Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

Takaya Namiki; Yuta Yokoyama; Motonori Kimura; Shogo Fukuda; Shoji Seyama; Osamu Iketani; Masaru Samura; Haruki Ishikawa; Aya Jibiki; Hitoshi Kawazoe; Hisakazu Ohtani; Naoki Hasegawa; Kazuaki Matsumoto; Hideki Hashi; Sayo Suzuki; Tomonori Nakamura

doi:10.1371/journal.pone.0322909

. 2025 Jul 28;20(7):e0322909. doi: 10.1371/journal.pone.0322909

Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

Takaya Namiki ^1,², Yuta Yokoyama ^1,^3,^*, Motonori Kimura ⁴, Shogo Fukuda ⁴, Shoji Seyama ^5,^¤, Osamu Iketani ⁶, Masaru Samura ⁷, Haruki Ishikawa ⁴, Aya Jibiki ³, Hitoshi Kawazoe ^1,³, Hisakazu Ohtani ⁴, Naoki Hasegawa ⁸, Kazuaki Matsumoto ⁹, Hideki Hashi ², Sayo Suzuki ^1,³, Tomonori Nakamura ^1,³

Editor: Mehmet Baysal¹⁰

¹Division of Pharmaceutical Care Sciences, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan

²Department of Pharmacy, Tokyo Bay Urayasu Ichikawa Medical Center, Chiba, Japan

³Division of Pharmaceutical Care Sciences, Center for Social Pharmacy and Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, Tokyo, Japan

⁴Department of Pharmacy, Keio University Hospital, Tokyo, Japan

⁵Division of Infectious Diseases and Infection Control, Keio University Hospital, Tokyo, Japan

⁶Division of Academic Research Support, Keio University Hospital, Tokyo, Japan

⁷Department of Pharmacy, Yokohama General Hospital, Kanagawa, Japan

⁸Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan

⁹Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan

¹⁰Tekirdag Namik Kemal University: Tekirdag Namik Kemal Universitesi, TÜRKIYE

Competing Interests: Dr. H. K. received research funding from Eli Lilly outside of the submitted work. Dr. K. M. received grants from Meiji Seika Pharma, Sumitomo Pharma and Shionogi outside of the submitted work. T.N. received research funding from Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical, Sanofi, and Shionogi outside of the submitted work. Conflicts that the editors consider relevant to the manuscript content have been disclosed. There are no conflicts of interest to declare. Although Dr. H. K, Dr. K. M, and Dr. T. N have received funding outside of the research, this does not alter our adherence to PLOS ONE policies on sharing data and materials. We have submitted to ICMJE.

^¤

Current address: Department of Clinical Microbiology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

^✉

* E-mail: yokoyama-yt@pha.keio.ac.jp

Roles

Takaya Namiki: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing

Yuta Yokoyama: Conceptualization, Methodology, Writing – review & editing

Motonori Kimura: Data curation, Writing – review & editing

Shogo Fukuda: Data curation, Writing – review & editing

Shoji Seyama: Data curation, Writing – review & editing

Osamu Iketani: Data curation, Writing – review & editing

Masaru Samura: Conceptualization, Formal analysis, Validation, Writing – review & editing

Haruki Ishikawa: Data curation

Aya Jibiki: Writing – review & editing

Hitoshi Kawazoe: Writing – review & editing

Hisakazu Ohtani: Writing – review & editing

Naoki Hasegawa: Writing – review & editing

Kazuaki Matsumoto: Writing – review & editing

Hideki Hashi: Writing – review & editing

Sayo Suzuki: Writing – review & editing

Tomonori Nakamura: Supervision

Mehmet Baysal: Editor

PMCID: PMC12303349 PMID: 40720441

Abstract

Patient risk factors related to coagulopathy and bleeding when using cefmetazole (CMZ) have not yet been identified, and no models exist to predict side effects during CMZ treatment. Moreover, reports that examine which patients should be careful when using CMZ to ensure safety are lacking. Our objective was to understand risk factors for elevated international normalized ratio (INR) in patients using CMZ and to develop a predictive model for INR elevation using a risk score to enable safe administration of CMZ. This multicenter, retrospective, and observational study was conducted in Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital using data from patients being treated with CMZ. Patients were classified into INR-elevated or non-INR-elevated groups. Univariate and multivariate analyses were performed to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). The actual probability of an elevated INR and probability of an elevated INR predicted by the regression β coefficients were calculated and classified into four categories according to the risk score. Binomial logistic regression analysis revealed that liver disorder (aOR, 5.65; 95% CI, 1.69–18.91; risk scores, 2), nutritional risk (aOR, 6.32; 95% CI, 3.14–12.74; risk scores, 2), no-diabetes mellitus (aOR, 4.53; 95% CI, 1.34–15.26; risk scores, 2), and warfarin use (aOR, 98.44; 95% CI, 7.05–1375.50; risk scores, 5) were significantly associated with INR elevation. The predicted incidence probabilities of INR elevation were < 5% (low risk), 5– < 30% (medium risk), 30– < 90% (high risk), and ≥ 90% (very high risk). The model validity showed a good fit (AUC, 0.79; 95% CI, 0.73–0.85, P < 0.001). We identified risk factors that contribute to INR elevation and constructed a model to predict INR elevation using the risk score. Using this predictive model enables the appropriate use of CMZ in a safe manner.

Introduction

Extended-spectrum β-lactamase-producing enterobacteria (ESBL-E) have become a major public health challenge owing to increasing number of patients affected by antimicrobial-resistant bacteria between 2012 and 2017, leading to increased morbidity and mortality rates [1,2]. ESBL-E strains are usually treated with carbapenems [3], but the emergence of carbapenem-resistant Enterobacteriaceae due to increased use of carbapenems remains a point of concern [4].

Among the cephem antibiotics, cefmetazole (CMZ), which is a cephamycin antibiotic, shows stability against hydrolysis of ESBL-E [5] and has recently attracted attention as an alternative to carbapenems [6,7]. The only cephamycin-type antibiotic available in Japan is cefmetazole, and cefotetan (CTT), which is available in the United States, cannot be used. However, CMZ and CTT has an N-methyltetrazolethiol (NMTT) group in its structure, and it has been reported that the NMTT group inhibits vitamin K 2, 3-epoxide reductase (VKOR) [8]. VKOR is required to convert vitamin K epoxide to vitamin K [9,10]. Inhibition of VKOR inhibits the vitamin K cycle and prevents the production of vitamin K. Therefore, it has been reported that the use of antibiotics containing NMTT groups is significantly associated with coagulopathy and bleeding [11–13]. Risk factors have been reported for some antibiotics containing the NMTT group. Risk factors for coagulopathy reported for latamoxef include cumulative defined daily doses (DDDs) and nutritional risk [11]. Risk factors for bleeding reported for cephem antibiotics include anticoagulant use, liver disorder, nutritional risk, and history of hemorrhagic events 6 months prior to the index date. Risk factors for bleeding for CMZ have not yet been identified, nor is there a model for predicting bleeding side effects for CMZ [12]. Furthermore, there are no reports that identified risk factors such as area under the blood concentration-time curve (AUC), which is an index of internal exposure, by calculated pharmacokinetic parameters for each patient treated with CMZ. In addition, there are no reports examining what kind of patients require caution when using CMZ in order to ensure safety.

This study aimed to identify the risk factors for INR elevation due to CMZ use, including determining AUC, and to construct a model to predict INR elevation using risk scores, thereby enabling the safe administration of CMZ.

Materials and methods

Patient information

This retrospective observational study was conducted on patients who were being administered CMZ at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital between January 2019 and October 2022. This study was reviewed and approved by the central comprehensive review of the Keio University School of Medicine Ethics Committee (Approval date: January 16, 2023, approval Number: 20221159). Approval was also obtained from the Tokyo Bay Urayasu Ichikawa Medical Center Ethics Review Committee (Approval date: January 27, 2023, approval Number: 819) and the Research Ethics Committee of the Faculty of Pharmaceutical Sciences, Keio University (Approval date: May 30, 2023, approval Number: 230530−1). Informed consent was obtained using an opt-out document on the hospital website. This study did not include minors. Data was collected in a form that does not allow personal information to be identified. The dates of access to electronic medical record data were from June/1/2023 to July/31/2023, after obtaining approval from the ethics committee of each facility.

