Skip to main content
PLOS One logoLink to PLOS One
. 2024 Oct 23;19(10):e0309969. doi: 10.1371/journal.pone.0309969

Emergence of resistance to last-resort antimicrobials in bacteremia patients: A multicenter analysis of bloodstream pathogens in Korea

Jin Sae Yoo 1,#, Hui-Jin Yu 2,#, Kuenyoul Park 3,*, Wee Gyo Lee 4, Bo-Moon Shin 3
Editor: Mabel Kamweli Aworh5
PMCID: PMC11498668  PMID: 39441859

Abstract

This study retrospectively reviewed the microbiological and clinical characteristics of patients diagnosed with bacteremia. Results from the first positive blood cultures were consecutively collected from July 2022 to June 2023 at a public secondary hospital, a university-affiliated tertiary hospital, and a university-affiliated secondary hospital in the Seoul metropolitan area. Antibiotic spectrum coverage (ASC) scores were calculated on the day the blood culture was performed (B0) and on two days after the blood culture results were reported (R+2). A total of 3,397 isolates were collected from 3,094 patients. Among these, 949 isolates obtained from 893 patients were classified as multidrug-resistant organisms (MDRO), including 170 imipenem-resistant gram-negative bacteria, 714 methicillin-resistant staphylococci, and 65 vancomycin-resistant enterococci. Interestingly, 13 and 42 gram-positive isolates were resistant to linezolid and quinupristin/dalfopristin, respectively. Moreover, 44 and 181 gram-negative isolates were resistant to amikacin and tigecycline, respectively. The proportion of ASC scores corresponding to broad or extremely broad-spectrum coverage was not significantly different between MDRO and non-MDRO groups at B0 (p = 0.0925). However, it increased in the MDRO group at R+2 (p <0.001). This study found that resistance to last-resort antimicrobials is emerging. Therefore, developing and incorporating molecular diagnostics using a wide range of resistance targets may facilitate rapid, tailored antimicrobial treatments.

Introduction

Bloodstream infections (BSI) are associated with a high global disease burden. The magnitude of the burden varies depending on the BSI type (e.g., community-acquired vs. hospital-acquired), involved pathogens, and geographic regions. A previous review reported an estimated incidence of 43 to 101 per 100,000 population, with case fatality ranging from 13 to 17% [1]. BSI caused by bacteria harboring antimicrobial resistance (AMR) is particularly concerning due to greater disease burden and poorer outcomes compared to those caused by wild-type pathogens, with one study estimating that approximately 1.5 million deaths were directly attributable to BSI with AMR [2]. Bacteria harboring resistance to several classes of antimicrobial agents are called multidrug-resistant organisms (MDRO). In 2017, the World Health Organization (WHO) listed several MDRO as “priority pathogens” requiring novel therapeutic agents, including vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant/extended beta-lactamase (ESBL)-producing Enterobacterales [3]. The increasing incidence of MDRO infections has prompted several guidelines on various infectious diseases to recommend empirical use of broad-spectrum antibiotics [4,5], resulting in the selection of pathogens that are resistant to these antibiotics. Conventional antimicrobial susceptibility testing is constrained by bacterial growth time, and a more rapid test that can direct appropriate antibiotic therapy is required to provide adequate antimicrobial coverage against MDRO infections and to discontinue the unnecessary administration of broad-spectrum antimicrobials as soon as possible.

Molecular diagnostics are employed more frequently to diagnose and manage BSI. Specific techniques include polymerase chain reaction (PCR), next-generation sequencing (NGS), and less commonly, fluorescence in situ hybridization. Notably, the impact of the BioFire blood culture identification (BCID; bioMérieux, Marcy l’Etoile, France) assay on the detection and management of AMR has been investigated in several studies because of its availability, ease of use, and relatively low cost compared with NGS. Overall, the use of BCID appears to be associated with a shorter time to optimal antibiotic therapy for BSI by 6.25 to 64 hours compared to traditional blood culture-based decisions [611] and optimization of antibiotic regimen in 31.8–45.1% of patients with BSI [12,13]. However, some studies have also reported no significant reduction in the time to appropriate antibiotic de-escalation or mortality rate associated with the use of BCID in patients with BSI [7,14]. In addition, the AMR genes detected by current BCID are limited to those associated with ESBL, carbapenemase production, and resistance to methicillin, vancomycin, and colistin. Recently, T2resistance (T2Biosystems, Lexington, MA, USA) has become available for research use, and one study reported an 84.6% detection rate of carbapenem resistance genes in blood culture-confirmed gram-negative BSI within 3 to 5 hours [15]. However, this method does not provide information regarding AMR to antibiotic class other than beta-lactam, carbapenem, and glycopeptide.

