Authors: Toshiki Miwa, Koh Okamoto, Kaito Fukasawa, Ryo Yamaguchi, Takehito Yamamoto, Takeya Tsutsumi
Categories: Original Article
Source: JAC-Antimicrobial Resistance
Evaluating the effectiveness of low-dose oral switch therapy for uncomplicated streptococcal or enterococcal bloodstream a retrospective cohort study
Authors: Toshiki Miwa, Koh Okamoto, Kaito Fukasawa, Ryo Yamaguchi, Takehito Yamamoto, Takeya Tsutsumi
Abstract
Background
Although oral switch therapy (OST) is increasingly recognized as a viable option for uncomplicated gram-positive bloodstream infections (GP-BSI), its optimal dosage remains unclear. In Japan, high-dose regimens of key oral antimicrobials, such as amoxicillin (1000 mg thrice daily) or levofloxacin (750 mg once daily), are not approved. This study investigated the effectiveness of low-dose OST for GP-BSI in a population with a low prevalence of obesity.
Methods
This retrospective, single-centre study involved patients aged ≥18 years with monomicrobial, uncomplicated BSI caused by ampicillin- or amoxicillin-susceptible Streptococcus or Enterococcus species treated between 2010 and 2023. Patients eligible for OST were identified on day 5 of microbiologically active therapy. Demographic, clinical, laboratory, and microbiological data were analysed. Using overlap weighting, we compared 90-day all-cause mortality between OST and intravenous therapy (IVT) only groups.
Results
A total of 172 patients (86 with OST and 86 with IVT only) were included. The median body mass index was 22.5 (interquartile range [IQR], 19.2–24.7), and the median duration of therapy was 14 days (IQR, 12–15 days). Common oral regimens included amoxicillin (n = 34, 39.5%), amoxicillin/clavulanate (n = 24, 27.9%), and levofloxacin (n = 12, 14.0%). No significant difference in 90-day all-cause mortality was observed between OST and IVT groups (odds ratio, 0.73; 95% confidence interval, 0.23–2.29).
Conclusions
Low-dose OST may be effective for clinically stable patients with uncomplicated GP-BSI in settings with low obesity prevalence.
Introduction
The 2016 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines on antimicrobial stewardship programs advocate for the transition from intravenous to oral therapy or oral switch therapy (OST) in relevant circumstances.^1^ Previous studies have indicated that OST could reduce costs, shorten hospital stays, and mitigate line complications.^1^ A growing body of evidence supports OST for various infections, prompting physicians to challenge the historical dogma that intravenous therapy (IVT) is superior to oral therapy.^2^ Regarding gram-positive bloodstream infections (GP-BSI), data on the effectiveness and safety of OST are less robust compared with those on gram-negative bloodstream infections (GN-BSI).^3–5^ Nevertheless, along with clinical trials for infective endocarditis,^6^ evidence based on observational studies is gradually increasing for streptococcal and enterococcal BSI.^7–15^
For OST, determining the optimal dosage of oral antimicrobial agents is important for several reasons. First, a high-dose can be toxic, and a population-based study revealed an association between high-dose levofloxacin and adverse events in older adult patients with advanced kidney diseases.^16^ In case of similar effectiveness, it is reasonable to select low-dose OST over high-dose. Second, regulatory bodies in certain countries such as Japan do not approve high doses of oral antimicrobial agents. However, the minimum effective dose of these antimicrobials (e.g. beta-lactams or fluoroquinolones) for GP-BSI has not been fully explored. In recent multicentre observational studies investigating the effectiveness of OST for GP-BSI, a few patients received low-dose OST, such as amoxicillin 500 mg thrice daily or levofloxacin 500 mg once daily,^12^ or the dosage was undocumented.^13^ Another study suggested the ineffectiveness of low-dose OST for GP-BSI;^17^ however, given that the body size was not considered, it remains uncertain whether its findings are applicable to settings with a low prevalence of obesity.
The present study aimed to investigate the effectiveness and safety of OST for uncomplicated streptococcal and enterococcal BSI considering the dosage of oral regimens and patient body size.
Materials and methods
Study design and settings
This retrospective, single-centre study was conducted at the University of Tokyo Hospital, a 1226-bed tertiary care facility in Tokyo, Japan. It is a solid organ transplantation (SOT) centre for the heart, lungs, liver, and kidneys. Blood cultures were performed at the discretion of the treating physicians and results were notified by the in-house microbiology laboratory. Infectious disease (ID) consultation was not mandatory for the management of BSI but was available upon treating physicians’ request. The antimicrobial stewardship team conducted daily microbiological rounds to monitor patients with positive blood cultures until susceptibility test results were available.