Patients for whom INR was unmeasured prior to commencing CMZ use, patients who were prescribed CMZ for prevention of surgical site infections, and patients with a history of CMZ use were excluded. Next, mainly when starting CMZ, patients were excluded according to the following criteria: continuous bleeding from before CMZ use, unstable baseline INR (prolonged from baseline INR due to acute illness, e.g., septic shock), started concurrently with other antibiotics, intravenous administration of vitamin K preparation during the hospitalization period, unstable effect of warfarin and direct oral anticoagulants (DOACs), continuous hemodiafiltration patients, intermittent hemodiafiltration patients, pregnant women, and children (Under 15 years old).

Data collection

Drug and molecular target nomenclature conforms to the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide standards [14]. The following patient information was collected from electronic medical records on the INR maximum day during CMZ use: age, sex, body weight, body mass index (BMI), creatinine clearance (CL_CR) using the Cockcroft-Gault formula, albumin (ALB), D-dimer, baseline INR (within 7 days prior to starting CMZ use), maximum INR when using CMZ, dosage up to the day of maximum INR, daily dose, AUC, hypertension, no-diabetes mellitus (patients not diagnosed with diabetes mellitus), cancer, nutritional risk (NRS2002 score of 3 or higher), [15] liver disorder (Child-Pugh classification of B or higher), hemodialysis, antibiotic use history within the past 6 months, surgery history within the past 6 months, bleeding history within the past 6 months, type of infection, concomitant use of warfarin, DOACs, antiplatelet drugs, nutrient drugs (containing vitamin K), NSAIDs, and steroids. Elevated INR was defined as a ratio of maximum INR to baseline INR (maximum INR divided with baseline INR) during CMZ use greater than 1.25 [11]. The NRS2002 score consists of four initial screening items, and if any of these items apply, final screening is carried out. 1: BMI is less than 20.5, 2: The patient has lost weight within the past 3 months, 3: The patient has decreased food intake in the past week, 4: The patient is seriously injured (e.g., is the patient receiving treatment in an Intensive Care Unit?) At the final screening, participants were scored according to the severity of malnutrition and the severity of disease or trauma: None, score 0; mild, score 1; moderate, score 2; severe, score 3. If patient age is 70 years or greater, add 1 to each total [15]. The dosage was evaluated as a daily dose, taking into consideration the difference due to the time of blood sampling. AUC was calculated by dividing the dose on the day of the highest INR by unbound CMZ clearance (CL). We performed a population pharmacokinetic analysis using unbound CMZ concentration in non-hemodialysis and constructed a final model formula of unbound CMZ. The final model formula was CL = 16.2 × (CL_CR/4.36)^0.781 × (ALB/28)^1.2 L/h [16]. The CL of unbound CMZ was calculated by substituting CL_CR and ALB for each patient into this formula. For CL in patients undergoing hemodialysis, we used the mean values of non-hemodialysis CL (CL_non-HD) and hemodialysis CL (CL_HD) that we clarified. CL_non-HD and CL_HD were 0.803 L/h and 12.6 L/h [17]. AUC was calculated by dividing the dose for each patient by the sum of CL_HD + CL_non-HD according to the hemodialysis time and the non-hemodialysis time. To define as stable state of warfarin therapy, we confirmed the following: no dose changes for at least 7 days prior to CMZ use and no dose change during CMZ use, 2 or more measurements of INR within the therapeutic range during the 7 days prior to commencement of CMZ use [18–20]. DOACs were patients with no dose changes for during and within 7 days prior to CMZ use.

Statistical analysis

SPSS version 28.0 (SPSS Inc., Chicago, IL) and R (Version 4.2.1) were used for data analysis. The following factors were compared between groups to identify risk factors for INR elevation when using CMZ; age, sex, body weight, BMI, CL_CR, ALB, baseline INR, daily dose, AUC, hypertension, no-diabetes mellitus, cancer, nutritional risk, liver disorder, hemodialysis, antibiotic use history within the past 6 months, surgery history within the past 6 months, bleeding history within the past 6 months, type of infection, concomitant use of warfarin, DOACs, antiplatelet drugs, nutrients drugs, NSAIDs, and steroids. Multicollinearity confirmation retained factors with lower P-values during univariate analysis when the correlation coefficient between each factor > 0.4. Furthermore, the variance inflation factor (VIF) was also confirmed. A VIF of 5 or more suggested the possibility of multicollinearity, and a VIF of 10 or more was multicollinear. Continuous variables were subjected to the Mann–Whitney U test after confirmation of normality. Fisher’s exact test and chi-square test were performed for categorical variables. Multivariate analysis was performed using the forced entry method for factors with P < 0.1 as a result of univariate analysis. To change the cut-off value, receiver operating characteristic (ROC) analysis was performed, the optimum value was obtained, and multivariate analysis was performed again. From the results of multivariate analysis using the stepwise method with P < 0.05 as statistically significant, risk score assignment and INR elevated prediction probability were determined. Multivariate analysis was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) to identify risk factors. Based on previous reports, we assigned a risk score to each risk factor using the β coefficient obtained from the binomial logistic regression analysis [21,22]. From the total score of each risk factor, four risk classifications of low risk (< 5%), medium risk (5– < 30%), high risk (30– < 90%), and very high risk (≥ 90%) were performed for each elevated INR occurrence probability [21,23]. The adequacy of the risk prediction model for the probability of elevated INR associated with CMZ was assessed using the Hosmer–Lemeshow test, and predictive and observed estimates of elevated INR associated with CMZ were compared using calibration plots. A bootstrap of 1000 replicates was set and a calibration curve was calculated using regression analysis. Verification was also performed using an ROC curve that evaluated the AUC.

Results

Patient data

The study covered 4,877 patients who used CMZ, with 565 intermediate target patients, for a final total of 429 patients after applying the exclusion criteria (61 in the elevated group and 368 in the non-elevated group) (Fig 1). The median age of the final target patients was 72 (interquartile range [IQR]: 60–82), and 74 (IQR: 65–83) and 72 (IQR: 60–82) years in the INR-elevated and non-INR-elevated groups, respectively. The proportion of males among the final target patients was 57.3% in the final target patients and 59% and 57.1%, in the INR-elevated and non-INR elevated groups, respectively (Table 1).

Table 1. Final target patients of this study and Univariate and multivariate analysis of risk factors for cefmetazole (CMZ)-induced international normalized ratio (INR) elevation.

	Final target patients (n = 429)	Univariate analysis			Multivariate analysis
	Final target patients (n = 429)	INR-elevated (n = 61)	Non-INR-elevated (n = 368)	P value	Adjusted OR (95% CI)	P value
Age (years old)	72 (60–82)	74 (65–83)	72 (60–82)	0.364
Sex (male)	246 (57.3)	36 (59.0)	210 (57.1)	0.775
Body weight (kg)	56.2 (47.8–66.0)	52.7 (45.2–63.1)	56.9 (48.5–66.2)	0.063
BMI (kg/m²)	21.6 (19.3–24.5)	20.3 (18.4–23.1)	21.8 (19.6–24.6)	0.016	1.02 (0.94–1.11)	0.645
CL_CR (mL/min)^a	64.8 (42.5–91.7)	51.8 (35.9–78.7)	66.9 (43.7–93.2)	0.011	1.00 (0.99–1.01)	0.596
Albumin (g/L)	30 (25–34)	27 (23–31)	30 (25–35)	0.008	1.64 (0.93–2.88)	0.086
D-dimer^b	5.8 (2.75–10.65)	7.39 (3.9–11.43)	5.6 (27–9.85)	0.378
Baseline INR	1.05 (0.99–1.14)	1.05 (0.97–1.16)	1.05 (0.99–1.14)	0.864
Total dose (g)^c	3 (2–8)	6 (2–13)	3 (2–7)	0.025
4 g or less daily	401 (93.5)	57 (93.4)	344 (93.5)	0.992
Over 4 g daily	28 (6.5)	4 (6.6)	24 (6.5)	0.992
AUC (g・h/L)^d	258.4 (100–697.2)	585.7 (135–1597)	245.1 (97.5–582.4)	<0.001
Hypertension	229 (53.4)	34 (55.7)	195 (53.0)	0.690
No-diabetes mellitus	349 (81.4)	55 (90.2)	294 (79.9)	0.056	4.53 (1.34–15.3)	0.015
Cancer	144 (33.6)	22 (36.1)	122 (33.2)	0.655
Nutritional risk^e	194 (45.2)	49 (80.3)	145 (39.4)	<0.001	6.32 (3.14–12.7)	<0.001
Liver disorder^f	338 (78.8)	58 (95.1)	280 (76.1)	0.001	5.65 (1.69–18.9)	0.005
Hemodialysis	14 (3.3)	5 (8.2)	9 (2.4)	0.036	3.08 (0.58–16.3)	0.185
Antibiotic use history^g	194 (45.2)	32 (52.5)	162 (44.0)	0.22
Surgical history^g	16 (3.7)	5 (8.2)	11 (3.0)	0.062	1.55 (0.39–6.09)	0.533
Bleeding history^g	61 (14.2)	7 (11.5)	54 (14.7)	0.437
Type of infection
Urinary tract	44 (10.3)	3 (4.90)	41 (11.1)	0.138
Gastrointestinal disease	347 (80.9)	50 (82.0)	297 (80.7)	0.817
Pneumonia	29 (6.8)	6 (9.8)	23 (6.3)	0.278
Bacteremia	48 (11.2)	5 (8.2)	43 (11.7)	0.423
Others^h	0 (0)	10 (2.3)	10 (2.7)	0.37
Concomitant use
Warfarin	6 (1.4)	5 (8.2)	1 (0.3)	<0.001	98.4 (7.05–1375.5)	<0.001
DOACs	24 (5.6)	7 (11.5)	17 (4.6)	0.040	1.75 (0.54–5.64)	0.347
Antiplatelet drugs	83 (19.3)	13 (21.3)	70 (19.0)	0.675
Nutrient drugsⁱ	28 (6.5)	5 (8.2)	23 (6.3)	0.575
NSAIDs	202 (47.1)	29 (47.5)	173 (47.0)	0.939
Steroids	74 (17.2)	9 (14.8)	65 (17.7)	0.578