Such limitations of commercially available molecular AMR panels for BSI raise questions about whether they are sufficient in their breadth and accurately address “real-world” BSI landscapes. Although a large-scale analysis of antimicrobial susceptibility patterns and clinical results of BSI would be useful in answering these questions, few such studies have been reported. Therefore, this study retrospectively reviewed the microbiological and clinical characteristics of patients diagnosed with BSI at three hospitals in the metropolitan area of Seoul, Korea, to investigate the current landscape of the susceptibility profiles of BSI pathogens.

Methods

Study design and procedures

This retrospective observational study was conducted using the medical records and blood culture results of patients admitted to three distinct hospitals from July 2022 to June 2023: a public secondary hospital (S), university-affiliated tertiary hospital (A), and university-affiliated secondary hospital (P). All hospitalized patients with positive blood culture during the study period were enrolled. Data were collected only for the first organism isolated from the positive blood culture of each patient’s duration of admission. However, all were included if two or more organisms were simultaneously identified on the first blood culture. At the three institutions, organisms isolated from blood cultures were subjected to bacterial identification using MALDI-TOF mass spectrometry (MALDI Biotyper, Bruker Daltonics, GmbH, or Vitek MS system, bioMérieux) and Vitek2 systems (bioMérieux). Antimicrobial susceptibility testing (AST) was performed using the Vitek2 system. Bacterial identification and AST were performed in the laboratory of the patient’s admitting hospital. The laboratories of all three participating hospitals were accredited for internal and external quality assurance programs by the Laboratory Medicine Foundation of Korea and Korean Association of External Quality Assessment Service during the study period. We also compiled data on the antibiotics administered during hospitalization, underlying disease of human immunodeficiency virus (HIV) infections and malignancies, history of transplantation, and in-hospital mortality rates. Underlying diseases such as HIV infection and malignancies, as well as transplantation history were searched against the main diagnosis codes registered in the electronic medical records.

Classification of antibiotic resistance

The percent susceptibility to each antimicrobial agent was calculated for all gram-positive bacteria, VRE, methicillin-resistant staphylococci (MRS), all gram-negative bacteria, and imipenem-resistant gram-negative bacteria (IRGN). Based on their susceptibility profiles, VRE, MRS, and IRGN were classified as MDRO [16]. Antibiotics prescribed to each patient on the day of the first blood culture (B0) and on the second day after reporting the blood culture results (R+2) were recorded to evaluate the pattern of antibiotic use for empirical treatment and tailored treatment after the culture results were reported, respectively. The antibiotic prescription was analyzed only for patients who stayed in the admitted hospital on R+2 to exclude patients who died or were transferred to other hospitals before R+2. Antibiotic spectrum coverage (ASC) score, which quantifies the breadth of antimicrobial coverage provided by the prescribed antibiotics [17], was calculated for B0 and R+2. Subsequently, we assigned each patient’s ASC score to specific categories based on the breadth of therapy: 0–4 for narrow-spectrum, 5–9 for narrow-to-moderate, 10–14 for moderate, 15–19 for broad, and ≥ 20 for very broad-spectrum therapy, adapted from previous literature that categorizes antibiotic coverage in five-point increments [18].

Statistical analysis

Descriptive statistics were used to summarize the frequency, distribution, and characteristics of the isolated organisms at the three hospitals, focusing on the prevalence of MDRO. Comparative analyses of nominal variables were conducted using Pearson’s chi-squared test and Fisher’s exact test, and continuous variables were analyzed using the Kruskal-Wallis test. A p-value < 0.05 was considered statistically significant. IBM SPSS Statistics (version 27.0; IBM Corp., Armonk, NY, USA) was used to perform all calculations and statistical analyses.

