: pneumonia, central line infection, urinary tract infection (UTI), intra-abdominal infection (IAI), and skin/soft tissue infection (SSTI). Survey questions focused on patients without severe immunocompromising conditions. For each source of GN-BSI, respondents answered the following general questions: (1) whether they typically transition to oral antibiotic therapy, (2) minimum duration of IV therapy prior to oral step-down therapy, and (3) factors influencing the decision to step-down to oral antibiotics (e.g., afebrile, normotensive, concern for poor oral absorption, normal WBC, bioavailability of oral agent, negative follow-up blood cultures, bacterial species, source control [central line infection and intra-abdominal infection only]). In addition, survey respondents were asked the following question: “Would you be willing to enroll your patients with gram-negative bacteremia in a trial of full IV treatment versus PO step down before 72 hours after index blood culture?” In a free text box, respondents were further asked to comment on barriers to enrolling patients in such a trial.

2.2. Survey distribution.

The survey was distributed by a link emailed to organizational listservs or message boards of international ID physicians and pharmacists. These organizations included the American College of Clinical Pharmacy, Antibacterial Resistance Leadership Group, Asia Pacific Foundation for Infectious Diseases, Australasian Society for Infectious Diseases, European Society of Clinical Microbiology and Infectious Diseases, Federation of Infectious Diseases in South Africa, Infectious Diseases Society of America, South African Society of Clinical Pharmacy, South African Society of Hospital Pharmacists, and Society of Hospital Pharmacists of Australia. The survey was opened on October 28, 2020 and closed on December 17, 2020. The survey link was emailed to potential respondents one time.

2.3. Definitions.

Extended IV therapy referred to IV therapy of ≥5 days. This included full courses of IV therapy and step-down to oral antibiotic therapy after 5 days of initial IV therapy.

2.4. Statistics.

Only respondents that completed the entire survey were included in the final analysis. Descriptive statistics included percentage for each response category, median, and interquartile range (IQR). Proportions were compared with chi-square tests. An adjusted model was employed to identify variables associated with the decision to step-down to oral antibiotics. Covariates included in this model were professional title, region of practice (United States [U.S.] versus outside US [ex-U.S.]), years of experience, and source of GN-BSI. In order to identify provider factors associated with oral step-down, a Generalized Estimating Equations (GEEs) model was used to account for clustering within respondents (given that each respondent provided recommendations for five different scenarios) [12, 13]. Independent variables in the GEE model included all collected provider demographics (position, experience, location of practice [i.e., U.S. vs. exU.S.) and BSI source. No independent variables were removed in the final model. The dependent variable in the GEE model was the decision to pursue oral step-down (as opposed to full IV therapy). An exchangeable correlation structure was specified. Statistical analyses were performed using GraphPad Prism version 9 (San Diego, CA, USA) and RStudio version 1.3.1073 (Boston, MA, USA).

3. RESULTS

3.1. Demographics of survey respondents.

The majority of respondents were ID physicians (176/277 [64%]) or ID pharmacists (86/277 [31%]) (SupplementalFigure 1). The location of respondents was as follows: North America (201/277 [73%]), Asia (36/277 [13%]), and Africa (19/277 [7%]). There was variability in the respondents’ years of experience since terminal degree (e.g., M.D., PharmD) as 104 (38%) had practiced as independent ID specialists for 1–10 years, 97 (35%) had practiced for 11–20 years, 39 (14%) had practiced for 21–30 years, and 37 (13%) had practiced for more than 30 years.

3.2. Adoption of oral step-down therapy.

Respondent preferences for step-down to oral antibiotic therapy varied between GN-BSI sources (Line: 176/277 [64%]; IAI: 208/277 [75%]; pneumonia: 215/277 [78%]; SSTI: 250/277 [90%]; urine: 256/277 [92%]) (p<0.001) (Figure 1A). Stratification by location of practice within the U.S. versus ex-U.S. revealed that oral step-down was more common in the U.S. for all GN-BSI sources (Pneumonia: 83% vs. 64%, p=0.002; Central line: 72% vs. 41%, p<0.00001; Urine: 97% vs. 80%, p=0.00001; IAI: 85% vs. 49%, p<0.00001; SSTI: 93% vs. 82%, p=0.002; Figure 1B). Stratification by years of experience did not demonstrate an association between experience and oral step-down practices (Figure 1C).