Open in a new tab

Data are presented as the median [interquartile range] for continuous variables and numbers (%) for categorical variables.

Abbreviations: BMI, body mass index; AUC, area under the curve; DOACs, direct oral anticoagulant; INR, international normalized ratio; NSAIDs, non-steroidal anti-inflammatory drugs.

^aCL_CR was estimated using the Cockcroft-Gault equation with measured body weight.

^bData from 65 people who measured D-dimer.

^cTotal dose was dosage up to the day of maximum INR.

^d AUC was calculated by dividing the total dose up to the day of maximum INR by unbound CMZ clearance (CL). For non-hemodialysis patients, the CL was calculated from CL_CR and albumin for each patient. For hemodialysis patients, the CL of hemodialysis and non-hemodialysis were calculated according to the hemodialysis time and the non-hemodialysis time.

^eNutritional risk was NRS2002 score of 3 or higher.

^fLiver disorder was Child-Pugh classification of B or higher.

^gWithin the last 6 months.

^hOthers were patients with skin infections, bone infections, renal abscesses, and febrile neutropenia.

ⁱNutrient drugs refers to drugs containing vitamin K.

INR-elevated risk factor identification

Univariate analysis showed P < 0.1 and statistically significant difference in body weight, BMI, CL_CR, ALB, AUC, no-diabetes mellitus, nutritional risk, liver disorder, history of surgery within the last 6 months, and concomitant use of warfarin and DOACs. Correlations were confirmed and correlations were shown between body weight and BMI (r = 0.86, P < 0.001) and CL_CR (r = 0.424, P < 0.001), respectively. According to univariate analysis, body weight was excluded because the P values for BMI and CL_CR were lower than the P values for body weight. AUC was correlated with various factors including ALB (r = 0.390, P < 0.001), hemodialysis (r = 0.287, P < 0.001), CL_CR (r = 0.240, P < 0.001), warfarin (r = 0.213, P < 0.001), and nutritional risk (r = 0.205, P < 0.001), respectively. The VIF results showed VIF < 5, indicating no multicollinearity. Binomial logistic regression analysis revealed liver disorder (aOR, 5.65; 95% CI, 1.69–18.91), nutritional risk (aOR, 6.32; 95% CI, 3.14–12.74), no-diabetes mellitus (aOR, 4.53; 95% CI, 1.34–15.26), and warfarin (aOR, 98.44; 95% CI, 7.05–1375.50) were significant at P < 0.05. The predicted correctness probability of the model was 73.8% sensitivity, 75.5% specificity, and 75.3% overall with the change in the cut-off value of binomial logistic regression analysis using ROC analysis. Although AUC was statistically significant at P = 0.04, it did not contribute to the elevated INR (aOR, 1.00; 95% CI, 1.00–1.00).

INR-elevated prediction model construction and accuracy verification

The results of stepwise binomial logistic regression analysis based on liver disorder, nutritional risk, no-diabetes mellitus, and use of warfarin are shown in Table 2. Using the β coefficient, risk scores were assigned as follows: liver disorder, 2; nutritional risk, 2; no-diabetes mellitus, 2; warfarin, 5. A risk score was calculated for each patient, and the predicted occurrence probability obtained from the regression equation and the actual occurrence probability for each risk score are shown in Fig 2. Risk scores between 0 and 2 were low risk (predicted probability < 5%), a risk score of 4 was medium risk (predicted probability 5– < 30%), those between 6–7 were high risk (predicted probability 30– < 90%), and those of 9 or higher were very high risk (predicted probability of occurrence ≥ 90%). The probability of INR elevation for each risk factor possessed by patients using CMZ is shown in Table 3. Patients with all risk factors had a risk score of 11 (very high risk). Patients with two of the three risk factors for liver disorder, nutritional risk, and no-diabetes mellitus, in addition to warfarin use, had a risk score of 9 (very high risk). Patients with all risk factors (liver disorder, nutritional risk, and no-diabetes mellitus), except for warfarin use, had a risk score of 6 (high risk). Patients not using warfarin and with one of the three risk factors, namely, liver disorder, nutritional risk, and no-diabetes mellitus, had a risk score of 2 (low risk).

Table 2. Multivariable analysis of risk factors for cefmetazole-induced international normalized ratio (INR) elevation.

Risk factor	β	SE	Wald	p value	Adjusted OR (95% CI)	Risk score
Liver disorder^a	1.73	0.62	7.88	0.005	5.65 (1.69–18.9)	2
Nutritional risk^b	1.84	0.36	26.6	<0.001	6.32 (3.14–12.7)	2
No-diabetes mellitus	1.51	0.62	5.93	0.015	4.53 (1.34–15.3)	2
Warfarin	4.59	1.35	11.6	<0.001	98.4 (7.05–1375.5)	5
Intercept	−5.86	0.88	44.0	<0.001	0.003

Open in a new tab

^a Liver disorder was Child-Pugh classification of B or higher.

^b Nutritional risk was NRS2002 score of 3 or higher.

Abbreviations: β, partial regression coefficient; SE, standard error; OR, odds ratio; CI, confidence interval.

Fig 2 — The individual risk score was calculated using Table 2. The percentages of incidence of INR elevation in the prediction set with patients using CMZ are shown as the mean of each score.

Table 3. Probability of cefmetazole-induced international normalized ratio (INR) elevation for each risk factor possessed by the patient.

		Risk factor
Risk classification	Incidence of INR elevation	Liver disorder	Nutritional risk	No-diabetes mellitus	Warfarin
Very high risk	≥ 90%	Yes	Yes	Yes	Yes
		Yes	Yes	No	Yes
		No	Yes	Yes	Yes
		Yes	No	Yes	Yes
High risk	30– < 90%	Yes	No	No	Yes
		No	Yes	No	Yes
		No	No	Yes	Yes
		Yes	Yes	Yes	No
Moderate risk	5– < 30%	Yes	Yes	No	No
		No	Yes	Yes	No
		Yes	No	Yes	No
Low risk	< 5%	Yes	No	No	No
		No	Yes	No	No
		No	No	Yes	No
		No	No	No	No

Open in a new tab

^aLiver disorder was Child-Pugh classification of B or higher.

^bNutritional risk was NRS2002 score of 3 or higher.

The Hosmer–Lemeshow test showed P = 0.782, and the calibration plot showed a small mean absolute error of 0.004, demonstrating the validity of the model (Fig 3). In addition, the validity of the model showed good fit in the ROC analysis (AUC, 0.79; 95% CI, 0.73–0.85, P < 0.001) (Fig 4).

Fig 3 — Perfect prediction is shown by the diagonal black dashed line. The black small, dotted line shows the entire cohort. The black solid line represents bias correction with bootstrapping.

Fig 4 — Area under the curve, 0.79 (95% confidence interval, 0.73–0.85); P < 0.001; sensitivity, 78.7%; specificity, 69.8%.