Ethical approval

This study was approved by the institutional review board of the three hospitals (approval No. Seoul Medical Center, 2023-08-001; Ajou University Hospital, AJOUIRB-DB-2023-498; Sanggye Paik Hospital, 2023-08-016). As this was a retrospective study using medical records, no additional information was obtained from the patients, and the need for documentation of informed consent was waived. Patient data were accessed for research purpose on October 18th, 2023: the informatics department of each hospital processed the primary data and distributed to the authors anonymized data with patient numbers, which could be used for patient identification either during or after data collection when necessary.

Results

A total of 3,064 patients, comprising 860, 1,855, and 349 patients from hospital S, hospital A, and hospital P, respectively, were enrolled in this study. The median age of the patients was 72 years (IQR: 61–82 years), 45.9% were female, and they significantly differed in age (p<0.001) and gender (p<0.001) between the institutions. Among the three institutions, the frequency of malignancy as an underlying disease showed significant differences (p<0.001) between the three institutions, with hospital A being the highest (20.3%), followed by hospital P (19.5%) and hospital S (3.7%). More than two bacterial species were isolated in 8% of cases. However, in the remaining 8%, multiple bacterial species were concurrently detected. Medical records revealed that 26.7% of the patients received antibiotics before blood culture collection, and hospital P exhibited a particularly high incidence of pre-sampling antibiotic administration at 71.3% with statistical significance (p<0.001) (Table 1).

Table 1. Demographic and clinical characteristics of the multicenter study population.

Characteristic Hospital S
(n = 860)
Hospital A
(n = 1,855)
Hospital P
(n = 349)
Total
(n = 3,064)
P-value
Female, number (%) 473 (55.0%) 800 (43.1%) 148 (42.4%) 1,421 (45.9%) p < 0.001a
Age, median [IQR] 78 [68–85] 69 [58–80] 74 [65–82] 72 [61–82] p < 0.001
Underlying disease, number (%)
    • Malignancy 32 (3.7%) 376 (20.3%) 68 (19.5%) 476 (15.4%) p < 0.001a
    • HIV 0 (0.0%) 2 (0.1%) 0 (0.0%) 2 (0.1%) p = 1.000b
    • Organ transplantation 0 (0.0%) 35 (1.9%) 0 (0.0%) 35 (1.1%) p < 0.001b
Number of isolated species from blood culture (BC), number (%)
    • 1 Species 816 (94.9%) 1,672 (90.1%) 332 (95.1%) 2,820 (92%) p < 0.001b
    • 2 Species 43 (5.0%) 157 (8.5%) 16 (4.6%) 216 (7%)
    • 3 Species 1 (0.1%) 21 (1.1%) 1 (0.3%) 23 (0.8%)
    • 4 Species 0 4 (0.2%) 0 (0%) 4 (0.1%)
    • 5 Species 0 1 (0.1%) 0 (0%) 1 (0%)
Antibiotic administration before blood culture sampling, number (%) 213 (24.8%) 356 (19.2%) 249 (71.3%) 818 (26.7%) p < 0.001a

a Pearson’s chi-squared test was performed to determine statistical significance.

b Fisher’s exact test was performed due to the low expected frequencies.

A total of 3,397 bacterial isolates were identified from the 3,064 individuals: 905, 2,070, and 422 from hospital S, hospital A, and hospital P, respectively. Among the isolates, Escherichia coli was the most frequently identified bacterium in hospitals S and A, whereas Staphylococcus epidermidis was the most frequently detected bacterium in hospital P (S1 Table).

Among the 1,551 gram-positive and 1,527 gram-negative species isolated from blood cultures, MDRO was found in 893 patients, with the isolates comprised of 170 IRGN, 714 MRS, and 65 VRE. MRS constituted the majority of the MDRO in each hospital. Hospital P exhibited the highest proportion of MDRO across all categories (Fig 1).