Figure 1.

Percentage of survey respondents that typically step-down to oral antibiotic therapy in managing gram-negative bloodstream infections (A). The data were stratified by location of practice (within United States [US] versus outside US [ex-US]) (B) and years of experience since terminal degree (e.g., M.D., PharmD, etc.) (C). Abbreviations: IAI, intra-abdominal infection; IV, intravenous; PNA, pneumonia; SSTI, skin/soft tissue infection.

Given that both source of GN-BSI and location of practice were associated with oral step-down practices, a multivariable GEE model was generated to adjust for both covariates. Practice location in the U.S. was associated with increased oral step-down (OR 4.35; 95% CI 2.57–7.36; p<0.00001) (Table 1). Relative to a line source of GN-BSI, oral step-down was more commonly reported in IAI (OR 1.96; 95% CI 1.48–2.61; p<0.001), pneumonia (OR 2.24; 95% CI 1.67–2.99; p<0.001), SSTI (OR 7.26; 95% CI 4.71–11.20; p<0.001), and urinary (OR 9.15; 95% CI 5.73–14.60; p<0.001) sources of GN-BSI.

Table 1.

Generalized estimating equations analysis of factors associated with oral step-down.

Variable	Odds ratio	95% CI	P-value
Position 1
ID pharmacist	1.48	0.86–2.54	0.16
Other	0.97	0.32–2.95	0.95
Years of experience 2
11–20 years	0.91	0.53–1.54	0.71
21–30 years	0.52	0.28–0.98	0.04
>30 years	1.37	0.61–3.08	0.45
Practice in U.S. 3	4.35	2.57–7.36	<0.001
Source of GN-BSI 4
Intra-abdominal infection	1.96	1.48–2.61	<0.001
Pneumonia	2.24	1.67–2.99	<0.001
Skin/soft tissue infection	7.26	4.71–11.20	<0.001
Urinary tract	9.15	5.73–14.60	<0.001

¹Reference group is ID physician

²Reference group is 0–10 years experience

³Reference group is providers that practice outside the U.S.

⁴Reference group is line source of infection

Abbreviations: BSI, bloodstream infection; CI, confidence interval; GN, gram-negative; ID, infectious diseases

For individual providers, there was variation in the oral step-down practices between GN-BSI sources. For example, among those that responded to all five of the oral step-down questions (n=270), 3% (9/270) practice full IV across all GN-BSI sources, 57% (154/270) practice oral step-down across all GN-BSI sources, and 40% (107/270) practice oral step-down for only some sources of GN-BSI (Figure 2).

Figure 2. Distribution of number of oral step-down responses for each provider.

For each provider, the number of gram-negative bloodstream infection (GN-BSI) sources in which oral antibiotic step-down is practiced was calculated. This number can range from 0 (no oral step-down practiced in any of the five GN-BSI sources) to 5 (oral step-down is practiced for all five GN-BSI sources). A histogram of the responses for the providers (n=270) is presented here.

Among those that step-down to oral antibiotic therapy, we further determined whether there are minimum durations of IV therapy typically administered prior to oral antibiotics. In total, 32% (79/250 in bacteremic SSTI) to 44% (77/176 in bacteremic central line infection) of providers that typically transition to oral therapy reported a minimum duration of IV therapy before step-down (Figure 3). This minimum number of days of IV antibiotics was ≥5 for most providers (Pneumonia: 45/87 [52%]; Line: 49/77 [64%]; Urine: 49/97 [51%]; IAI: 35/72 [49%]; SSTI: 40/79 [51%]) (Figure 3). Among all providers, extended IV therapy (i.e., ≥5 days of IV therapy prior to considering oral step-down therapy) is practiced by 39% (107/277) of all providers for bacteremic pneumonia, 53% (148/277) for bacteremic central line infection, 24% (67/277) for bacteremic UTI, 36% (101/277) for bacteremic IAI, and 23% (65/277) for bacteremic SSTI.

Figure 3. Minimum duration of intravenous (IV) antibiotics prescribed in bacteremic pneumonia (A), bacteremic central line infection (B), bacteremic urinary tract infection/pyelonephritis (C), bacteremic intra-abdominal infection (D), and bacteremic skin/soft tissue infection (E).