Bleeding of patients using CMZ

Bleeding of patients using CMZ was observed in 3 patients in the INR-elevated group (4.9%) and 3 patients in the non-INR-elevated group (0.82%), P = 0.04, showing a statistically significant difference.

Discussion

Risk factors INR elevation in patients using CMZ were liver disorder, nutritional risk, no-diabetes mellitus, and concomitant administration of warfarin. In addition, we presented the probability of elevated INR for each risk score in patients with these risk factors, which we believe will contribute to the safe use of CMZ.

Liver disorder, nutritional risk, and anticoagulant use have previously been reported as risk factors affecting bleeding and coagulopathy [11,12] The liver is the site of production of coagulation factors for hemostasis, and patients with liver disorder experience a decline in the ability to synthesize coagulation factors. In addition, impaired excretion of bile acids into the intestinal tract results in impaired absorption of vitamin K. These factors result in INR elevation [24]. In patients with nutritional risk, lower dietary vitamin K intake may have led to elevated INR due to reduced functional activity of vitamin K-dependent clotting factors [25]. In the regulation of blood coagulation Vitamin K is reduced to reduced vitamin K by vitamin K reductase during the synthesis of different vitamin K-dependent proteins such as prothrombin and factors VII, IX and X. Reduced vitamin K is the active cofactor required for γ-carboxylation of glutamate. During this reaction, reduced vitamin K is then converted to vitamin K epoxide, which is converted back to vitamin K by VKOR [9,10]. The γ-carboxylated glutamic acid groups of these proteins promote the coagulation cascade by binding with Ca²⁺. Vitamin K plays a vital role in clotting activity [9]. Warfarin inhibits VKOR and causes INR elevation. The reason why warfarin was the factor most strongly associated with elevated INR may be that it has the same mechanism of action as CMZ [26] In this study, no-diabetes mellitus was first identified as a risk factor for coagulopathy by antibiotics containing the NMTT group. It has been reported that diabetes mellitus patients are more prone to thrombosis than those without diabetes mellitus due to factors such as increased platelet reactivity, increased coagulation factors, and impaired fibrinolysis [27]. It has also been reported that patients with diabetes mellitus require 1.5 to 2 times the dosage of warfarin to maintain INR as compared to patients without diabetes mellitus [28]. Therefore, the clotting tendency of diabetes mellitus patients may have suppressed INR elevation in patients using CMZ. It should be noted that the risk score for no-diabetes mellitus patients is 2 points, and with a risk score of 2, the risk of INR elevation is approximately 1%, so not all no-diabetes mellitus patients will develop coagulation disorders when using CMZ. However, we think it would be prudent to use CMZ while keeping in mind that the INR may elevate when combined with other factors such as liver disorder and nutritional risk.

The CL of unbound CMZ for each patient was calculated, and the AUC calculated using this was statistically significant at P = 0.04, but the aOR was 1.00 and had almost no effect on INR elevation. This might be owing to differences in blood collection dates and other correlation factors and was excluded from the final model. DOACs were dabigatran (0 in the INR-elevated group, 1 in the non-INR-elevated group), rivaroxaban (0 in the INR-elevated group, 5 in the non-INR-elevated), apixaban (5 in the INR-elevated group, 3 in the non-INR-elevated group), and edoxaban (2 in the INR-elevated group, 8 in the non-INR-elevated group). DOACs were statistically significant in univariate analysis, but not in multivariate analysis. If patients on CMZ require anticoagulants, using DOACs instead of warfarin may prevent INR elevation. However, since the effect on INR elevation varies depending on the type of DOACs, it is necessary to be careful when judging based on this result alone [29]. In this study, the factors identified as risk factors were not factors related to CMZ exposure, but factors affecting vitamin K and clotting factors. The synergistic effect of CMZ inhibition of VKOR and each risk factor suggests the possibility that coagulopathy may have appeared more strongly.

Patients taking warfarin are more likely to have their INR checked regularly. However, even in patients with stable INR prior to CMZ use, CMZ use was shown to result in elevated INR. Therefore, INR measurements should be considered for several days after starting CMZ. Patients not taking warfarin may not undergo regular INR measurements. However, patients with any one of these risk factors of liver disorder, nutritional risk, and no-diabetes mellitus were newly found to be at risk of elevated INR. In particular, patients possessing all of these risk factors are at high risk (probability of INR elevated: 30– < 90%) and may require INR monitoring.

Previously, what kind of patients were likely to experience INR elevation among those using CMZ was unclear. However, it has become possible to calculate the risk score for each patient before using CMZ and use it after considering the probability of INR elevation. In addition, since the median maximum elevated INR after commencing the use of CMZ was observed on day 3, it is considered that elevated INR can be detected early by measuring INR around 3 days after starting CMZ. On the other hand, low-risk patients with a risk score of 0 or 2 had a very low probability of INR elevation. Low-risk patients are less likely to experience INR elevation and are expected to experience less bleeding. Therefore, it can be administered without excessive concern for bleeding-related side effects or frequent blood sampling for INR measurements. Due to the variety of patients in clinical practice, there is a need for a simple, visual tool to determine how much risk a patient is at risk for INR elevation before starting CMZ. Table 3 shows the probability of INR elevation in patients using CMZ for each risk factor possessed by the patient. Using this will enable the safe administration of CMZ. In addition, since there were no actual patients, validity evaluation was not possible, but when assuming a patient with the risk factor of warfarin use only (risk score 5), the probability of INR elevation was calculated by regression equation to be 20.9%. This probability of INR elevation is between the risk score of 4 and 6–7 points shown in Fig 2. In this study, the identified risk scores were 2 for three factors and 5 for one factor, and due to issues with the combination of explanatory variables in the regression equation constructed, the probability of INR elevation could not be evaluated for risk scores of 3 and 8. However, based on the above assumptions, it is assumed that the probability of INR elevation is between 2 and 4 for a risk score of 3, and between 6–7 and 9 for a risk score of 8.

Previous reports have shown that CMZ significantly increases bleeding [12]. There was a statistically significant difference when comparing bleeding after CMZ use between the INR-elevated group and the non-elevated group. In this study, elevated INR was defined as a ratio of a ratio of maximum INR to baseline INR (maximum INR divided with baseline INR), during CMZ use, greater than 1.25 [11]. Regarding the relationship between INR elevated and bleeding risk, a previous report reported that the higher the INR, the more bleeding occurred [13]. This criterion was used because the aim was to find patients with elevated INR at an early stage. Early use of vitamin K preparations should be considered if significant elevated is observed during INR monitoring to prevent bleeding.

A limitation of this study is that it is a retrospective study, so unobserved risk factors could not be identified. We were unable to collect VKOR gene polymorphisms due to study design limitations. Furthermore, as this study was based on data from one city hospital and one university hospital in Japan, the sample size was limited to 429 patients. In addition, because the study only included Japanese subjects, it is unclear whether similar results would be obtained in non-Japanese patients. Therefore, it is considered that the influence of factors other than the identified risk factors has not been comprehensively evaluated. For further investigations, it is necessary to expand the sample size by including more survey facilities and using big data.

Conclusion

Liver disorder, nutritional risk, no-diabetes mellitus, and warfarin use were significantly associated with INR elevation in patients using CMZ. In addition, we successfully constructed a predictive model for INR elevation using risk scores. Even without warfarin use, INR should be monitored, as there is a high risk of INR elevation in patients with liver disorder, nutritional risk, and no-diabetes mellitus. CMZ can be used relatively safely in patients with no risk factors, or only one of the three risk factors other than warfarin. Therefore, in terms of safety, it has become possible to use the CMZ appropriately.

Acknowledgments

The authors thank Hiromi Shikano and Izumi Nishisaka at the Division of Supporting Services, Tokyo Bay Urayasu Ichikawa Medical Center. The authors thank everyone at the Department of Hospital Information System Department, Keio University Hospital. We also thank Takanori Ogawa at Certara GK for advice regarding the analysis. We would like to thank Editage (www.editage.com) for English language editing.