Fig 1. Proportions of multidrug-resistant organisms (MDROs) within blood culture isolates from the three hospitals (S, A, and P).

Fig 1

The bar graph shows the prevalence of imipenem-resistant gram-negative bacteria (IRGN), methicillin-resistant Staphylococcus spp. (MRS), and vancomycin-resistant enterococci (VRE) across the hospitals. MRS (light gray) is the predominant MDRO, followed by IRGN (dark gray) and VRE (medium gray). Notably, Hospital P demonstrated the highest incidence of each MDRO type, whereas Hospitals S and A showed similar MDRO profiles.

Notably, 66% of all gram-positive organisms were methicillin-resistant, and approximately 40% were gentamicin-resistant. Resistance to teicoplanin and linezolid was reported in 7% and 1%, respectively (Table 2).

Table 2. Antimicrobial susceptibility profiles of gram-positive organisms isolated from blood cultures.

Antimicrobial Overall susceptibility Susceptibility in MRSa Susceptibility in VREb
Ampicillin 59.8% (257/430) 7.7% (5/65)
Ampicillin/Sulbactam 47.8% (130/272) 7.7% (5/65)
Cefotaxime 94.9% (150/158)
Ceftriaxone 78.2% (158/202)
Ciprofloxacin 50.9% (604/1186) 33.3% (238/714) 0.0% (0/23)
Clindamycin 57.3% (762/1331) 46.0% (328/713) 0.0% (0/23)
Erythromycin 42.3% (641/1515) 32.1% (229/714) 4.6% (3/65)
Gentamicin 58.4% (627/1074) 46.0% (329/715)
Linezolid 99.1% (1484/1497) 99.4% (711/715) 93.8% (61/65)
Oxacillin 33.3% (359/1077) 0.0% (0/717)
Quinupristin/Dalfopristin 94.0% (657/699) 100.0% (325/325) 86.2% (50/58)
Rifampicin 92.3% (1000/1083) 88.9% (635/714)
Teicoplanin 92.3% (1246/1350) 92.9% (666/717) 33.8% (22/65)
Tetracycline 79.7% (1061/1331) 78.7% (562/714) 100.0% (23/23)
Trimethoprim/Sulfamethoxazole 75.5% (903/1196) 74.2% (532/717) 0.0% (0/23)
Vancomycin 95.6% (1483/1551) 100.0% (717/717) 0.0% (0/65)

a Methicillin-resistant Staphylococcus spp.

b Vancomycin-resistant enterococci.

In gram-negative bacteria, resistance to piperacillin-tazobactam, imipenem, amikacin, and tigecycline was reported in 20%, 12%, 3%, and 12%, respectively (Table 3). Strains that were not susceptible to imipenem yet were susceptible to ertapenem constituted 4.3% (55/1,293) of all Enterobacterales isolates. Most of these strains were identified as Proteus species, with 77.1% (37/48) of all Proteus species isolates demonstrating resistance to imipenem and susceptibility to ertapenem. In particular, 13 and 42 gram-positive isolates were resistant to linezolid and quinupristin/dalfopristin, respectively, whereas 44 and 181 gram-negative isolates were resistant to amikacin and tigecycline, respectively. The in-hospital mortality rate among patients with MDRO bacteremia (MDRO group) was 27.3% (244/893), which was significantly higher compared to 17.5% (379/2,171) mortality rate observed in patients with bacteremia caused by organisms other than MDRO (non-MDRO group), with statistical significance (p<0.001).

Table 3. Antimicrobial susceptibility profiles of gram-negative organisms isolated from blood cultures.

