What is the risk of development of C. difficile infection with cefazolin compared to ceftriaxone?

What is the risk of development of C. difficile infection with cefazolin compared to ceftriaxone?

Comment by InpharmD Researcher

Direct comparisons investigating the risk of Clostridioides difficile infection between cefazolin and ceftriaxone are limited. Two retrospective studies (Tables 1 and 2) have attempted to assess this risk as a secondary outcome. Results were conflicting; one study determined no significant difference, but the other suggests ceftriaxone may be associated with nearly double the risk of health care facility–onset Clostridioides difficile infection compared to cefazolin.

Background

A retrospective study reviewed hospital records between 2003 to 2005 of patients with hospital-acquired Clostridium difficile (C. difficile) infections and compared various factors between those who received certain antibiotics during their hospitalization. The control group consisted of patients from the general hospital database without C. difficile diagnosis and matched with the same age and primary diagnosis of the non-control group. Groups were further matched based on pre-C. difficile hospital length of stay. Of 121 hospital-acquired infections, 103 cases matched with controls. The C. difficile group had a longer average length of stay (8.7 days) and more estimated hospital cost ($1200 per day), compared to the control group. Of the 121 total cases, 68 patients received ceftriaxone, 46 vancomycin, 28 ceftazidime, 13 cefazolin, 13 clindamycin, 12 metronidazole, and 7 ampicillin, while 15 patients did not receive antibiotics at all. Ceftriaxone was associated with five times more C. difficile infections compared to cefazolin, despite nearly equal utilization. Of note, multiple patients received more than one antibiotic during their hospital course. Ultimately, these results suggest that third-generation cephalosporins are associated with incidence of C. diff infections, hospital length of stay, and hospital costs. [1]

A dated prospective study from 1991 investigated the incidence of C. difficile colonization following the administration of prophylactic antibiotics, specifically cephalosporins versus mezlocillin, in patients undergoing elective surgical procedures. A total of 108 patients (cefazolin, n= 14; ceftriaxone, n= 12) were randomized to be given a single 2 g intravenous prophylactic dose of either a cephalosporin or mezlocillin. Stool samples were cultured for C. difficile the day before the operation and later on postoperative days 4, 7, and 14. Overall, C. difficile was detected in 23% of patients who received a cephalosporin, with incidence rates of 14.3% for cefazolin and 25% for ceftriaxone, indicating that ceftriaxone may be associated with a higher incidence of C. difficile compared to cefazolin, although a direct statistical comparison was not performed. [2]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the risk of development of c. difficile infection with cefazolin compared to ceftriaxone?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Comparison of Cefazolin and Ceftriaxone Enterobacterales Susceptibilities for Inpatient Treatment of Urinary Tract Infections and Risk of Hospital-onset Clostridioides difficile Infection
Design	Retrospective single-center observational study N= 26,462
Objective	To assess the comparative activity of cefazolin and ceftriaxone for Enterobacterales urinary isolates and incidence of hospital-onset Clostridioides difficile infection (HOCDI) to determine the usefulness of cefazolin as an empirical agent to manage inpatient urinary tract infection (UTI) and limit ceftriaxone collateral damage
Study Groups	Cefazolin (n= 7,042) Ceftriaxone (n= 19,420)
Inclusion Criteria	Adult inpatients (≥ 18 years old) with urinary specimens of E. coli, K. pneumoniae, and P. mirabilis, and inpatients who received cefazolin or ceftriaxone during admission for at least 4 days
Exclusion Criteria	N/A
Methods	Microbiological susceptibility data were analyzed from an adult inpatient facility. Patients could receive cefazolin or ceftriaxone for any indication to determine the risk of HOCDI While the primary outcome focused on susceptibility patterns, the secondary outcome reported HOCDI risk associated with cefazolin and ceftriaxone, which will be the focus of this table.
Duration	Enrollment period: January 1, 2022 to December 31, 2022
Outcome Measures	Secondary outcome: HOCDI incidence associated with treatment (defined as a positive stool specimen collected ≥ 4 days since admission according to the Centers for Disease Control and Prevention's National Healthcare Safety Network definition)
Baseline Characteristics		Cefazolin (n= 7,042)	Ceftriaxone (n= 19,420)
	Age	63.4	66.1
	Female	53.8%	59.2%
	Weight, kg	86.7	85.2
	Days of antibiotic exposure	1.0	2.6
	UTI	4.6%	34.9%
	Length of stay, days	6.5	6.8
Results	Endpoint	Cefazolin (n= 7,042)	Ceftriaxone (n= 19,420)	Unadjusted odds ratio (95% confidence interval [CI]; p-Value)	Adjusted odds ratio (95% CI; p-Value)
Results	Incidence of HOCDI	11 (0.15%)	78 (0.40%)	2.58 (1.37 to 4.85; 0.03)	2.44 (1.25 to 4.76; 0.01)
Adverse Events	N/A
Study Author Conclusions	This study observed a > 60% relative risk reduction for HOCDI associated with cefazolin compared with ceftriaxone.
InpharmD Researcher Critique	The incidence of HOCDI was a secondary investigational outcome. Furthermore, the influence of additional antibiotics was not controlled within the study which could have affected the incidence rates in both patient groups.

References:

Wombwell E, Rosa A. Comparison of Cefazolin and Ceftriaxone Enterobacterales Susceptibilities for Inpatient Treatment of Urinary Tract Infections and Risk of Hospital-Onset Clostridioides difficile Infection. Clin Ther. Published online March 28, 2024. doi:10.1016/j.clinthera.2024.02.011

A Comparison of Cefazolin Versus Ceftriaxone for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia in a Tertiary Care VA Medical Center
Design	Retrospective, observational cohort study N= 71
Objective	To compare cefazolin and ceftriaxone treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia
Study Groups	Cefazolin (n= 38) Ceftriaxone (n= 33)
Inclusion Criteria	Diagnosis of MSSA bacteremia and treatment with cefazolin or ceftriaxone for ≥14 days
Exclusion Criteria	Received outpatient parenteral antimicrobial therapy (OPAT) with another antistaphylococcal antimicrobial in addition to cefazolin or ceftriaxone (with the exception of patients with a prosthesis or mycotic aneurysm), received empiric antimicrobials >72 hours after finalized cultures, OPAT was not used as curative modality, or if polymicrobial infection
Methods	Patients were identified and charts were reviewed via the Louis Stokes Cleveland Department of Veterans Affairs (VA) Medical Center's OPAT registry and electronic medical record system. Treatment failure was defined as unplanned extension of parenteral antimicrobial therapy, failure to complete the course of parenteral therapy, relapse of infection within 90 days of treatment completion, unplanned addition of suppressive oral antimicrobial therapy (except patients with a prosthesis or mycotic aneurysm), readmission or unanticipated surgical intervention related to the primary site of infection within 90 days of treatment completion, or the patient being lost to follow-up.
Duration	2009-2014
Outcome Measures	Primary outcome: rates of treatment failure Secondary outcome: rates of overall 90-day mortality, Clostridium difficile (C. diff) infection, adverse events
Baseline Characteristics		Cefazolin (n= 38)	Ceftriaxone (n= 33)	p-Value
	Age, years	63	64	0.724
	Male	95%	97%	0.641
	Race (n= 67)^ African American White	35% 65%	27% 73%	0.457
	Hemodialysis	24%	0	0.003
	Prosthesis	53%	24%	0.015
	Intravenous drug use	13%	0	0.039
	Duration of parenteral therapy	37.8 ± 8.3	38.1 ± 18.8	0.938
	Duration of empiric therapy	3.7 ± 2.5	3.9 ± 2.2	0.734
	Primary source of infection Osteoarticular Endovascular Presumed endocarditis Skin and soft tissue Urinary tract Unknown	42% 32% 13% 8% 5% 13%	36% 15% 6% 33% 3% 12%	0.086
	Achievement of source control	56%	58%	0.631
	Duration of bacteremia	2.8 ± 1.8	3.5 ± 3.3	0.276
	Blood culture clearance within 72 hours	74%	66%	0.439
	Bacteremia that persists ≥7 days	3%	3%	0.949
	Comorbid states including hypertension, diabetes mellitus, peripheral vascular disease, coronary artery disease, heart failure, hematologic/oncologic disorder, psychiatric disorder, and alcohol/tobacco use were not statistically difference ^Other and unknown race excluded from statistical analysis
Results	Endpoint	Cefazolin (n= 38)	Ceftriaxone (n= 33)	p-Value
	Treatment failure*† Extension of parenteral therapy Incomplete course Relapse after treatment Readmission Unplanned surgical intervention Unplanned oral antimicrobials Lost to follow-up	11 (29%) 0 5 (13%) 2 (5%) 5 (13%) 1 (3%) 2 (5%) 2 (5%)	18 (55%) 7 (21%) 0 4 (12%) 6 (18%) 5 (15%) 4 (12%) 4 (12%)	0.029 0.003 0.031 NS NS NS NS NS
	Mortality	4 (11%)	1 (3%)	NS
	C. diff infection	2 (5%)	1 (3%)	NS
	Adverse events Change of therapy due to adverse events	2 (5%) 2 (5%)	1 (3%) 0	NS NS
	NS: not significant (p≥ 0.05) *Treatment failure based on OPAT setting: reported as 41% (n= 39 of home) vs. 17% (n= 18 of community living center), 71% (n= 14 of skilled nursing facility), with skilled nursing facility patients having significantly increased incidence of treatment failure over community living center patients (p= 0.008) †Risk factors predictive of treatment failure: duration of parenteral therapy (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.01 to 1.10; p= 0.015) and heart failure (OR 7.93; 95% CI 2.43 to 25.92; p< 0.001)
Adverse Events	See results
Study Author Conclusions	Results suggest that cefazolin may be preferred to ceftriaxone for MSSA bacteremia in a high-acuity Veteran population, based on higher rates of treatment failure in the ceftriaxone group. Potential reasons for this could include the higher protein binding of ceftriaxone, ultimately resulting in lower serum concentrations of free drug, or other unknown factors. Further studies are warranted to confirm these results
InpharmD Researcher Critique	Incidence of C. diff infection in this patient population did not significantly differ, though the small sample size limits these results.

References:

Carr DR, Stiefel U, Bonomo RA, Burant CJ, Sims SV. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible staphylococcus aureus bacteremia in a tertiary care va medical center. Open Forum Infectious Diseases. 2018;5(5):ofy089.