Data Availability

We have made the data available in a public repository on Figshare. You can access the data through the following private link URL: https://figshare.com/s/a7cc966004fa34980f25.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Septimus EJ. Antimicrobial Resistance: An Antimicrobial/Diagnostic Stewardship and Infection Prevention Approach. Med Clin North Am. 2018;102(5):819–29. doi: 10.1016/j.mcna.2018.04.005 [DOI] [PubMed] [Google Scholar]
2.Antibiotic resistance threats in the United States, 2019. Atlanta, Georgia; doi: 10.15620/cdc:82532 [DOI] [Google Scholar]
3.Tamma P, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa) Version 1.1 2 Running Title: AMR Treatment Guidance. Available: www.idsociety.org/practice-
4.Hussein K, Sprecher H, Mashiach T, Oren I, Kassis I, Finkelstein R. Carbapenem resistance among Klebsiella pneumoniae isolates: risk factors, molecular characteristics, and susceptibility patterns. Infect Control Hosp Epidemiol. 2009;30(7):666–71. doi: 10.1086/598244 [DOI] [PubMed] [Google Scholar]
5.Pitout JDD, Laupland KB. Review Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern. 2008. Available: http://infection.thelancet.com [DOI] [PubMed] [Google Scholar]
6.Matsumura Y, Yamamoto M, Nagao M, Komori T, Fujita N, Hayashi A, et al. Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-β-lactamase-producing Escherichia coli bacteremia. Antimicrob Agents Chemother. 2015;59(9):5107–13. doi: 10.1128/AAC.00701-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Fukuchi T, Iwata K, Kobayashi S, Nakamura T, Ohji G. Cefmetazole for bacteremia caused by ESBL-producing enterobacteriaceae comparing with carbapenems. BMC Infect Dis. 2016;16(1):427. doi: 10.1186/s12879-016-1770-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Lipsky JJ. N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia. Lancet. 1983;2(8343):192–3. doi: 10.1016/s0140-6736(83)90174-5 [DOI] [PubMed] [Google Scholar]
9.Furie B, Furie BC. Molecular basis of vitamin K-dependent y-carboxylation h e vitamin K-dependent blood clotting and regula. Blood. 1990. [PubMed] [Google Scholar]
10.Vermeer C. Review article y-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J. 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Cai Y, Zhang M, Wang Y, Wang N, Zhang L, Zhang K. Latamoxef-induced coagulation disorders: Incidence and risk factors. J Clin Pharm Ther. 2021;46(5):1382–6. doi: 10.1111/jcpt.13435 [DOI] [PubMed] [Google Scholar]
12.Chen L-J, Hsiao F-Y, Shen L-J, Wu F-LL, Tsay W, Hung C-C, et al. Use of Hypoprothrombinemia-Inducing Cephalosporins and the Risk of Hemorrhagic Events: A Nationwide Nested Case-Control Study. PLoS One. 2016;11(7):e0158407. doi: 10.1371/journal.pone.0158407 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Park GH, Kim S, Kim MS, Yu YM, Kim GH, Lee JS, et al. The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2019;16(20):3937. doi: 10.3390/ijerph16203937 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Alexander SP, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol. 2015;172:5744–869. doi: 10.1111/bph.13348/full [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Kondrup J, Rasmussen HH, Hamberg O, Stanga Z, Ad Hoc ESPEN Working Group. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr. 2003;22(3):321–36. doi: 10.1016/s0261-5614(02)00214-5 [DOI] [PubMed] [Google Scholar]
16.Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, et al. Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum β-lactamase producing Enterobacterales (ESBL-E). Pharmacotherapy. 2024;44(2):149–62. doi: 10.1002/phar.2894 [DOI] [PubMed] [Google Scholar]
17.Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, et al. Pharmacokinetics/Pharmacodynamics Analysis and Establishment of Optimal Dosing Regimens 1 Using Unbound Cefmetazole Concentration for Patients Infected with Extended-Spectrum β-2 lactamase Producing Enterobacterales (ESBL-E) 3 4. [DOI] [PubMed]
18.Yagi T, Naito T, Kato A, Hirao K, Kawakami J. 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;55(2):157–64. doi: 10.1177/1060028020940728 [DOI] [PubMed] [Google Scholar]
19.Clark NP, Delate T, Riggs CS, Witt DM, Hylek EM, Garcia DA, et al. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med. 2014;174(3):409–16. doi: 10.1001/jamainternmed.2013.13957 [DOI] [PubMed] [Google Scholar]
20.O’reilly RA. WARFARIN METABOLISM AND DRUG-DRUG INTERACTIONS. [PubMed]
21.Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, et al. Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability. Open Forum Infect Dis. 2021;8(12):ofab568. doi: 10.1093/ofid/ofab568 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Lindstr̈om J, Lindstr̈om L, Tuomilehto J. The Diabetes Risk Score A practical tool to predict type 2 diabetes risk. Available: http://diabetesjournals.org/care/article-pdf/26/3/725/665299/dc0303000725.pdf [DOI] [PubMed] [Google Scholar]
23.Miyai T, Imai S, Kashiwagi H, Sato Y, Kadomura S, Yoshida K, et al. A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study. Antibiotics (Basel). 2020;9(12):920. doi: 10.3390/antibiotics9120920 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Vascular and Coagulation Disorders of the Liver. Semin Liver Dis. 2002. [DOI] [PubMed] [Google Scholar]
25.Couris R, Tataronis G, McCloskey W, Oertel L, Dallal G, Dwyer J, et al. Dietary vitamin K variability affects International Normalized Ratio (INR) coagulation indices. Int J Vitam Nutr Res. 2006;76(2):65–74. doi: 10.1024/0300-9831.76.2.65 [DOI] [PubMed] [Google Scholar]
26.Wu S, Chen X, Jin D-Y, Stafford DW, Pedersen LG, Tie J-K. Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition. 2018. Available: http://ashpublications.org/blood/article-pdf/132/6/647/1373017/blood830901.pdf [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Schafer AI. The Hypercoagulable States. Ann Intern Med. 1985. Available: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19622/. [DOI] [PubMed] [Google Scholar]
28.Acar T, Aras YG, Gül SS, Acar BA. Effective INR Level May Be Delayed in Secondary Prevention of Stroke Due to Atrial Fibrillation with Warfarin in the Patients with Diabetes Mellitus. Noro Psikiyatr Ars. 2018;56(4):273–6. doi: 10.29399/npa.23395 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612–76. doi: 10.1093/europace/euab065 [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0322909.r001

Decision Letter 0

Girish Joseph

PONE-D-24-16951Identification of Risk Factors and Development of a Predictive Model in Patients Using Cefmetazole for International Normalized Ratio ElevationPLOS ONE

Dear Dr. YOKOYAMA,

1. Between 2012 and 2017- Rewrite this as it does not seem appropriate to start a paragraph with this.

2. Why were minors not included in this study?

3. IUPHAR/BPS - Kindly mention the fullform of this

4. Limit the discussion as it is very exhaustive and the deviating from the main reason of the study

5. Also elaborate regarding limitations of the study

Please submit your revised manuscript by Aug 31 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Girish Joseph, MD

Guest Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for stating the following in the Competing Interests section: "Dr. H. K. received research funding from Eli Lilly outside of the submitted work. Dr. K. M. received grants from Meiji Seika Pharma, Sumitomo Pharma and Shionogi outside of the submitted work. T.N. received research funding from Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical, Sanofi, and Shionogi outside of the submitted work. Conflicts that the editors consider relevant to the manuscript content have been disclosed."

We note that you received funding from a commercial source: "Eli Lilly, Meiji Seika Pharma, Sumitomo Pharma and Shionogi, Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical,and Sanofi".

Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf.

3. In the online submission form, you indicated that "We do not make the data publicly available, but you can do so if you wish. Please contact the corresponding author."

All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.

This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval.

4. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

5. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

Additional Editor Comments:

Between 2012 and 2017- Rewrite this as it does not seem appropriate to start a paragraph with this.

Why were minors not included in this study?

IUPHAR/BPS - Kindly mention the fullform of this

Limit the discussion as it is very exhaustive and the deviating from the main reason of the study

Also elaborate regarding limitations of the study

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

PLoS One. 2025 Jul 28;20(7):e0322909. doi: 10.1371/journal.pone.0322909.r002

Author response to Decision Letter 1

9 Aug 2024

Responses to Reviewer #1

We deeply appreciate the reviewers' comments and suggestions. We have revised the manuscript as suggested and ensured that it adheres to the required format. Our point-by-point responses to reviewers’ comments are provided below. Furthermore, all the changes made in the revised manuscript are highlighted in yellow.

1) When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Thank you for your comment. Accordingly, we added the following statements: “Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation”, “Yuta Yokoyama1,3 *”, “* Corresponding author”, and “E-mail: yokoyama-yt@pha.keio.ac.jp (YY)”

Page 1 Lines 1–2, Page 1 Line 3, Page 1 Line 20, and Page 2 Line 22

All major sections were also modified to bold type, 18pt font and Sub-sections of major sections were modified to bold type, 16pt font.

Page 3 Line 26, Page 4 Line 47, Page 5 Line 70, Page 9 Line 140, Page 18 Line 221, Page 22 Line 300, Page 23 Line 307, and Page 24 Line 325 and Page 5 Line 71, Page 5 Line 90, Page 7 Line 118, Page 9 Line 141, Page 12 Line 168, Page 13 Line 182, and Page 17 Line 218

Furthermore, the abstract has been revised as required by the guidelines.

Pages 3 Lines 27–46

The position of tables and figures have also been revised in accordance with the guidelines.

Pages 10–11 Lines 150–167, Pages 15 Lines 211–214, Pages 16 Lines 215–217

Pages 9 Lines 148–149, Pages 13 Lines 196–198, Pages 14 Lines 203–206, Pages 14 Lines 208–210

Furthermore, we deleted " Address: 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan Tel.: +81-03-5400-2639; Fax: +81-03-5400-2651." and " Background, Methods, Results, Conclusions " and Author contributions.

Page 2 Lines 23–24 and Page 3 Lines 27, 33, 38, 44 and Page 23 Lines 314–324

2) Thank you for stating the following in the Competing Interests section: "Dr. H. K. received research funding from Eli Lilly outside of the submitted work. Dr. K. M. received grants from Meiji Seika Pharma, Sumitomo Pharma and Shionogi outside of the submitted work. T.N. received research funding from Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical, Sanofi, and Shionogi outside of the submitted work. Conflicts that the editors consider relevant to the manuscript content have been disclosed."

We note that you received funding from a commercial source: "Eli Lilly, Meiji Seika Pharma, Sumitomo Pharma and Shionogi, Chugai, Daiichi Sankyo, Kyowa Kirin, Otsuka Pharmaceutical,and Sanofi".

If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf.

Thank you for your comment. Based on the comments, we have added the following to the cover letter: “Although Dr. H. K, Dr. K. M, and Dr. T. N have received funding outside of the research, this does not alter our adherence to PLOS ONE policies on sharing data and materials. We have submitted to ICMJE.”

Cover letter

3) In the online submission form, you indicated that "We do not make the data publicly available, but you can do so if you wish. Please contact the corresponding author."

Thank you for your suggestion. We have made the data available in a public repository. You can access the data through the following private link URL: https://figshare.com/s/a7cc966004fa34980f25

4) When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

Thank you for your comment. We have published the data as mentioned above. We request you to review it.

5) We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data.

We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository.

Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data.

Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

Thank you for your comment. The text “data not shown” has been deleted as the data are now available on Figshare.

Responses to Reviewer #2

We really appreciate your time and effort in reviewing our manuscript and thank you for the insightful comments, constructive criticisms, and helpful advice. We have addressed the concerns raised by the reviewer and revised the manuscript to improve its overall readability.

1) Between 2012 and 2017- Rewrite this as it does not seem appropriate to start a paragraph with this.

Thank you for your comment. We have modified “Extended-spectrum β-lactamase-producing enterobacteria (ESBL-E) have become a major public health challenge owing to increasing number of patients affected by antimicrobial-resistant bacteria between 2012 and 2017, leading to increased morbidity and mortality rates [1,2].”

Page 4 Lines 48–50

2) Why were minors not included in this study?

Thank you for your confirmation. We excluded pediatric patients from the study owing to their increased vulnerability to vitamin K deficiency compared to adults, as well as the challenge of accurately diagnosing coagulopathy caused by CMZ in children. Various factors contribute to vitamin K deficiency in children, such as immature intestinal microflora and lower vitamin K production compared to adults, or low placental passage of vitamin K in neonates.

3) IUPHAR/BPS - Kindly mention the fullform of this

Thank you for your suggestion. Accordingly, we have modified “Drug and molecular target nomenclature conforms to the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide standards”

Page 6 Lines 91–92

4) Limit the discussion as it is very exhaustive and the deviating from the main reason of the study

Thank you for your comment. As you pointed out, I have revised the discussion content and relevant references. The following sentence has been deleted.

“In this study, patients with an unstable baseline INR were excluded, and all patients with coagulopathy due to infections such as septic shock were excluded. Coagulopathy due to infection is caused by various factors, one of which is disseminated intravascular coagulation (DIC) [23]. D-dimer is generally used as an indicator of DIC [24], but at our institution it is not an item that is tested in general practice, and it is measured at the doctor's discretion if there is a concern about a coagulation abnormality. Since there was no difference between the two groups in patients for whom D-dimer was measured, it is thought that there was no coagulopathy due to infection.”

“Univariate analysis showed a statistically significant difference in the total dose of CMZ in INR-elevated group compared to non-INR-elevated group, but not a significant difference in daily dose. In the INR-elevated group, the median maximum INR during CMZ use was on day 3, compared to the INR non-elevated group, where the median maximum INR was observed on day 1. In this study, blood sampling was performed on arbitrary dates. The lack of significant difference in daily dose may be due to the difference in blood sampling date. The CMZ treatment period (period from the start of CMZ to the day of maximum INR) is also thought to be greatly affected by differences in blood sampling date. Therefore, the CMZ treatment period was not included in this analysis.”

“The reason for this may be due to the difference in blood sampling dates described above; the INR-elevated group received a higher dose, which may have affected the statistical significance of the AUC. In addition, AUC was considered to be the effect of other correlated factors and was excluded from the final model.”

“However, the number of patients who underwent bleeding was very small: 3 (4.9%) in the INR-elevated group and 3 (0.82%) in the INR-non-elevated group, so further research is considered necessary.”

“This means that the error in the INR measurement reagent is approximately 10%, and the increase is due to some factor other than measurement error (Manufacturer data reference).”

“23. Levi M, Keller TT, Van Gorp E, Ten Cate H. Infection and inflammation and the coagulation system. Cardiovascular Research. 2003. pp. 26–39. doi:10.1016/S0008-6363(02)00857-X”

“24. Adam SS, Key NS, Greenberg CS. D-dimer antigen: Current concepts and future prospects. Blood. American Society of Hematology; 2009. pp. 2878–2887. doi:10.1182/blood-2008-06-165845”

Page 18 Lines 225–230, Page 19 Lines 248–254, Page 19 Lines 256–258, Page 21 Lines 285–287, Page 21 Lines 288–290, Page 25 Lines 385–386, Page 25 Lines 387–388

Furthermore, the following sentence has been added to supplement the discussion.” This might be owing to differences in blood collection dates and other correlation factors and was excluded from the final model.”

Page 19 Lines 258–259

5) Also elaborate regarding limitations of the study

Thank you for your comment. As you pointed out, we have added the following sentence regarding the limitations of the study. “Furthermore, as this study was based on data from one city hospital and one university hospital in Japan, the sample size was limited to 429 patients. Therefore, it is considered that the influence of factors other than the identified risk factors has not been comprehensively evaluated. For further investigations, it is necessary to expand the sample size by including more survey facilities and using big data.”

Page 21 Lines 296–299

In addition, the following sentence has been deleted. “Further research is expected in the future for factors that have not been identified.”

Page 21 Lines 295–296

The error is found in Page 3 Line 45.

We deleted “,”

Finally, we would like to express our gratitude for your comments and suggestions, which greatly helped us improve our manuscr

Attachment

Submitted filename: Response to Reviewers 20240806.docx

pone.0322909.s001.docx^{(44.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0322909.r003

Decision Letter 1

Sarah Jose

PONE-D-24-16951R1Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevationPLOS ONE

Dear Dr. YOKOYAMA,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please accept our apologies for the delays in the peer review of this manuscript; it has been difficult to secure reviewers for this work. We have only been able to secure one review, but I am sending you their comments now to avoid further delays. You can find their comments attached to this email. Please do carefully consider their comments and respond to each point in your response to reviewers.

Please submit your revised manuscript by Jun 01 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Sarah Jose, Ph.D.

Staff Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: Yes: Komsing Methavigul

**********

Attachment

Submitted filename: PONE-D-24-16951_R1_Comments.pdf

pone.0322909.s002.pdf^{(82.9KB, pdf)}

PLoS One. 2025 Jul 28;20(7):e0322909. doi: 10.1371/journal.pone.0322909.r004

Author response to Decision Letter 2

1 May 2025

Responses to Reviewer #1

We deeply appreciate the reviewers' comments and suggestions regarding our manuscript. Our point-by-point responses to reviewers’ comments are provided below. Furthermore, all changes made to the revised manuscript are highlighted in yellow.