In Japan, amoxicillin, amoxicillin-clavulanate, and levofloxacin are approved with dosages of 500 mg thrice daily, 500–125 mg thrice daily, and 500 mg once daily, respectively.^18^
Participants
This study included patients aged ≥18 years with monomicrobial, uncomplicated BSI due to ampicillin- or amoxicillin-susceptible Streptococcus or Enterococcus species treated between April 2010 and March 2023. The patients were considered eligible for OST on day 5 of microbiologically active therapy. Based on the Clinical and Laboratory Standards Institute (CLSI)-defined criteria, MIC of ampicillin ≤0.25 mg/L was deemed susceptible for beta-hemolytic or viridans group Streptococcus species, the MIC of amoxicillin ≤2.0 mg/L for non-meningitis Streptococcus pneumoniae, and the MIC of ampicillin ≤8.0 mg/L for Enterococcus species.^19^ Uncomplicated BSI was defined as an infection treated with 6–16 days of antimicrobial therapy without any residual foci.^13^ Patients with an intravenous prosthesis, such as a central venous catheter or cardiac implantable electronic devices, were included only if it was extracted. The eligibility criteria for OST (i) initial IVT, (ii) Pitt bacteraemia score (PBS) ≤1 on day 5,^20^ and (iii) the ability to tolerate oral intake or tube feeding on day 5. Only the index event was included for patients who experienced BSI, multiple times during the study period. The exclusion criteria were initial white blood cell count ≤1000/μL and mortality during antimicrobial therapy to mitigate bias for OST.
Data collection
We retrospectively collected the following data of the study participants from electronic medical age, sex, Charlson comorbidity index (CCI), history of SOT, presence of intravascular prostheses or any immunosuppressant use, onset type [e.g. community-onset (<2 days of admission) versus nosocomial onset (≥2 days of admission)], source of BSI, intensive care unit admission, PBS on days 1 and 5, laboratory data of days 1 and 5, microbiological data, ID consultation by day 7, the choice, dosage, and duration of antimicrobial therapy, and outcome variables. BSI without an apparent portal of entry was classified as primary bacteraemia. The distinction between high-dose and low-dose oral regimens was based on a previous amoxicillin 1000 mg thrice daily or 875 mg twice daily, or levofloxacin 750 mg once daily was regarded as a high-dose, whereas amoxicillin 500 mg three times daily or levofloxacin 500 mg once daily was regarded as a low-dose.^17^
All participants were classified into either the OST group if they received oral antimicrobial therapy for at least 1 day or the IVT-only group. The primary outcome was the 90-day all-cause mortality. Secondary outcomes included a 90-day recurrence of BSI due to the same species, any adverse events necessitating modification or cessation of antimicrobial therapy, Clostridioides difficile infection, and length of hospital stay.
Statistical analyses
In univariable analyses, we used the chi-square test or Fisher's exact test for categorical variables and t-test or Mann−Whitney U test for continuous variables, as appropriate. Additionally, we performed an overlap weighting analysis to compare the two groups.^21^ This approach effectively estimates the average treatment effect of the overlapping population by mitigating the bias arising from extreme propensity scores.^21^ In this analysis, we computed the propensity score using a logistic regression model involving demographics, underlying medical conditions, clinical manifestations, microbiological data, and ID consultations. We confirmed that the standardized difference of each covariate was <0.01 to ensure appropriate balancing. Furthermore, we performed subgroup analyses to compare (i) the effectiveness of early OST, defined as the transition from intravenous to oral therapy by day 7, and late OST, defined as the transition beyond day 7, and (ii) streptococcal and enterococcal BSI. Statistical significance was defined as P value <0.05. All analyses were performed using Stata version 16 software (StataCorp, College Station, TX, USA).
Patient consent statement
This study was approved by the Institutional Review Board of the University of Tokyo Hospital (approval 2020171NI). Given the retrospective nature of the study, the requirement for patient consent was waived in accordance with the Declaration of Helsinki. This study was performed in accordance with Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Results
Characteristics of study participants
During the study period, 180 patients with streptococcal or enterococcal BSI met the study criteria, of whom 88 received OST and 92 were treated with IVT only (Figure 1). None of those who were otherwise eligible except for their mortality between day 7 and the end of therapy were excluded at this stage. Of the 180 potential study participants, eight (4.4%) patients were lost to follow-up within 90 days of BSI 2 (25.0%) and six (75.0%) patients in the OST and IVT-only groups, respectively (Table S1, available as Supplementary data at JAC-AMR Online). The characteristics of the remaining 172 patients (86 with OST and 86 with IVT-only) are presented in Table 1. The median body mass index (BMI) was 22.5 [interquartile range (IQR), 19.2–24.7], and the median creatinine clearance calculated using the Cockcroft–Gault formula was 61.8 mL/min (IQR, 44.8–91.8 mL/min). At BSI onset, the intravascular prosthesis was placed only in five patients in the IVT-only group, and all of them were diagnosed with catheter-related bloodstream infection (CRBSI). Univariable analyses revealed no statistically significant differences among other variables, including demographics, underlying conditions, microbiological data, clinical manifestations, and ID consultation. Of 12 patients with S. pneumoniae BSI, 11 (91.7%) were infected by strains with an amoxicillin MIC ≤0.25 mg/L. All strains of Enterococcus species in this study exhibited an ampicillin MIC ≤2.0 mg/L.
The median therapy duration was 14 days (IQR, 12–15 days), with no statistically significant differences between the two groups (Table 2). In the OST group (n = 86), the patients received IVT for a median of 8 days (IQR, 6–10 days) and OST for a median of 6 days (IQR, 4–7 days). The three frequently used oral regimens were amoxicillin (n = 34, 39.5%), amoxicillin/clavulanate (n = 24, 27.9%), and levofloxacin (n = 12, 14.0%) (Table 3). Other antimicrobials included cefaclor (n = 7, 8.1%), ampicillin (n = 2, 2.3%), sultamicillin (n = 2, 2.3%), cefcapene pivoxil (n = 2, 2.3%), and a combination of these agents (n = 3, 3.5%). Among patients with estimated creatinine clearance ≥50 mL/min who used amoxicillin or amoxicillin/clavulanate (n = 37), 36 (97.3%) were prescribed ≤1500 mg per day of amoxicillin, with 13 (35.1%) particularly receiving 750 mg per day of amoxicillin. None of the patients in this study received levofloxacin 750 mg daily. Of the 12 patients receiving oral levofloxacin therapy, the causative organisms in 4 patients (33.3%) had a levofloxacin MIC of 2.0 mg/L.
The comparison of outcomes between the groups
The primary outcome occurred in 16 patients (9.3%) (Table 2), with a median BMI of 23.7 (IQR, 21.8–25.7). Univariable analyses revealed no statistically significant difference in the primary outcome, 90-day recurrence of BSI, or antimicrobial-related adverse events between the groups. The length of hospital stay from BSI onset was significantly shorter in those receiving OST than in those treated with IVT only [10 days (IQR, 8–13 days) versus 16 days (IQR, 14–23 days); P < 0.01].
As CRBSI occurred exclusively in the IVT-only group (n = 5), these patients were excluded from the subsequent propensity score-based analysis. Overlap weighting analysis was performed for the remaining 167 patients (86 with OST and 81 with IVT only) after adjusting for demographics, underlying medical conditions, pathogens, clinical manifestations, and ID consultations (Figures S1 and S2). Patients in the OST group exhibited no statistically significant difference in the primary outcome [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.23–2.29] or in antimicrobial-related adverse events (OR, 0.43; 95% CI, 0.07–2.79) compared with those in the IVT-only group.
The subgroup analyses on the timing of OST and species
Of 86 patients in the OST group, 38 (44.2%) and 48 (55.8%) were further categorized into early and late OST groups, respectively (Table 4). Compared with the early OST group, those in the late OST group had a higher propensity for ID consultation (50.0% versus 23.7%; P = 0.01) and prolonged hospitalisation [median, 11 days (IQR, 10–14 days) versus 8 days (IQR, 7–12 days); P < 0.01]; however, there was no statistically significant difference in 90-day mortality (8.3% versus 5.3%; P = 0.58).
In the cohort of patients with streptococcal BSI (n = 123), no statistically significant differences were observed in the demographics, underlying medical conditions, clinical manifestations, ID consultation, and outcomes between those treated with OST (n = 60) and those treated with IVT only (n = 63), except that the former had a shorter median hospital stay [10 days (IQR, 9–14 days) versus 16 days (IQR, 14–22 days); P < 0.01] (Table S2). In contrast, among patients with enterococcal BSI (n = 49), those with OST (n = 26) had a lower 90-day mortality than those with IVT only (n = 23) (3.8% versus 30.4%; P < 0.01).
Discussion
This study analysed the data of patients with uncomplicated streptococcal or enterococcal BSI treated primarily using low-dose oral regimens for OST. A propensity score-weighted analysis found no statistically significant differences in mortality and antimicrobial-related adverse events between patients receiving OST and those treated with IVT only. However, the length of hospital stay was shorter in the former group compared with that in the latter group. The inferiority of OST remained unobserved even when patients were stratified by the timing of OST (i.e. by versus beyond day 7) or microbiological data (i.e. streptococci versus enterococci). Notably, our study population was characterized by a smaller body size compared with that in recent observational studies, where the median BMI of the study participants exceeded 25 [12, 13]. Our findings support the use of low-dose oral regimens, especially for patients with GP-BSI who adopted source control measures in the absence of obesity.
In this study, the common beta-lactam dosage for OST was amoxicillin 500 mg (with or without clavulanate) thrice daily. From a pharmacokinetic viewpoint, the efficacy of beta-lactams correlates with the proportional time above MIC for the unbound fraction (%fT > MIC), and for penicillin, it is generally recommended that %fT > MIC should be ≥50% for bactericidal effect and ≥30% for bacteriostatic effect, regardless of the species.^22,23^ Specifically, when using amoxicillin 500 mg thrice daily dosage in individuals with 70 kg body weight, the bactericidal threshold (i.e. ≥50% fT/MIC) is theoretically achieved for organisms with a MIC ≤0.5 mg/L.^24^ A previous study involving individuals with a mean body weight of 77 kg demonstrated that this regimen surpassed 95% of the probability of target attainment (PTA) for the 40% fT/MIC against organisms with a MIC ≤0.5 mg/L.^25^ Given the CLSI-defined breakpoints,^19^ low-dose OST using amoxicillin 500 mg thrice daily may be a reasonable option for streptococcal BSI in patients with similar body sizes. Notably, some of our patients received amoxicillin 250 mg thrice daily. Although we did not have a sufficient number of patients to clinically endorse it, this ‘very low-dose’ regimen reportedly had 95% PTA for the 40% fT/MIC against organisms with MIC ≤0.25 mg/L.^25^
Compared with Streptococcus species, Enterococcus species had higher MIC for beta-lactams,^19^ rendering it less likely for low-dose OST to attain the target MIC in general.^26^ Nevertheless, amoxicillin 500 mg thrice daily regimen theoretically achieves ≥30% fT/MIC in patients with 70 kg body weight, provided the MIC is ≤2 mg/L,^24^ which is enough to exert a bacteriostatic effect.^22,23^ It remains uncertain whether OST with a bacteriostatic effect, not a bactericidal effect, is effective for patients with BSI following adequate initial IVT; this warrants further evidence before the application of low-dose OST for enterococcal BSI.
Levofloxacin was administered at a dose of 500 mg once daily in this study. From a pharmacokinetic viewpoint, the ratio of the area under the curve of the unbound fraction to the MIC (fAUC/MIC) is a useful indicator of fluoroquinolone activity.^27^ Streptococcus and Enterococcus species share the common susceptibility breakpoint of MIC ≤2 mg/L.^19^ Levofloxacin has almost 100% bioavailability, and the fAUC does not change significantly between oral and intravenous administration.^27^ Considering this, levofloxacin 500 mg once daily is theoretically effective against gram-positive organisms with a MIC ≤1.0 mg/L, where fAUC/MIC exceeds the ideal target of 30 without noting the body size data.^28^ Whether this regimen is effective even for organisms with a MIC of 2.0 mg/L merits further studies.
In addition to the OST dosage, the timing of the oral switch is clinically important. In this study, approximately 44% and 56% of the patients in the OST group started OST by and beyond day 7, respectively. Early OST was associated with a shorter length of hospital stay, without increased mortality or adverse events. However, recent studies showed that a short course (5–10 days) of antimicrobial therapy might be non-inferior to conventional therapy in patients with uncomplicated streptococcal BSI.^13,29^ Although less robust, a similar trend may also hold for uncomplicated enterococcal BSI.^15,30^ Together with our findings, short-course therapy or OST should be considered in selected patients with uncomplicated GP-BSI.
The present study has certain limitations. First, owing to the inherent nature of a single-centre retrospective study design, our study succumbs to information bias, such as inadequate documentation in medical records, inappropriate workup for complicated BSI, or unmeasured confounders, despite employing overlap weighting analysis to mitigate it. Moreover, the small sample size precludes drawing firm conclusions, and our findings may not apply to other hospitals with different patient backgrounds. Second, patients in the OST group received a median of 8 days of IVT before OST in the main analysis. Therefore, the safety of OST on day 5 for clinically stable patients remains uncertain, although we found no difference in the outcomes between early versus late OST in the subgroup analysis. Third, we did not directly compare the effectiveness of low-dose OST with that of high-dose one. Fourth, we did not assess the recurrence of local infections. In contrast to BSIs, the pathogens causing recurrent local infections may not always be obvious. For instance, the organisms responsible for skin and soft tissue infections are usually unidentified in the absence of accompanying BSI. Fifth, the effectiveness of low-dose OST for organisms with relatively elevated ampicillin or amoxicillin MIC (i.e. S. pneumoniae with amoxicillin MIC 1–2 mg/L and Enterococcus species with ampicillin MIC 4–8 mg/L) was not explored in this study.
In conclusion, for patients with uncomplicated ampicillin- or amoxicillin-susceptible GP-BSI, who achieve early clinical stability, low-dose OST following a sufficient course of IVT may be effective and safe in settings where the prevalence of overweight or obesity is low. Given the evolving evidence, short-course therapy or OST using low-dose regimens may be encouraged in this setting.