Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy

Table 1 Protocol-defined broad-spectrum antibiotic regimens

Monotherapy	Gram-positive/negative	Gram-positive	Gram-negative	Anaerobic
Ampicillin-sulbactam	Cefazolin	Vancomycin	Aminoglycosides	Metronidazole
Amoxicillin-clavulanate	Cephalexin	Linezolid	Polymyxin B and colistin	Clindamycin
Piperacillin-tazobactam	Cefuroxime	Daptomycin	Aztreonam
Cefoxitin	Cefdinir	Quinupristin-dalfopristin	Cefiderocol
Meropenem +/- vaborbactam	Cefixime	Rifampin
Imipinem-cilastatin +/- relebactam	Ceftazidime +/- avibactam	Rifabutin
Ertapenem	Ceftriaxone	Penicillins
Tigecycline	Cefepime
Eravacycline	Ceftaroline
	Ceftolozane-tazobactam
	Ciprofloxacin
	Levofloxacin
	Doxycycline
	Sulfamethoxazole-trimethoprim

Broad-spectrum antibiotic therapy is defined as: (1) Any agent from “Monotherapy”; (2) one agent from each of “Gram-positive/negative” and “Anaerobic”; (3) one agent from each of “Gram-positive,” “Gram-negative,” and “Anaerobic.”

Table 2 Baseline characteristics

Variable	Control (n = 32)	Protocol (n = 32)	P value
Male	19 (59.4)	18 (56.2)	0.21
Age (yr)	57.9 (± 12.9)	53.0 (± 12.7)	0.13
Race			0.01
White	26 (81.3)	24 (75)
Unavailable	4 (12.5)	2 (6.3)
Black	1 (3.1)	1 (3.1)
American Indian/Alaskan native	1 (3.1)	0 (0)
Asian	0 (0)	0 (0)
Multiracial-Multicultural	0 (0)	0 (0)
Weight (kg)	85.4 (± 23.1)	91.3 (± 29.2)	0.37
Direct Intensive Care Unit Admission	15 (46.9)	12 (37.5)	0.45
SOFA score	10.2 (± 3.0)	11 (± 3.2)	0.34
NE requirements, mcg/kg/min	0 (0, 0.136)	0.023 (0, 0.309)	0.02
MELD-Na	28.5 (± 8.5)	30.0 (± 8.2)	0.48
West-Haven grade			0.31
Unavailable	10 (31.3)	6 (18.8)
0	6 (18.8)	8 (25)
1	6 (18.8)	6 (18.8)
2	4 (12.5)	6 (18.8)
3	5 (15.6)	5 (15.6)
4	1 (3.1)	1 (3.1)
Glasgow Coma Score	9 (6, 14)	11 (7, 15)	0.69
Cirrhosis Etiology			0.21
Ethanol	17 (53.1)	21 (65.6)
Non-alcoholic steatohepatitis	9 (28.1)	5 (15.6)
Primary biliary cholangitis	2 (6.3)	1 (3.1)
Autoimmune hepatitis	2 (6.3)	1 (3.1)
Primary sclerosing cholangitis	0 (0)	1 (3.1)
Unknown	2 (6.3)	0 (0)
Other	0 (0)	3 (9.4)
Pre-ICU rifaximin treatment	12 (37.5)	17 (48.6)	0.21
Antibiotic Indication			0.80
Empiric; source unknown	20 (62.5)	23 (71.9)
Pneumonia	6 (18.8)	3 (9.4)
Intraabdominal	4 (12.5)	4 (12.5)
Bloodstream infection	1 (3.1)	1 (3.1)
Skin and soft tissue	1 (3.1)	0 (0)
Bone and joint infection	0 (0)	1 (3.1)
Rifaximin regimen			0.37
550 mg BID	31 (96.9)	31 (96.9)
400 mg BID	1 (3.1)	0 (0)
200 mg BID	0 (0)	1 (3.1)
Deep sedation use	5 (15.6)	9 (28.1)	0.38
Benzodiazepine use	3 (9.4)	0 (0)	0.29
Continuous neuromuscular blockade use	2 (6.3)	3 (9.4)	1.00
Polyethylene glycol use	9 (28.1)	13 (40.6)	0.29
Lactulose use	29 (90.6)	31 (96.9)	0.30
Gastrointestinal bleeding treatment	8 (25)	14 (43.8)	0.11
Alcohol withdrawal diagnosis	1 (3.1)	0 (0)	1.00
Ileus	6 (18.8)	9 (28.1)	0.56
C. difficile infection	1 (3.1)	2 (6.3)	1.00

All values are presented as mean ± SD, median (interquartile range), or N (%). BID: bis in die; ICU: Intensive care units; MELD-Na: Model for End-Stage Liver Disease Sodium score; NE: Norepinephrine; SOFA: Sequential Organ Failure Assessment score.

Table 3 Clinical, safety, and cost outcomes

Outcome	Control (n = 32)	Protocol (n = 32)	P value
Primary outcome
Days alive and free of delirium and coma to day 14	3 (0, 8)	2 (0, 9.5)	0.93
Secondary outcomes
Days alive and free of delirium	3 (0, 8.5)	2 (0, 9)	0.85
Days alive and free of coma (RASS)	6 (3.5, 12)	8 (4, 11)	0.81
Days alive and free of coma (GCS)	8 (5.5, 13)	7.5 (5.5, 9)	0.21
Glasgow Coma Score 48-h change	0 (-3, 1.5)	0 (-1, 0.5)	0.43
ICU mortality (%)	13 (40.6)	15 (46.9)	0.61
ICU length of stay	10 (4.5, 20.5)	11 (7, 17)	0.73
Time to first extubation from day 1 of intubation	6 (4, 14) (n = 23)	5 (4, 9) (n = 26)	0.49
Rate of reintubation (%)	4 (17.4)	3 (11.5)	0.56
IVVP requirement 48-h change, NE mcg/kg/min equivalents	0 (0, 0.12)	0 (0, 0.01)	0.45
Days of MICU combination therapy	6 (3, 9.5)	1 (0, 1)	< 0.01
Protocol adherence	-	91.4%	-
Time to rifaximin discontinuation, days	-	1 (0, 1)	-
Cost of rifaximin therapy per patient to day 14, USD
Minimum	379.20 (189.60, 600.40)	63.20 (0, 63.20)	< 0.01
Maximum	758.40 (379.20, 1200.80)	126.40 (0, 126.40)	< 0.01

GCS: Glasgow Coma Score; ICU: Intensive care unit; IVVP: Intravenous vasopressor; MICU: Medical intensive care unit; NE: Norepinephrine; RASS: Richmond Agitation-Sedation Scale; USD: United States dollar.

Table 4 Negative binomial multivariable model

(n = 60)	DAFD ratio (95%CI)
Group assignment (protocol)	0.78 (0.39, 1.56)
Deep sedation (yes)	0.89 (0.39, 2.02)
Gastrointestinal bleeding (yes)	0.65 (0.32, 1.31)
MELD-Na (per unit increase)	0.97 (0.94, 1.01)
Mechanical ventilation duration (per day)	0.79 (0.72, 0.87)

Reference value listed in parentheses. DAFD: Days alive and free of delirium and coma to day 14; MELD-Na: Model for End-Stage Liver Disease Sodium score; CI: Confidence interval.