Major comments

1) In abstract section, what group do you classify in patients with the predicted incidence probabilities of INR elevation ranging > 10 to < 30% and > 40 to 90%?

Thank you for pointing this out. We have defined the probability of INR elevation based on the total score of each risk factor, referring to previous reports, so that we can classify all occurrence probabilities. We classified the probability of INR elevation into four categories: low risk (< 5%), medium risk (5–< 30%), high risk (30–< 90%), and very high risk (≥ 90%). The following passage was added to the method section:

Page 8 Lines 129–131, Reference 23

“From the total score of each risk factor, four risk classifications of low risk (< 5%), medium risk (5–< 30%), high risk (30–< 90%), and very high risk (≥ 90%) were performed for each elevated INR occurrence probability[21,23]”

Furthermore, we revised the description in each related section.

Page 3 Lines 37–38

“The predicted incidence probabilities of INR elevation were < 5% (low risk), 5–< 30% (medium risk), 30–< 90% (high risk), and ≥ 90% (very high risk). ”,

Page 13 Lines 182–184

“Risk scores between 0 and 2 were low risk (predicted probability < 5%), a risk score of 4 was medium risk (predicted probability 5–< 30%), those between 6–7 were high risk (predicted probability 30–< 90%), and those of 9 or higher were very high risk (predicted probability of occurrence ≥ 90%).”

Page 19 Lines 256–257

“In particular, patients possessing all of these risk factors are at high risk (probability of INR elevated: 30–< 90%) and may require INR monitoring.”

Table 3 has also been accordingly modified.

2) The definition of elevated INR in data collection section (93th – 94th line and 266th line) should be a ratio of maximum INR to baseline INR (maximum INR divided with baseline INR).

Thank you for pointing this out. We corrected the notation as follows:

Page 6 Lines 93–95

“Elevated INR was defined as a ratio of maximum INR to baseline INR (maximum INR divided with baseline INR) during CMZ use greater than 1.25.”

Page 20 Lines 276–278

“In this study, elevated INR was defined as a ratio of a ratio of maximum INR to baseline INR (maximum INR divided with baseline INR), during CMZ use, greater than 1.25.”

3) What is the full name of DOAC in data collection section (109th line)? If DOAC is direct oral anticoagulant, please revised the sentence “DOAC were patients with no dose changes for during and within 7 days prior to CMZ use.”

Thank you for your comment. In this study, direct oral anticoagulant (DOAC) was written as direct oral anticoagulants (DOACs) because there were multiple target drugs. We initially wrote ‘DOAC’ in the part you pointed out, but we will standardize it to DOACs to indicate multiple DOACs. The official name is written on lines 80-81, so we will correct this to DOACs.

Page 7 Lines 110–111

“DOACs were patients with no dose changes for during and within 7 days prior to CMZ use.”

In addition, there were also places in the discussion where the ‘DOAC’ was written, so we will correct it to ‘DOACs’.

Page 19 Lines 247–249

“However, since the effect on INR elevation varies depending on the type of DOAC, it is necessary to be careful when judging based on this result alone.”

4) Why does the p-value for the liver disorders in multivariate analysis in Table 1 reach 0.005, while their p-value in Table 2 reach only 0.05? Which is wrong?

Thank you for pointing that out. We checked the analysis data and corrected Table 2 because the p-value was 0.005.

Table 2 has been accordingly modified.

5) In INR-elevated prediction model construction and accuracy verification section, what group do you classify in patients with score of 3, 5, and 8?

Thank you for your comment. This time, the value of the β coefficient calculated from the results of the binomial logistic regression analysis was converted into a risk. As a result, warfarin use was scored as 5, and other factors were scored as 2. There were no patients with risk scores of 3, 5, and 8, in the case of 5, so the validity could not be evaluated, but it is possible to calculate from the regression equation assuming a patient with the risk factor of warfarin use only. When calculated under these conditions, the probability of INR elevation was estimated to be 20.9%. This probability of INR elevation is between the risk score of 4 and 6–7 points shown in Fig 2. Risk scores of 3 and 8 cannot be calculated as risk score values among the combinations of explanatory variables in the regression equation constructed this time, so the probability of INR elevation cannot be predicted. However, based on the above assumptions, it is assumed that the probability of occurrence is between 2 and 4 or 6–7 and 9 for risk scores of 3 and 8. Therefore, the following content has been included in the Discussion section:

Page 20 Lines 267–274

“In addition, since there were no actual patients, validity evaluation was not possible, but when assuming a patient with the risk factor of warfarin use only (risk score 5), the probability of INR elevation was calculated by regression equation to be 20.9%. This probability of INR elevation is between the risk score of 4 and 6–7 points shown in Fig 2. In this study, the identified risk scores were 2 for three factors and 5 for one factor, and due to issues with the combination of explanatory variables in the regression equation constructed, the probability of INR elevation could not be evaluated for risk scores of 3 and 8. However, based on the above assumptions, it is assumed that the probability of INR elevation is between 2 and 4 for a risk score of 3, and between 6–7 and 9 for a risk score of 8..”

6) Why does patients with no-diabetes being the risk factors for CMZ-induced INR elevation? Your discussion proposed the clotting tendency of diabetes mellitus patients may have suppressed INR elevation in patients using CMZ, but healthy person without diabetes mellitus should not have coagulopathy. Please clearly explain in your discussion section.

Thank you for pointing this out. As you pointed out, it is thought that coagulation disorders will almost never occur in all no-diabetes mellitus patients who use CMZ. It has been reported that diabetic mellitus patients are more susceptible to thrombosis than no-diabetes mellitus patients due to various factors, as described in the discussion. However, as a result of this risk score analysis, no-diabetes mellitus patients had a score of 2, and the probability of INR elevation in patients with a score of 2 is approximately 1%. A tendency was shown that the risk of INR elevation when combined with other risk factors such as liver disorder and nutritional risk. Therefore, we noted that not all no-diabetes mellitus patients develop coagulation disorders, and that caution is required when combined with other risk factors.

Page 19 Lines 237–240

“It should be noted that the risk score for no-diabetes mellitus patients is 2 points, and with a risk score of 2, the risk of INR elevation is approximately 1%, so not all no-diabetes mellitus patients will develop coagulation disorders when using CMZ. However, we think it would be prudent to use CMZ while keeping in mind that the INR may elevate when combined with other factors such as liver disorder and nutritional risk.”

7) Another limitation of your study is only Japanese patients were included, so this risk score model had have limited to generalizability in other races. Please add this limitation in your discussion section.

Thank you for pointing this out. As you have stated, this study only included Japanese patients, and it was not possible to study non-Japanese patients. For this reason, we have added the following passage to the section detailing the limitations of the study.

Page 21 Lines 284–286

“In addition, because the study only included Japanese subjects, it is unclear whether similar results would be obtained in non-Japanese patients.”

Minor comments

1) In patient information part of materials and methods section, the dates of access to electronic medical record data in 73th-74th line should be used with the name of months instead of the number of months. It helps to reduce the confusion between month/date/year and date/month/year for readers.

Thank you for pointing that out. We have corrected it to the name of months.

Page 5 Lines 73–75

“The dates of access to electronic medical record data were from June/1/2023 to July/31/2023, after obtaining approval from the ethics committee of each facility.”

2) Please add the full name of INR under Table 1.

Thank you for your comment. We included the full form of “INR, international normalized ratio” under Table 1.

Table 1 has been modified accordingly.

Finally, we would like to express our gratitude to the reviewers for their comments and suggestions, which greatly helped us improve our manuscript.

Attachment

Submitted filename: Response_to_Reviewers.docx

pone.0322909.s003.docx^{(43.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0322909.r005

Decision Letter 2

Mehmet Baysal

<p>Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

PONE-D-24-16951R2

Dear Dr. YOKOYAMA,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Mehmet Baysal

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: Yes: Komsing Methavigul

**********

PLoS One. doi: 10.1371/journal.pone.0322909.r006

Acceptance letter

Mehmet Baysal

PONE-D-24-16951R2

PLOS ONE

Dear Dr. Yokoyama,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Mehmet Baysal

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Response to Reviewers 20240806.docx

pone.0322909.s001.docx^{(44.5KB, docx)}

Attachment

Submitted filename: PONE-D-24-16951_R1_Comments.pdf

pone.0322909.s002.pdf^{(82.9KB, pdf)}

Attachment

Submitted filename: Response_to_Reviewers.docx

pone.0322909.s003.docx^{(43.2KB, docx)}

Data Availability Statement

We have made the data available in a public repository on Figshare. You can access the data through the following private link URL: https://figshare.com/s/a7cc966004fa34980f25.