Antimicrobial Overall susceptibility Susceptibility in IRGNa
Amikacin 97.0% (1406/1450) 76.4% (107/140)
Amoxicillin/Clavulanic Acid 68.9% (902/1310) 21.7% (20/92)
Ampicillin 20.7% (275/1331) 11.5% (10/87)
Cefepime 69.7% (1036/1486) 32.2% (55/171)
Cefotaxime 60.9% (919/1509) 20.6% (35/170)
Ceftazidime 66.6% (1011/1519) 27.5% (47/171)
Ciprofloxacin 59.7% (903/1513) 26.9% (46/171)
Colistin 93.5% (157/168) 94.9% (74/78)
Ertapenem 97.4% (1259/1293) 64.0% (55/86)
Gentamicin 77.4% (1150/1485) 40.6% (69/170)
Imipenem 88.5% (1314/1485) 0.0% (0/171)
Minocycline 66.1% (119/180) 87.3% (69/79)
Piperacillin/Tazobactam 79.4% (565/712) 21.8% (24/110)
Tigecycline 87.8% (1298/1479) 53.5% (91/170)
Trimethoprim/Sulfamethoxazole 66.7% (1018/1527) 36.5% (62/170)

aImipenem-resistant gram-negative bacteria.

For the ASC score analysis, medical records pertaining to antimicrobial prescriptions were utilized for 2,400 patients, following the exclusion of individuals lost to follow-up on day R+2. Interestingly, the proportion of ASC scores ≥ 15, indicating broad- or extremely broad-spectrum antibiotic coverage, was not significantly different between the MDRO and non-MDRO groups at B0 yet significantly decreased in the non-MDRO group at R+2 (p<0.001, Table 4).

Table 4. Distribution of patients according to the antibiotic spectrum coverage (ASC) score grade.

Empirical treatment (B0) Tailored treatment (R+2)
Antibiotic spectrum ASC grade (score) Non-MDRO MDRO Non-MDRO MDRO
Narrow Grade 1 (0~4) 27.2% (460) 27.9% (198) 45% (761) 42.6% (302)
Narrow-to-moderate Grade 2 (5~9) 32.3% (546) 21.9% (155) *** 26.5% (448) 20.5% (145) **
Moderate Grade 3 (10~14) 22.2% (375) 28.9% (205) *** 19.2% (324) 17.1% (121)
Broad Grade 4 (15~19) 9.1% (154) 10.4% (74) 6.4% (109) 13.7% (97) ***
Very broad Grade 5 (≥20) 9.2% (156) 10.9% (77) 2.9% (49) 6.2% (44) ***
Total 100% (1691) 100% (709) 100% (1691) 100% (709)

Pearson’s chi-squared test was performed for each ASC grade, and statistically significant differences in MDRO values compared to non-MDRO are indicated as * (p<0.05)

** (p<0.01), and

*** (p<0.001).

aB0, the day when blood culture was performed.

bR+2, the second day after the blood culture results were obtained.

Discussion

This retrospective study demonstrated the significant mortality burden of bacteremia and the emergence of MDRO as major pathogens associated with bacteremia. According to the Global Antimicrobial Resistance and Use Surveillance Program in Korea (Kor-GLASS), which collects and annually reports AMR data across nine tertiary hospitals across Korea [19], a high prevalence of multidrug resistance were observed among blood-isolated organisms in large-scale hospitals in Korea. In 2022, the susceptibility rate of Staphylococcus aureus to cefoxitin was 54.3%, and Enterococcus faecium to vancomycin was 64.9%. Carbepenem susceptibility among blood-isolated Enterobacterales has also steadily declined since 2019 (imipenem-susceptible Escherichia coli and Klebsiella pneumoniae- 99.2% in 2019 to 94.0% in 2022) [20]. These data corroborate the substantial prevalence of MDRO among BSI in Korea. Interestingly, the susceptibility to imipenem was lower than that of ertapenem among the gram-negative isolates in this study, mainly for two reasons. First, susceptibility to ertapenem was not tested in non-fermenting gram-negative species, leading to the potential exclusion of carbapenem-resistant organisms in this group. Second, most IRGNs that demonstrated susceptibility to ertapenem were identified as Proteus and Morganella species, which are known to have elevated minimal inhibitory concentration to imipenem by mechanisms other than by the production of carbapenemases. Adverse clinical outcomes associated with MDRO infections compared with non-MDRO infections have been widely reported. Previous studies have reported that the proportion of MDRO in overall bacteremia ranges from 28–31%, with an overall mortality of 25–40% [21,22]. A recent Southern European cohort study reported 23.8% mortality for infections caused by carbapenem-resistant Enterobacterales

(CRE) compared to 10.6% for non-CRE infections, with a similar trend being observed in a subgroup analysis of bloodstream infections caused by CRE [23]. Other studies and meta-analyses have reported worse outcomes for infections caused by CRE [24,25], MRSA [26], and VRE [27,28] than their susceptible counterparts. Therefore, the lack of optimal therapeutic agents against MDRO warrants concern for these organisms.