All data are from providers who stated that they typically step-down to oral antibiotic therapy for the respective infections. Among such providers, the percentage that have a minimum duration of IV antibiotics prior to oral step-down is shown in the graphs on the left. For providers that have a minimum number of days of IV antibiotics they provide, the graphs on the right show the distribution of the minimum days of IV antibiotics.

3.3. Factors influencing decision on oral step-down therapy.

Factors that influence the decision to transition to oral antibiotics were assessed in providers that typically practice step-down therapy (Figure 4). Absorption issues were strongly considered in the oral step-down decision. For example, concern for poor oral absorption in the patient (e.g., vomiting, diarrhea, decreased gastric motility, etc.) was deemed highly relevant by 75–87% (depending on source of GN-BSI) of providers. Similarly, having an effective antibiotic with high oral bioavailability was strongly considered by 68–78% of providers. The clinical status of the patient was also strongly considered. For example, 64–73% of providers strongly considered whether the patient was normotensive and 51–62% strongly considered whether the patient was afebrile. Factors that were not considered as important by providers included a normal WBC count (11–13%), bacterial species (17–23%), and negative follow-up blood cultures (22–38%). In bacteremic central line infections, whether the line is removed within the first few days is strongly considered by 49% of providers, whereas in bacteremic IAI, whether surgical source control is of great importance by 76% of providers. When we examined differences in factors that influence the oral step-down decision between providers inside and outside the U.S., the only factor that was consistently different across all sources of BSI was how strongly bacterial species was considered. For all BSI sources, providers outside the U.S. were more likely to strongly consider bacterial species in the step-down decision (bacteremic pneumonia: 39% vs. 18% [p=0.006]; bacteremic central line infection: 52% vs. 13% [p<0.0001];bacteremic UTI: 34% vs. 12% [p=0.0001]; bacteremic IAI: 38% vs. 14% [p=0.002]; bacteremic SSTI: 34% vs. 18% [p=0.03]).

Figure 4. Factors that influence decision to step-down to oral antibiotic therapy.

Providers that step-down to oral antibiotics were surveyed on how strongly they consider each listed variable before transitioning to oral therapy.

3.4. Willingness to enroll patients in an oral step-down trial.

Most survey respondents (210/277 [76%]) and ID physicians (141/176 [80%]) would be willing to enroll patients in a trial of full IV treatment versus oral step-down before 72 hours after index blood culture. Willingness to enroll in such a trial was common among providers that reported having no personal minimum duration of IV treatment (80–84%, depending on source of GN-BSI), providers that usually provide extended IV treatment (58–80%), and providers that give IV treatment for the full treatment course (68–80%). Providers’ reasons for not wanting to enroll their patients were varied as some did not feel comfortable with oral step-down (e.g., “concern for inadequate oral absorption and inadequate treatment”), while others did not feel comfortable with full IV therapy (e.g., “We already do significant IV to oral step-down therapy and would not want to risk being forced to put PICCs in patients.”). The full set of free text responses for providers that would not be interested in enrolling patients in a clinical trial of early oral step-down therapy are listed in Supplemental Table 1.

4. DISCUSSION

Some of the key management decisions in GN-BSI are whether to step-down to oral antibiotics and, if so, when to do so. We conducted a survey of provider practice patterns involving these key decisions to identify areas of controversy that need to be investigated in future trials. Prior surveys of GN-BSI clinical practice patterns have been published [14–16]; however, we believe that this work makes a substantial contribution to the literature for several reasons. First, our survey broadly assessed the factors that contribute to providers’ decision-making regarding the oral-stepdown decision. Second, it captured a granular level of detail that allowed for a comprehensive understanding of intra- and inter-provider variability in practice patterns. Third, this is the first survey to specifically address the question of whether providers would enroll their patients in a trial of early oral step-down versus full IV therapy for GN-BSI. It is critical evidence to establish equipoise and feasibility of such a trial.

There were several major findings in this study. First, we identified considerable variability in the oral antibiotic step-down decision. A majority of providers (60–90%, depending on GN-BSI source) stated that they would step-down to oral therapy at some point in the treatment course. There was significant variation within individual ID specialists as 40% of providers typically practice oral step-down for some GN-BSI sources (e.g., urine) but not others (e.g., vascular catheter), 3% practice full IV therapy in all cases of GN-BSI, and 57% practice oral step-down in all cases of GN-BSI. In addition, there was considerable geographic variation in oral step-down as the percentage of providers outside the U.S. that step-down to oral therapy was significantly lower than that for U.S. providers across all sources of GN-BSI. In fact, for providers outside the U.S., <50% typically step-down to oral therapy for gram-negative bacteremic line infection (41%) or bacteremic IAI (49%). Geographic variation in oral step-down practices has also been suggested by prior surveys as the percentage of providers that reported never transitioning to oral antibiotics was 20–33% among European providers [15, 16] relative to 3% among U.S. providers [14]. In our survey, providers inside and outside the U.S. differed primarily in how strongly they considered bacterial species in the decision on whether to step-down to oral therapy, as providers outside the U.S. were more likely to strongly consider this variable. Geographic variation in rates of antimicrobial resistance among different bacterial species could be playing a role. For example, cephalosporin resistant and carbapenem resistant E. coli and K. pneumoniae BSI are less likely to be treated with oral step-down therapy, and rates of such infections are generally higher outside the U.S. [17, 18] Higher rates of antibiotic resistance in particular bacterial species could be influencing the oral step-down responses in ex-U.S. providers.

Second, we found that even among those that typically step-down to oral antibiotic therapy there is wide variation in how much IV therapy is provided. For example, extended IV therapy for ≥5 days is practiced by 23–53% of providers, regardless of whether they ultimately transition to oral step-down or not. This finding is echoed in prior studies showing that >40% of providers either transition to oral antibiotics ≥7 days after the initial positive blood culture or pursue full IV therapy [15, 16]. When to transition to oral antibiotics is an important open question as the decision on whether to pursue extended IV antibiotic therapy has a meaningful impact on patients and the healthcare system more generally. Extended IV therapy, relative to early oral step-down therapy, would likely be associated with longer hospital stays, transfer to skilled nursing facilities, and higher overall healthcare costs and so the need for this approach must be assessed through RCTs.

Third, most providers stated that they would be willing to enroll patients in a trial of early oral step-down (within 72 hours of index blood culture) versus full IV therapy for treatment of GN-BSI. We further examined the providers that would not enroll their patients in such a trial. These providers did not have markedly different treatment patterns than the entire cohort, so it does not appear that one subgroup (e.g., those that treat all GN-BSI with full IV) were particularly reluctant to enroll patients. Interestingly, the free text comments from these providers about barriers to enrollment demonstrated significant variability. Some providers felt uncomfortable with the full IV arm while others felt uncomfortable with oral step-down. This lack of clarity on the correct treatment approach is one of the hallmarks of equipoise and should motivate RCTs in this area.

This study had several limitations. First, we are unable to quantitate the nonresponse bias in this voluntary online survey. Providers that either did not have strong feelings about these management decisions or were too busy to respond could have influenced the results. Second, providers who do not belong to professional organizations would not have been contacted to complete this survey. It is unclear how practices surrounding the management of GN-BSI differ among providers who do and do not belong to professional organizations. Third, there may have been response bias. The survey relies on self-report, and we cannot verify that the providers’ responses are truly carried out in clinical practice. Finally, only 27% of respondents practiced outside the US, and this limited our ability to fully explore the factors driving differences in U.S. versus ex-U.S. providers. The survey was only provided in English, and this may have limited the response from ex-U.S. providers.

In summary, the results of this study showed varied oral step-down practice patterns for managing GN-BSI. Clinical equipoise is defined by a lack of certainty as to which therapeutic approach is superior, and the variability in oral step-down practice patterns we observed is congruent with a lack of certainty. The fact that >80% of ID physicians in this survey would enroll their patients in a trial of early oral step-down versus full IV therapy further supports equipoise between these arms as well as the feasibility of such a trial. We believe that further RCTs surrounding the issues of oral step-down would be helpful in defining the optimal therapy for managing GN-BSI.

HIGHLIGHTS.

• Among ID providers, there is wide variety in oral-stepdown practices when managing GN-BSI

• Many ID providers (40%) practice oral step-down for some sources of GN-BSI but not others

• ID providers in the U.S. are more likely to practice oral step-down that ID providers outside the U.S. (odds ratio 4.35; p<0.001)

• Most ID providers (76%) would be willing to enroll patients in a randomized controlled trial of early oral step-down versus full IV therapy for management of GN-BSI