[pone.0322909.ref001] 1.Septimus EJ. Antimicrobial Resistance: An Antimicrobial/Diagnostic Stewardship and Infection Prevention Approach. Med Clin North Am. 2018;102(5):819–29. doi: 10.1016/j.mcna.2018.04.005 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref002] 2.Antibiotic resistance threats in the United States, 2019. Atlanta, Georgia; doi: 10.15620/cdc:82532 [DOI] [Google Scholar]

[pone.0322909.ref003] 3.Tamma P, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa) Version 1.1 2 Running Title: AMR Treatment Guidance. Available: www.idsociety.org/practice-

[pone.0322909.ref004] 4.Hussein K, Sprecher H, Mashiach T, Oren I, Kassis I, Finkelstein R. Carbapenem resistance among Klebsiella pneumoniae isolates: risk factors, molecular characteristics, and susceptibility patterns. Infect Control Hosp Epidemiol. 2009;30(7):666–71. doi: 10.1086/598244 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref005] 5.Pitout JDD, Laupland KB. Review Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern. 2008. Available: http://infection.thelancet.com [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref006] 6.Matsumura Y, Yamamoto M, Nagao M, Komori T, Fujita N, Hayashi A, et al. Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-β-lactamase-producing Escherichia coli bacteremia. Antimicrob Agents Chemother. 2015;59(9):5107–13. doi: 10.1128/AAC.00701-15 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref007] 7.Fukuchi T, Iwata K, Kobayashi S, Nakamura T, Ohji G. Cefmetazole for bacteremia caused by ESBL-producing enterobacteriaceae comparing with carbapenems. BMC Infect Dis. 2016;16(1):427. doi: 10.1186/s12879-016-1770-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref008] 8.Lipsky JJ. N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia. Lancet. 1983;2(8343):192–3. doi: 10.1016/s0140-6736(83)90174-5 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref009] 9.Furie B, Furie BC. Molecular basis of vitamin K-dependent y-carboxylation h e vitamin K-dependent blood clotting and regula. Blood. 1990. [PubMed] [Google Scholar]

[pone.0322909.ref010] 10.Vermeer C. Review article y-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J. 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref011] 11.Cai Y, Zhang M, Wang Y, Wang N, Zhang L, Zhang K. Latamoxef-induced coagulation disorders: Incidence and risk factors. J Clin Pharm Ther. 2021;46(5):1382–6. doi: 10.1111/jcpt.13435 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref012] 12.Chen L-J, Hsiao F-Y, Shen L-J, Wu F-LL, Tsay W, Hung C-C, et al. Use of Hypoprothrombinemia-Inducing Cephalosporins and the Risk of Hemorrhagic Events: A Nationwide Nested Case-Control Study. PLoS One. 2016;11(7):e0158407. doi: 10.1371/journal.pone.0158407 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref013] 13.Park GH, Kim S, Kim MS, Yu YM, Kim GH, Lee JS, et al. The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2019;16(20):3937. doi: 10.3390/ijerph16203937 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref014] 14.Alexander SP, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol. 2015;172:5744–869. doi: 10.1111/bph.13348/full [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref015] 15.Kondrup J, Rasmussen HH, Hamberg O, Stanga Z, Ad Hoc ESPEN Working Group. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr. 2003;22(3):321–36. doi: 10.1016/s0261-5614(02)00214-5 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref016] 16.Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, et al. Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum β-lactamase producing Enterobacterales (ESBL-E). Pharmacotherapy. 2024;44(2):149–62. doi: 10.1002/phar.2894 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref017] 17.Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, et al. Pharmacokinetics/Pharmacodynamics Analysis and Establishment of Optimal Dosing Regimens 1 Using Unbound Cefmetazole Concentration for Patients Infected with Extended-Spectrum β-2 lactamase Producing Enterobacterales (ESBL-E) 3 4. [DOI] [PubMed]

[pone.0322909.ref018] 18.Yagi T, Naito T, Kato A, Hirao K, Kawakami J. 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;55(2):157–64. doi: 10.1177/1060028020940728 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref019] 19.Clark NP, Delate T, Riggs CS, Witt DM, Hylek EM, Garcia DA, et al. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med. 2014;174(3):409–16. doi: 10.1001/jamainternmed.2013.13957 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref020] 20.O’reilly RA. WARFARIN METABOLISM AND DRUG-DRUG INTERACTIONS. [PubMed]

[pone.0322909.ref021] 21.Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, et al. Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability. Open Forum Infect Dis. 2021;8(12):ofab568. doi: 10.1093/ofid/ofab568 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref022] 22.Lindstr̈om J, Lindstr̈om L, Tuomilehto J. The Diabetes Risk Score A practical tool to predict type 2 diabetes risk. Available: http://diabetesjournals.org/care/article-pdf/26/3/725/665299/dc0303000725.pdf [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref023] 23.Miyai T, Imai S, Kashiwagi H, Sato Y, Kadomura S, Yoshida K, et al. A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study. Antibiotics (Basel). 2020;9(12):920. doi: 10.3390/antibiotics9120920 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref024] 24.Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Vascular and Coagulation Disorders of the Liver. Semin Liver Dis. 2002. [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref025] 25.Couris R, Tataronis G, McCloskey W, Oertel L, Dallal G, Dwyer J, et al. Dietary vitamin K variability affects International Normalized Ratio (INR) coagulation indices. Int J Vitam Nutr Res. 2006;76(2):65–74. doi: 10.1024/0300-9831.76.2.65 [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref026] 26.Wu S, Chen X, Jin D-Y, Stafford DW, Pedersen LG, Tie J-K. Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition. 2018. Available: http://ashpublications.org/blood/article-pdf/132/6/647/1373017/blood830901.pdf [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref027] 27.Schafer AI. The Hypercoagulable States. Ann Intern Med. 1985. Available: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19622/. [DOI] [PubMed] [Google Scholar]

[pone.0322909.ref028] 28.Acar T, Aras YG, Gül SS, Acar BA. Effective INR Level May Be Delayed in Secondary Prevention of Stroke Due to Atrial Fibrillation with Warfarin in the Patients with Diabetes Mellitus. Noro Psikiyatr Ars. 2018;56(4):273–6. doi: 10.29399/npa.23395 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0322909.ref029] 29.Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612–76. doi: 10.1093/europace/euab065 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

Takaya Namiki

Yuta Yokoyama

Motonori Kimura

Shogo Fukuda

Shoji Seyama

Osamu Iketani

Masaru Samura

Haruki Ishikawa

Aya Jibiki

Hitoshi Kawazoe

Hisakazu Ohtani

Naoki Hasegawa

Kazuaki Matsumoto

Hideki Hashi

Sayo Suzuki

Tomonori Nakamura

Roles

Abstract

Introduction

Materials and methods

Patient information

Data collection

Statistical analysis

Results

Patient data

Fig 1. Flowchart describing study cohort enrollment, international normalized ratio (INR)-elevated group, and non-INR-elevated group.

Table 1. Final target patients of this study and Univariate and multivariate analysis of risk factors for cefmetazole (CMZ)-induced international normalized ratio (INR) elevation.

INR-elevated risk factor identification

INR-elevated prediction model construction and accuracy verification

Table 2. Multivariable analysis of risk factors for cefmetazole-induced international normalized ratio (INR) elevation.

Fig 2. Incidence of international normalized ratio (INR) elevation for increasing risk score in the predicted set and the observed set with patients using CMZ.

Table 3. Probability of cefmetazole-induced international normalized ratio (INR) elevation for each risk factor possessed by the patient.

Fig 3. Calibration curve showing consistency between the predicted probability (x-axis) with the observed real risk (y-axis) for elevated international normalized ratio (INR) associated with cefmetazole.

Fig 4. Validation was performed using the receiver operating characteristic (ROC) curve for the discriminatory power of the predictive risk for the incidence of elevated international normalized ratio (INR) associated with cefmetazole.

Bleeding of patients using CMZ

Discussion

Conclusion

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Girish Joseph

Roles

Author response to Decision Letter 1

Decision Letter 1

Sarah Jose

Roles

Author response to Decision Letter 2

Decision Letter 2

Mehmet Baysal

Roles

Acceptance letter

Mehmet Baysal

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases