Cephalosporins with warfarin increase the risk of bleeding: myth or fact?

Figures & data

Figure 1. Search terms used for literature search in PubMed and Scopus.

INR, international normalized ratio

Table 1. Summary of clinical studies evaluating cephalosporin–warfarin interaction.

Author [Ref]	Year	Study Design	Sample Size	Studied Cephalosporins	Outcomes
Angaran, et al. [6]	1987	Prospective randomized trial	20	Cefamandole Cefazolin	From the first to third day of antibiotic therapy, PT was significantly increased in the cefamandole group than in the cefazolin group (64 ± 14% vs. 51.1 ± 18%; P  < 0.0001)
Baillargeon, et al. [7]	2012	Retrospective case-control	75*	Cefaclor monohydrate Cefpodoxime Cefdinir Cefixime Cefuroxime Ceftizoxime Cefadroxil Ceftriaxone Ceftazidime Cefalexin Cefazolin	aOR for hospitalization for bleeding, 2.45; 95% CI, 1.52–3.95
Saum, et al. [8]	2014	Retrospective cohort	120	Cefazolin Cephalexin Ceftriaxone	Ceftriaxone increased INR by a median [IQR] of 54.4% [23.9–119], whereas first-generation cephalosporins (cefazolin and cephalexin) increased it by 39.6% [0.76–77.2]. Median [IQR] days to peak INR was 3 [1–5] with ceftriaxone and 2 [0.75–3] with first-generation cephalosporins. No bleeding events were reported.
Teklay, et al. [9]	2014	Prospective observational	133	Ceftriaxone Ceftazidime Cephalexin Cefotaxime	35 patients received cephalosporins in this study, 30 received ceftriaxone, 2 received ceftazidime, 2 received cephalexin, and 1 received cefotaxime. Ceftriaxone was associated with moderate interaction with warfarin, whereas the remaining cephalosporins were associated with major interaction. aOR (95% CI) for bleeding in case of major interaction was 1.52 (0.60–3.80; P  = 0.39).
Yagi, et al. [10]	2020	Retrospective cohort	1185	Cefdinir Cefpodoxime Cefcapene Cefditoren Cefazolin Ceftriaxone Cefepime Cefoperazone/sulbactam Cefmetazole Cefozopran	This study compared various β-lactams, including cephalosporins, with fluoroquinolones on INR changes when co-administrated with warfarin. INR values significantly increased from baseline in both groups (P < 0.01); though, the effect was more pronounced with fluoroquinolones (change was 0.23 with IV β-lactams and 0.06 with oral β-lactams vs. 0.4 with IV fluoroquinolones and 0.17 with oral fluoroquinolones). Odds of having INR > 2.5 was significantly higher with IV fluoroquinolones than with IV β-lactams (OR, 8.6; 95% CI, 1.03–68.4; P  < 0.01) but not when oral formulations were compared.
Imai, et al. [11]	2020	Retrospective cohort	203	Cefotiam Cefmetazole Cefmenoxime Cefoperazone Cefoperazone/sulbactam Ceftriaxone Cefotaxime Ceftazidime	Among 203 patients, 100 patients (50 per group) were matched by propensity score. Patients were divided by whether they received a cephalosporin with an NMTT side chain (cefotiam, cefmetazole, cefmenoxime, cefoperazone, or cefoperazone/sulbactam) on not (ceftriaxone, cefotaxime, or ceftazidime). The proportion of patients administered vitamin K was 6% in both groups (P  = 1). No bleeding was observed in either group. The proportion of patients subjected to a reduction in the daily dose of warfarin was 6.5% and 4.3% in the NMTT and non-NMTT groups, respectively (P = 1).

aOR, adjusted odds ratio; CI, confidence interval; INR, international normalized ratio; IQR, interquartile range; NMTT, N-methylthiotetrazole; OR, odds ratio; PT, prothrombin time.

*This is the sample size in the cephalosporins subgroup in the regression analysis as the study examined the impact of various antibiotics.

Table 2. Summary of case reports involving cephalosporin–warfarin interaction.

Author [Ref]	Year	Patient Age and Gender	Reported Cephalosporin and Dose	Outcome
Clark, et al. [12]	2011	67-year-old woman	Ceftriaxone 1 g daily	INR elevated 4 days after IV ceftriaxone administration for urinary tract infections on 2 different occasions.
Bohm, et al. [13]	2012	85-year-old woman	Ceftaroline (dose not specified)	Development of hemarthrosis due to INR elevation.
Farhat, et al. [14]	2016	65-year-old man	Ceftaroline 400 mg q12h	INR elevation to > 18 after 12 days of ceftaroline therapy.
Chartier, et al. [15]	2020	80-year-old woman	Cephalexin 500 mg q12h	Development of epistaxis for 24 hours with INR elevation to > 10 after a 7-day course of twice-daily cephalexin.

Angaran DM, Dias VC, Arom KV, et al. The comparative influence of prophylactic antibiotics on the prothrombin response to warfarin in the postoperative prosthetic cardiac valve patient. Cefamandole, cefazolin, vancomycin. Ann Surg. 1987 Aug;206(2):155–161. doi: 10.1097/00000658-198708000-00007

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Baillargeon J, Holmes HM, Lin YL, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 Feb;125(2):183–189. doi: 10.1016/j.amjmed.2011.08.014

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Saum LM, Balmat RP. Ceftriaxone potentiates warfarin activity greater than other antibiotics in the treatment of urinary tract infections. J Pharm Pract. 2016 Apr;29(2):121–124. doi: 10.1177/0897190014544798

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Teklay G, Shiferaw N, Legesse B, et al. Drug-drug interactions and risk of bleeding among inpatients on warfarin therapy: a prospective observational study. Thromb J. 2014;12(1):20. doi: 10.1186/1477-9560-12-20

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Yagi T, Naito T, Kato A, et al. Association between the prothrombin time-international normalized ratio and concomitant use of antibiotics in warfarin users: focus on type of antibiotic and susceptibility of bacteroides fragilis to antibiotics. Ann Pharmacother. 2021 Feb;55(2):157–164. doi: 10.1177/1060028020940728

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Imai S, Kadomura S, Momo K, et al. Comparison of interactions between warfarin and cephalosporins with and without the N-methyl-thio-tetrazole side chain. J Infect Chemother. 2020 Nov;26(11):1224–1228. doi: 10.1016/j.jiac.2020.07.014

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Clark TR, Burns S. Elevated international normalized ratio values associated with concomitant use of warfarin and ceftriaxone. Am J Health Syst Pharm. 2011 Sep 1;68(17):1603–1605. doi: 10.2146/ajhp100681

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Bohm NM, Crosby B. Hemarthrosis in a patient on warfarin receiving ceftaroline: a case report and brief review of cephalosporin interactions with warfarin. Ann Pharmacother. 2012 Jul;46(7–8):e19. doi: 10.1345/aph.1Q771

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Farhat NM, Hutchinson LS, Peters M. Elevated international normalized ratio values in a patient receiving warfarin and ceftaroline. Am J Health Syst Pharm. 2016 Jan 15;73(2):56–59. doi: 10.2146/ajhp140897

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Chartier AR, Hillert CJ, Gill H, et al. Acquired factor V inhibitor after antibiotic therapy: a clinical case report and review of the literature. Cureus. 2020 Jul 30;12(7):e9481. doi: 10.7759/cureus.9481

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