The proportion of patients with underlying malignancy- at greater risk of BSI- was lower in hospital S. Hospital P reported a higher proportion of MRS and IRGN than the other two institutions. The proportions of E. coli and K. pneumoniae were also significantly lower at hospital P. Differences in the proportion of MDRO in bacteremia between institutions have also been previously reported, with MDRO being more common in long-term care facility-acquired sepsis. This phenomenon may have been influenced by the relatively poor compliance with disinfection in long-term care facilities and by the infection type [29]. Differences between institutions emphasize the effect of local epidemiology on the antimicrobial susceptibility profile pattern of a medical institution, which should be considered when designing empiric antibiotic regimens and antibiotic policies.

Although molecular markers associated with AMR have been extensively investigated and are examined in some clinical microbiology laboratories, current available commercial molecular panels may not provide sufficient information to direct appropriate antimicrobial choice for bacteremia. For example, most PCR-based molecular-based panels target only genes with established association to specific AMR, such as mecA/C in Staphylococcus aureus, vanA/B in Enterococcus species, and beta-lactamase genes [30,31]. The proportion of resistance against other antibiotic classes such as aminoglycoside, glycylcycline, and oxazolidinone, among commonly encountered pathogens was relatively low in this study. Nevertheless, it is present and may contribute to additional mortality due to ineffective empiric antimicrobial therapy or the virulence of the organisms themselves, as demonstrated by the previously mentioned analyses of CRE, MRSA, and VRE infections. Rapid detection of such antimicrobial resistance is necessary to better prepare physicians for these infections. At least one United States Food and Drug Administration (FDA)-approved PCR-based panel with AMR gene detection extending to aminoglycoside, fluoroquinolone, trimethoprim-sulfamethoxazole, and polymyxin is available and has reported > 94% positive percent agreement and negative percent agreement compared with the composite reference standard [32]. However, most panels with such extended capabilities appear limited to research use only [33], likely because of a lack of clinical data, high equipment costs, or other issues. Furthermore, the correlation between the presence of AMR genes and phenotypic resistance to antibiotics has not yet been adequately established in many cases, and further studies are required to accurately predict of phenotypic resistance associated with AMR genes. However, some resistance determinants, such as optrA for linezolid and tetA for tigecycline, are known to be associated with phenotypic resistance [34,35]. While treatment options for MDRO are extremely limited, earlier detection of these resistance mechanisms would prevent physicians from empirically prescribing non-susceptible antibiotics and would help them determine the prognosis of bacteremia.

The proportion of patients receiving broad or extremely broad-spectrum antibiotics was not significantly different between the non-MDRO and MDRO groups at the empirical treatment stage yet significantly decreased in the non-MDRO group at the post-culture reporting stage. This implies that physicians appropriately adjust antibiotic regimens according to the susceptibility pattern of the organisms and that a more rapid report on the presence of antibiotic resistance may lead to earlier antibiotic de-escalation. Several studies have reported that the adoption of rapid molecular rapid diagnostic tests is associated with decreased time to effective therapy [8,36], suggesting that physicians react to microbiological reports on a timely basis. One study examined the impact of a real-time PCR assay detecting methicillin-resistant and methicillin-susceptible S. aureus in tissue specimens from skin and soft tissue infections on antibiotic prescription and found 48 cases where antibiotic modification was recommended based on the results of molecular diagnostics and two-thirds of the cases accepted the recommendations. The findings of this study suggest a possible role for rapid molecular tests in antimicrobial stewardship [37]. A recent survey also found that intensivists were willing to incorporate molecular diagnostics results when deciding on antibiotic regimens for pneumonia [38]. Although the potential suboptimal interpretation of molecular diagnostics reports is a concern [39], faster confirmation of antibiotic resistance through molecular diagnostics in bacteremia may encourage more rapid antibiotic de-escalation.

This study has several limitations. First, this study was conducted retrospectively and was therefore susceptible to selection bias. Second, the susceptibility profile in this study was obtained from commercialized breakpoint panels and was not confirmed by broth microdilution methods. However, this method allowed analysis of susceptibility profiles for a wide range of antimicrobial agents. Third, the three participating hospitals in this study were geographically clustered, and a single hospital accounted for nearly 60% of the positive blood cultures included in this study, which may also have been a source of selection bias. Nonetheless, the study cohort is comprised of patients from three hospitals with distinct capabilities and patient populations, and the results may more accurately reflect the overall picture of bacteremia among large-scale hospitals located in Seoul and the surrounding metropolitan areas. Finally, this study may have underestimated underlying diseases and comorbid conditions because these data were extracted only from the main diagnosis codes assigned to the patients. However, the proportion of underlying diseases was described by simply comparing the patient profiles across the three institutions, and we did not aim to analyze the data associated with BSI in this specific patient group.

In conclusion, this study found that resistance to last-resort antimicrobials, such as linezolid, tigecycline, and aminoglycoside, is emerging in Korea and that higher mortality is observed in patients with MDRO bacteremia. In addition, antibiotic prescribers escalate or de-escalate antibiotic regimens according to the reported antimicrobial susceptibility profile on a timely basis. Therefore, developing and incorporating molecular diagnostics that detect a wider range of antimicrobial resistance than what is currently available may facilitate rapidly tailored antimicrobial treatment.

Supporting information

S1 Table. Prevalence of microbial isolates in blood cultures across three hospital settings.

(DOCX)

pone.0309969.s001.docx (19KB, docx)

Data Availability

The availability of the raw data described in this study is restricted by the Institutional Review Boards of three institutions (Seoul Medical Center, seoulmc.irb@gmail.com; Ajou University Hospital, ajouirb@aumc.ac.kr; Sanggye Paik Hospital, spirb@paik.ac.kr) because it contains potentially identifiable patient information and is therefore not publicly available.

Funding Statement

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

References

  • 1.Laupland KB, Church DL. Population-based epidemiology and microbiology of community-onset bloodstream infections. Clin Microbiol Rev. 2014; 27: 647–664. doi: 10.1128/CMR.00002-14 , PubMed Central PMCID: PMC4187633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022; 399: 629–655. Epub 20220119. doi: 10.1016/S0140-6736(21)02724-0 , PubMed Central PMCID: PMC8841637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018; 18: 318–327. Epub 20171221. doi: 10.1016/S1473-3099(17)30753-3 . [DOI] [PubMed] [Google Scholar]
  • 4.Delgado V, Ajmone Marsan N, de Waha S, Bonaros N, Brida M, Burri H, et al. 2023 ESC Guidelines for the management of endocarditis. Eur Heart J. 2023; 44: 3948–4042. doi: 10.1093/eurheartj/ehad193 . [DOI] [PubMed] [Google Scholar]
  • 5.Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJC, Gorbach SL, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59: e10–e52. doi: 10.1093/cid/ciu444 . [DOI] [PubMed] [Google Scholar]
  • 6.Agnetti J, Büchler AC, Osthoff M, Helfenstein F, Weisser M, Siegemund M, et al. Identification of microorganisms by a rapid PCR panel from positive blood cultures leads to faster optimal antimicrobial therapy—A before-after study. BMC Infect Dis. 2023; 23: 730. Epub 20231026. doi: 10.1186/s12879-023-08732-9 , PubMed Central PMCID: PMC10601314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.MacVane SH, Nolte FS. Benefits of adding a rapid PCR-based blood culture identification panel to an established antimicrobial stewardship program. J Clin Microbiol. 2016; 54: 2455–2463. Epub 20160803. doi: 10.1128/JCM.00996-16 , PubMed Central PMCID: PMC5035429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Pérez-Lazo G, Del Valle-Mendoza J, Sandoval-Ahumada R, