International Journal of Medicine

Comparison of the efficacy of cefmetazole and meropenem for patients with extended-spectrum beta-lactamase- producing Escherichia coli bacteremia: a single-center experience

Authors:
  • Tomoyuki Kato , Antimicrobial Stewardship Team, Musashino Red Cross Hospital, Tokyo, Japan
  • Emi Ono , Department of General Practice, Musashino Red Cross Hospital, Tokyo, Japan
  • Yoko Hiroshima , Antimicrobial Stewardship Team, Musashino Red Cross Hospital, Tokyo, Japan
  • Kaoru Nagata , Department of General Practice, Musashino Red Cross Hospital, Tokyo, Japan
  • Shinichirou Suzaki , Department of Emergency and Critical Care Medicine, Musashino Red Cross Hospital, Tokyo, Japan
  • Takashi Yamazaki , Department of Orthopedics, Musashino Red Cross Hospital, Tokyo, Japan
  • Masayuki Nagasawa , 1Antimicrobial Stewardship Team, Musashino Red Cross Hospital, Tokyo, Japan 5Department of Pediatrics, Musashino Red Cross Hospital, Tokyo, Japan

Article Information:

DOI:10.5455/im.56234
Published:October 30, 2022
Article Type:Original Research
Pages:1 - 6
Received:July 10, 2022
Accepted:October 17, 2022

Abstract:

Background: We retrospectively investigated whether cefmetazole (CMZ) was equivalently as effective as meropenem (MEPM) for treating bloodstream infections with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli). Methods: From 2012 through 2017, ESBL-E. coli were cultured from the blood of 74 patients at our institute. Excluding 17 ineligible patients, 31 patients were treated with CMZ and 26 patients were treated with MEPM as definitive therapy. The primary infection site was the urinary tract in 37 patients, the abdomen in 4, and undetermined in 16. Results: There was no significant difference between both groups with respect to sex differences, Sequential Organ Failure Assessment (SOFA) score and Pitt bacteremia score, except for age (CMZ vs. MEPM: 79.5±13.4 vs. 71.4±15.5 years; p=0.045) and the frequency of undetermined infection site (CMZ vs. MEPM: 5/36 vs. 11/26; p=0.028). There was no significant difference in 30-day mortality after treatment between the CMZ and MEPM groups (4/31 vs. 3/26; p=0.88). Furthermore, there was no recurrence within 30 days after treatment in both groups. Multivariate analysis revealed that the SOFA score was significantly (p=0.026) and the undetermined infection focus was relatively (p=0.055) associated with 30-day mortality after treatment. Conclusions: CMZ for bloodstream infections with ESBL-E. coli originating in the urinary tract may be as effective as MEPM when the SOFA score is not high.

Keywords:

bacteremia beta-lactamase cefmetazole meropenem organ dysfunction score

Article :

Introduction:

Bloodstream infection is a clinically serious condition with a high mortality rate, and thus, rapid intervention with proper antibiotics is required [1]. Escherichia coli is a common enteric bacterium that causes bloodstream infections in both community and health care units [2]. The incidence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, including ESBL-producing E. coli (ESBL- E. coli), has increased worldwide [3]. In general, carbapenems are recommended for treating infections with ESBL-producing Enterobacteriaceae [4,5]. However, the emergence of carbapenem-resistant Enterobacteriaceae (CRE) is of high concern and is associated with increased consumption of carbapenems [6]. Therefore, the proper use of antibiotics is important and recommended to reduce the prevalence of CRE. Cephamycins such as cefmetazole (CMZ) are effective against ESBL-producing bacteria in vitro [7]. Recent clinical papers reported that CMZ was as effective as carbapenems for treating urinary tract infections due to ESBL-producing Enterobacteriaceae [8]. However, although carbapenems are still recommended for the empirical treatment of clinically severe cases [9,10], no study has reported the significant superiority of carbapenems to cephamycins. Therefore, we evaluated and compared the efficacy of CMZ and meropenem (MEPM) as a definitive therapeutic antimicrobial agent for treating bloodstream infections with ESBL-E. coli.

Methods:

From January 2012 through December 2017, ESBL-E. coli were cultured from the blood of 74 patients at our hospital [Figure 1]. Among them, five patients died before the results of the blood culture could be obtained, six were transferred and untraceable and three were determined to be contaminants. In the other three patients, neither CMZ nor MEPM was used even after the blood culture results. Excluding these 17 patients, 57 patients were enrolled in this study [Figure 2].

 

 Medical information was retrospectively obtained from the clinical records of 57 patients. To evaluate the status of the patients, the Sequential Organ Failure Assessment (SOFA) score [11], which is usually used to track a patient’s condition during their stay in an intensive care unit, and the Pitt bacteremia score (PBS) [12] were used as markers of severity and prognosis. ESBL-E. coli was isolated using the broth microdilution method according to the break-point criteria advocated by the Clinical and Laboratory Standard Institut [13,14] and was confirmed using AmpC/ESBL differential discs (Kanto Chemical Co. Inc., Japan). The primary endpoint was death within 30 days after initiating treatment.

 

Statistical analysis

For the statistical analysis, a Chi-square test, Mann-Whitney U test and logistic regression were performed. All statistical analyses were performed using Excel Statistics version 6.0 (Microsoft Corporation, Redmond, WA, USA). Analysis items with p-values <0.05 were considered statistically significant.

 

Ethical assessment

This study was conducted in accordance with the tenets of the Declaration of Helsinki. The study protocol was approved by the institutional review board of our hospital. The aim of the study was explained to the patients and informed consent was obtained via the opt-out method.

Results:

As shown in Figure 1, the number of cases of ESBL-E. coli bloodstream infection remained unchanged between 2012 and 2015 but increased from 2016, compared with the slight increase in the incidence of ESBL-nonproducing E. coli bloodstream infection. CMZ was used in 31 patients and MEPM in 26 patients as definitive therapy after obtaining the blood culture results. There was no significant change in the preference for selecting CMZ or MEPM according to age (data not shown). The summarized profile of the 57 patients is presented in Table 1. There were no significant differences between both groups with respect to sex differences, the SOFA score and PBS, except for age (CMZ vs. MEPM: 79.5±13.4 vs. 71.4±15.5 years; p=0.045) and the frequency of undetermined infection site (CMZ vs. MEPM: 5/36 (16%) vs. 11/26 (42%); p=0.028).

 

The urinary tract was identified as the primary infection site in 37 patients, the abdomen in 4, and undetermined in 16. MEPM was preferentially used in patients with undetermined infection focus [Table 1]. The mortality rate was higher among patients with undetermined primary infection focus than in those with the urinary tract or abdomen as the primary infection site (5/16 (31.3%) vs. 2/41 (4.9%), p=0.006). Regarding the initial choice of antimicrobial agents, various antimicrobial agents effective against gram-negative bacteria were used [Table 2], and there seemed to be no constant preferential selection. For interpretation, MEPM was not used in the CMZ group as an empiric therapy because the effect of MEPM was completely negligible in the CMZ group.

 

CMZ was initially used and changed to MEPM in four cases arbitrarily after ESBL-E. coli bloodstream infection was confirmed. Three of four patients had a high SOFA score with a shock when blood culture samples were taken [Table 3] and were considered serious. Multiple pathogens were cultured from the blood of eight patients. MEPM was preferentially used to treat these patients, and mortality was associated with the SOFA score in these eight patients (data not shown).

 

There was no significant difference in the 30-day mortality rate after treatment between the CMZ and MEPM groups [Table 1]. The SOFA score was significantly higher among dead patients than among survivors (5.86±2.27 vs. 2.64±2.17; p<0.004), but there was no significant difference in PBS (1.71±1.89 vs. 1.12±1.55; p=0.421). The SOFA score was higher among cases with undetermined infection focus (4.00±6.53) than among those with the urinary tract (2.65±5.51) and abdomen (2.75±2.91) as infection foci, without statistical significance. The multivariate analysis revealed that the SOFA score was significantly (p=0.026) and the undetermined infection site was relatively (p=0.055) associated with 30-day mortality after treatment [Table 4]. No patients had a recurrent infection within 30 days in both groups.

Discussion:

In this study, the urinary tract was the most common primary infection site (37/57, 64.9%) as previously reported [13]. ESBL-producing Enterobacteriaceae colonize the intestinal tract of healthy subjects and are reported to eventually cause bloodstream infections [15,16]. It is considered that healthy subjects acquire ESBL-producing Enterobacteriaceae via domestic animals and food or environmental exposure [17], and the spread of ESBL-producing Enterobacteriaceae among the population is a matter of concern these days [18].

 

As shown in Figure 1, the number of patients in whom ESBL-E. coli was cultured from the blood has increased at our hospital since 2016. It is speculated that the improper use of antimicrobial agents among healthy subjects leads to an expansion of ESBL-producing Enterobacteriaceae by pharmacological selection and eventually results in an increased incidence of infection with this pathogen. As the universal use of carbapenems is prohibited along with the creation of antimicrobial stewardship programs, it becomes important to make a proper diagnosis and evaluate infection with ESBL-producing Enterobacteriaceae. As an initial choice, various antimicrobial agents effective against gram-negative bacteria were used [Table 2], and there seemed to be no constant preference in the selection of initial antibiotics. At our institute, the choice of definitive therapy was based on the result of in vitro sensitivity data for ESBL-producing Enterobacteriaceae and not on the site of infection.

 

Although a previous report clearly showed that CMZ was clinically effective for urinary tract infection with ESBL-E. coli [8], the efficacy of CMZ for bloodstream infections with ESBL-E. coli is not still confirmed. In this study, CMZ was sufficiently effective and feasible for treating bloodstream infections with ESBL-E. coli. Although fatal cases were observed frequently among patients with undetermined infection focus, there was no significant difference in the mortality rate between the CMZ (2/5, 40%) and MEPM (3/11, 27.3%) groups (p=0.61). However, CMZ was initially used among four patients and changed to MEPM arbitrarily after bloodstream ESBL-E. coli infection was confirmed. Three of four patients had high SOFA scores with a shock when blood culture samples were obtained, and the primary infection focus was undetermined in two patients. As mentioned above, the SOFA score was higher among patients with undetermined primary infection focus in this cohort. Consequently, these four patients survived, which might be explained by the fact that MEPM was somehow superior to CMZ in managing serious infections.

 

The multivariate analysis revealed that death within 30 days after treatment was significantly associated with the SOFA score but not with the choice of antimicrobial agent (CMZ or MEPM). However, there seemed to be an arbitrary choice of MEPM rather than CMZ for patients with serious infections in this cohort; thus, we have to interpret our results with caution. The SOFA score was devised to evaluate the degree of organ damage in septicemic patients and the mortality rate of patients with high SOFA scores was predicted to be high. Several studies have reported a positive association of SOFA score or quick SOFA score, which is devised for the screening of septic patients outside intensive care units [19], with an increased mortality rate [20-22]. However, other studies have reported no relationship between quick SOFA score and the mortality rate of inpatients with ESBL-producing bacteremia [23,24]. This discrepancy might be explained by the pathologic difference between sepsis and bacteremia; however, further studies will be necessary in the future. In our retrospective study, we concluded that CMZ may be as effective as MEPM for treating patients with ESBL-E. coli bacteremia originating in the urinary tract if the SOFA score is not high.

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