Controversies of Antimicrobial Transitions in Adults With Gram-Negative Bacteremia

Inevitably, most clinicians and antimicrobial stewards will encounter a challenging clinical decision: Can a patient with transient gram-negative bacteremia be treated with something other than 14 days of intravenous (IV) antimicrobial therapy? The potential disadvantages of a 2-week course of IV antibiotics (line infections, adverse effects, monitoring outpatient parenteral antimicrobial therapy [OPAT], prolonged hospital stay) are enough to cause second thoughts. Recent literature suggests that shorter courses of antibiotics and oral agents are reasonable alternatives for many patients, given several key considerations (see Sidebar).

Bloodstream infections (BSIs) due to gram-negative bacilli are typically manifestations of complicated urinary tract (UTI) or intra-abdominal infections. Some of the most common stewardship strategies for these infections include rapid organism identification and pharmacokinetic/ pharmacodynamic dose optimization of empiric and targeted therapy. However, practice guidelines offer little direction on the management of the bacteremic patient regarding antimicrobial transitions from IV therapy, selection of stepdown agents, and the duration of treatment.^1,2 Until recently, management strategies for gram-negative BSIs have only been examined in observational studies or subgroups of randomized trials.^3-5 Much of the available data are limited due to retrospective study designs, varying definitions of outcomes, differences in organisms studied, and a lack of complete antimicrobial administration information with follow-up.^6-9 Given that each additional antimicrobial day/central-line day is associated with increased risk of Clostridium difficile infection, adverse effects, and reinfection, it is critical that antibiotic stewards critically evaluate each case individually.¹⁰

CAN ORAL ANTIBIOTICS BE USED?

More than 20 years of evidence from observational and randomized studies support the practice of using sequential IV-to-highly bioavailable oral agent when treating bacteremia.^3,6-9,11-13 IV-to-oral conversion upon clinical stability is becoming the expected standard of care, in large part because of the benefits of reduced hospital stay, costs, and avoidance of the risks associated with OPAT. About 1 in 4 patients are readmitted by 30 days following discharge with OPAT, with many of the reasons for readmission possibly related to the IV therapy.¹⁴

Clinical trials in disease states such as pyelonephritis, in which over 30% of patients can have a secondary BSI, can be helpful for directing therapy in gram-negative bacteremia.^4,15 When comparing IV-only to oral ciprofloxacin for pyelonephritis/complicated UTI in a randomized study, the microbiologic and treatment failure rates were less than 5% in each group.¹⁵ In Enterobacteriaceae BSIs from urinary sources, a large retrospective study concluded there were no differences in clinical failure between IV-only and IV/ oral therapy.⁸ Patients with bacteremia secondary to cholangitis converting from IV to oral therapy also showed comparable outcomes to those only receiving IV therapy. For example, Park et al randomized 59 patients starting on IV therapy to either oral transition or all IV route and found no difference in microbiologic eradication or recurrence.¹⁶ However, length of stay was shorter in the oral conversation group.¹⁶

Similarly, in a retrospective observational study of 263 patients with bacteremic cholangitis, 36.5% were converted to oral therapy.¹⁷ In the short- and long-course treatment arms, oral antibiotics were received for 3 and 7 days, respectively.¹⁷ Although the clinical impact of oral conversion was not described, there was no difference in mortality, recurrence, or composite outcome of failure between the arms.¹⁷ Reliable pharmacokinetic profiles and improvement in patient safety and quality of life, without increasing risk of treatment failure, justify IV to oral conversion for uncomplicated gram-negative BSIs.

WHEN TO “GO P.O.”?

Gram-negative BSIs do not typically advance to persistent infections such as endocarditis, where duration depends on surgical intervention and no growth in repeated blood cultures, at which point many experts begin counting antibiotic days. The first day of active antibiotic therapy seems to be the accepted “day 1” for uncomplicated gram-negative BSIs, and it is also likely unnecessary to confirm clearance of bacteremia.¹⁸ The results of single-center observational studies suggest that repeating blood cultures for gram-negative BSIs may be unlikely to alter management, while increasing resource utilization.^19,20 Ongoing clinical trials may provide further insight on the significance of confirming microbiologic eradication in gram-negative BSI.²¹

The median transition period to oral therapy was between 3 and 5 days in observational IV/oral gram-negative studies.^6-8 One such study examined the impact of a short (≤3 days) versus longer time to conversion, and there was no difference in clinical success, although it was a secondary outcome.⁷ Trending procalcitonin and C-reactive protein levels may also help predict early clinical improvement for patients with gram-negative BSI.²⁸ Clinical trials often allow oral conversion at the discretion of the provider.^3,12 This approach is appropriate, as oral conversion should be based on clinical stability, adequate control of infectious foci, and meeting criteria for enteral antibiotic administration.

WHICH STEP-DOWN AGENT CAN BE USED?

Poorer microbiologic clearance and clinical response for UTIs has been documented for β-lactams and sulfamethoxazole- trimethoprim (SXT) compared with quinolones, raising concern for their utility as stepdown agents for urosepsis.^2,5,22 Additionally, β-lactams have reduced bioavailability compared with quinolones and SXT. Kutob et al stratified oral stepdown agents by bioavailability for gram-negative BSIs (n = 362): low bioavilability (β-lactams), moderate bioavailability (SXT, ciprofloxacin), and high bioavailability (levofloxacin). Patients using low/moderately bioavailable antibiotics had worse clinical cure (86% and 88%, respectively) compared with the highly bioavailable agent (98%) and the use of highly bioavailable/IV therapy was associated with lower risk of treatment failure in multiple regression modeling.⁶ In contrast, oral β-lactams were noninferior to fluoroquinolones (86.9% vs 87.1%, respectively) in another retrospective cohort of clinically stable patients, with a source control for uncomplicated Enterobacteriaceae BSIs.⁷ Patients with urinary abnormalities and diabetes were less likely to achieve clinical success. Reasons for these varying results could be differences in study design and definitions, the organisms included, patient populations, and sites of infection.

IV/oral stepdowns to ciprofloxacin (65%), β-lactams (19%), and SXT (9%) were also assessed by Rieger et al. The prevalence of failures in the stepdown ciprofloxacin group was 6.8% (6/88) and 11.1% (5/45) in the remaining IV/oral cases.⁸ Other studies, not specifically designed to examine outcomes in bacteremia, also suggest oral β-lactams may be reasonable. Hospitalized women with Escherichia coli pyelonephritis (n = 328) were shown to have 97.8% clinical and 93.4% microbiologic cures at follow-up, 4 to 14 days after completing therapy, when the organism was susceptible.²³ Most patients received a 7-day course of an oral β-lactam following 7 days of IV cefuroxime; 28% of the population had a BSI. Predictors of early clinical failure (72 hours) included bacteremia, C-reactive protein greater than or equal to 20 mg/dL, chronic liver disease, and resistance to cefuroxime.²³

There is sufficient evidence to conclude that highly bioavailable agents are efficacious as stepdown therapy for gram-negative BSIs. Given widespread quinolone and SXT resistance and the risks associated with OPAT therapy, oral β-lactams could be considered for use in stable patients with minimal adherence barriers, source control, and organisms with low minimum inhibitory concentrations.⁷ Although reduced bioavailability is concerning, success rates remain high across studies. Data from large randomized trials are anticipated to confirm these findings.

HOW LONG TO TREAT?

Until recently, observational and pooled clinical trial data were the best available evidence for the duration of antibiotic therapy for gram-negative BSIs. A meta-analysis of randomized trials including only bacteremic subpopulations from urinary sources found no difference in clinical success between treatment with a fluoroquinolone that was less than or equal to 7 days and greater than 7 days.²⁴ The trial that provided the most patients for this meta-analysis assigned 156 females with pyelonephritis (27% with E coli bacteremia) to either 7 or 14 days of ciprofloxacin. Only 16% received initial IV ciprofloxacin, yet 93% achieved clinical success, with 27% of the population having BSIs. Patients on longer courses of ciprofloxacin durations had more mucosal candida infections.⁴

In a multicenter propensity-matched cohort of adults with Enterobacteriaceae BSIs, mortality at 30 days for short-course treatment (range, 6-10 days) was no different when compared with long-course treatment (range, 11-16 days).²⁵ The largest observational study that did not support a shorter treatment duration for gram-negative bacteremia determined that predictors of treatment failure were cirrhosis, nonimmunocompetent status, and use of short-course therapy.⁹ Doi et al concluded no difference in mortality or composite primary outcome in a propensity-scored retrospective cohort (n = 263) comparing short (≤7 days) and long (>7 days) durations of therapy for bacteremic cholangitis, with source control. There were notable differences between the groups related to severity of illness, microbiology, appropriate empiric therapy, and utility of expert consultation.¹⁷ In a multicenter study, Daneman et al also found comparable mortality between short and long durations (27% vs 29%) in critically-ill patients with uncomplicated bacteremia, although this was not specific to gram-negative organisms.²⁶ Other observational studies have also determined no correlation between clinical success and longer durations of therapy, but they were underpowered to assess this specific endpoint.^7,27

Yahav et al recently presented the results of their randomized trial assessing noninferiority of 7 days versus 14 days of antibiotics for uncomplicated gram-negative BSIs (n = 602) at the 28th European Congress of Clinical Microbiology and Infectious Diseases.¹⁸ Enterobacteriaceae represented more than 90% of the organisms that were isolated. Most sources of bacteremia stemmed from the urinary tract, and patients were required to achieve clinical instability within 48 hours before randomization (day 7) and have source control of infection. Short-course therapy was noninferior to the 14-day course in the primary outcomes of mortality, failure, and readmission/extended hospitalization at 90 days.¹⁸ There were also only minor differences in 90-day mortality (11.8% vs 10.7%), treatment failure, adverse drug events, or development of resistant organisms. However, patients treated with a short course had improved “time to return to baseline activity” (14 vs 21 days; P <.001).¹⁸ Based on these observational and randomized data, patients who are clinically stable after several days of appropriate antibiotic therapy can safely receive a 7- to 10-day course for Enterobacteriaceae BSI.

IN SUMMARY

It appears that the dogma of a 2-week IV-antibiotic course for uncomplicated gram-negative BSIs has had its day. With similar treatment success, clinicians can reduce the risk of additional antibiotic-related harm by using shorter durations. Although not all from randomized trials, there are ample data to support the practice of oral stepdown to a highly bioavailable agent for BSIs due to Enterobacteriaceae from a urinary or intra-abdominal source and completing at least 7 days of active therapy. It is not yet clear which subsets of patients are poor candidates for shorter courses or agents with lower bioavailability. Stepdown is conditional on clinical stability and criteria for oral medication administration. β-lactams may be useful in cases involving resistance or intolerance to quinolone/SXT, although it is difficult to maintain optimal serum concentrations. Final results from ongoing clinical trials are highly anticipated.

Dr. Mercuro is an infectious diseases pharmacotherapy fellow at Wayne State University and Henry Ford Hospital in Detroit, Michigan. He completed a PharmD at the University of Rhode Island, a PGY1 residency at Henry Ford Hospital, and PGY2-ID residency at Maine Medical Center in Portland, Maine. He is an active member of the Society of Infectious Diseases Pharmacists (SIDP).

Dr. Davis is a clinical professor of pharmacy practice at Wayne State University and an infectious diseases pharmacist at Henry Ford Hospital in Detroit, Michigan. She completed a PharmD at the University of Michigan, Ann Arbor, and residency and fellowship training at the Detroit Medical Center and Wayne State University. She is an active member of the Society of Infectious Diseases Pharmacists (SIDP) and Making a Difference in Infectious Diseases Pharmacotherapy (MAD-ID).

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