Rifaximin does not increase the rate of 30-day mortality in patients with cirrhosis and daptomycin in two National US-based cohorts

Recently, a higher rate of resistance to daptomycin in patients exposed to rifaximin has been shown¹. However, since laboratory resistance patterns do not account for the complex patient, microbial, and host-related factors, the clinical impact of rifaximin on resistance to daptomycin needs clarification². The main reason for long-term rifaximin use is hepatic encephalopathy (HE) in cirrhosis. Patients with cirrhosis are prone to suffer consequences of antibiotic resistant infections³, which makes the study of the daptomycin effectiveness crucial⁴. Our aim was to determine 30-day outcomes in two large US-based cohorts in daptomycin users with/without pre-existing rifaximin. These were Veterans Affairs Corporate Data Warehouse (VA-CDW) and TriNetX database (Figure 1). Data were extracted from 2010–2019 (2010: Rifaximin FDA approval, 2019 to avoid COVID-19). In VA-CDW we identified cirrhosis patients who received daptomycin and defined rifaximin usage as ≥1 prescription up to 90 days pre-index daptomycin initiation. We collected information on demographics, medications, cirrhosis history and severity [MELD-Na, HE and ascites details, prior spontaneous bacterial peritonitis (SBP), etc], and hospital course (Supplement). The primary outcome was 30-day all-cause mortality. Inpatient sepsis was a secondary outcome. The above analysis using similar eligibility criteria was replicated within TriNetX – a national database of insured patients sourced from participating large non-VA academic institutions (trinetx.com). TriNetX contains information regarding demographics, diagnoses/procedures through ICD/CPT codes, laboratory values, prescription data, liver transplant (LT), and death records. Because LT rates are higher here, we assessed composite 30-day mortality/LT, 30-day transplant-free mortality, and 30-day LT. Statistical analyses are in the supplement.

Figure 1: Forest Plots + Flowchart.

A: Flowchart of patients in Veterans Affairs Corporate Data Warehouse, B: Flowchart of patients in TriNetX, C: Forest plot of logistic regression in VA CDW, 30-day mortality outcome, D: Forest plot of logistic regression in TriNetX, composite 30-day mortality or LT outcome. WBC: white blood cell count, PPI: proton pump inhibitor use, ICU: intensive care unit, HE: hepatic encephalopathy, BP: spontaneous bacterial peritonitis.

In VA-CDW we found 2237 patients that were given daptomycin, of which 118 (5.3%) were on rifaximin. Among these, 511 (22.8%) died within 30-days post-daptomycin, 59 (2.6%) received LT and 695 (31.1%) had sepsis. The average daptomycin dose was 6.15 mg/kg, and 316 (14.1%) patients also received linezolid. Cohort comparisons (Table S1) showed that patients on rifaximin were slightly younger and were more likely to be on admission proton pump inhibitors (PPI), diuretics, lactulose, or beta-blockers. These patients also had higher MELD-Na and higher proportion with prior SBP, variceal bleed, and chronic viral hepatitis. During their hospitalization, rifaximin users were also more likely to be transferred to the ICU. 62 patients grew Enterococcus spp and received daptomycin(Supplement). On univariable analysis, rifaximin was associated with significantly higher 30-day mortality rates (OR:2.10 [1.42–3.08], p<0.001) but not sepsis (OR:0.70 [0.59–1.33], p=0.59). After adjustment, the mortality association was no longer statistically significant (adjusted OR:0.97 [0.52–1.55], p=0.92, Figure 1C). This was not affected by linezolid use (p=0.932) or by changing the window of pre-admission rifaximin use to 60, 180 or 365-days (supplement).

In TriNetX we identified 2,291 patients who were given daptomycin, of which 643 (28.1%) were on rifaximin. Among these, 753 (32.9%) died/received LT, 422 (18.4%) died within 30-days post-daptomycin without LT, 342 (14.9%) received LT, and 396 (17.3%) had sepsis. Weight-based dose data was not available. Among the 1131 patients with dose available, 97.5% were on the 500mg dose, which was then adjusted in a categorical manner. 468 (20.4%) patients also received linezolid. Cohort comparisons (Supplementary Table 1) were like VA-CDW. No resistance data was available. On univariable analysis, rifaximin was associated with significantly higher 30-day composite mortality/LT rate (OR:3.80: [3.14–4.60], p<0.001), which was again strongly diminished after adjusting for cirrhosis severity and hospital course (Figure 1D, adjusted-OR:1.14 [0.83–1.57], p=0.411). LT-free mortality (OR:3.96 [3.14–5.00], p<0.001) was also significantly higher in rifaximin patients on univariable analysis, but not significant following adjustment (Figure S1A). LT rates alone (OR:2.52 [1.99–3.19], p<0.001) were again higher in rifaximin patients on univariable (24.3% vs. 11.3%) but not on multivariable analysis (Figure S1B) demonstrating that rifaximin use was not a barrier to LT. Outcomes were not affected by linezolid use (Death without LT: p=0.63, LT only: p=0.87, Composite: p=0.66) or by changing the window of pre-admission rifaximin use to 60, 180 or 365-days (supplement).

Finally, sepsis rates were higher in rifaximin patients on univariable analysis(OR:3.69 [2.90–4.69], p<0.001), but not after adjustment (adjusted-OR:1.10 [0.75–1.62], p=0.62). This data demonstrate that concomitant rifaximin use in patients with cirrhosis that are subsequently prescribed daptomycin is uncommon and does not increase the risk of 30-day mortality across two national US-based cohorts. While AMR testing is important, care must be taken to interpret these results in a clinical context². Rifaximin has grade A evidence to prevent HE recurrence⁵ and improves clinical outcomes without a clinically significant infection or resistant infection-related signal^{6 7}. Rifaximin improves intestinal barrier function, thus enhancing protection against invading pathobionts in cirrhosis^{8, 9}. Furthermore, there was no signal for selective increase in gram-positive taxa including enterococci from an overall microbiome or culture-based analysis¹⁰.

Despite controlling for important factors that typically link with inpatient outcomes in cirrhosis, we did not demonstrate a significant mortality difference with rifaximin in daptomycin users. This is especially noteworthy since rifaximin is usually initiated in patients with more advanced cirrhosis. Moreover, this result remained consistent despite adjustment for rifaximin initiation timing, linezolid use, daptomycin dose, and sepsis outcomes. Additionally, since Veterans are usually older, less diverse and more co-morbid than the TriNetX population, similar patterns among cohorts with diverse representation is reassuring. We chose mortality due to the “last resort” status of daptomycin and included LT as well. However, we cannot definitively exclude the possibility that rifaximin increases potential for daptomycin resistance or conclusively determine the utility in daptomycin users with vancomycin-resistant enterococci due to sparse culture data. Furthermore, lack of longer-term mortality is a limitation along with incomplete daptomycin dosage information. Since LT eligibility requires infection control, lack of impact on LT rates in TriNetX shows that rifaximin use was not a systematic barrier.

In summary, we found no significant changes in 30-day mortality, LT or severe sepsis/septic shock with pre-existing rifaximin use in the setting of daptomycin after controlling for clinically important variables. The impact of rifaximin on daptomycin resistance development cannot be excluded due to the sparse culture results but the data demonstrate that concomitant administration of rifaximin and daptomycin does not translate into worse short-term outcomes in patients across two national US-based cohorts.

Data transparency:

Due to IRB restrictions, data, analytic methods, and study materials beyond what is already in this paper will not be available to other researchers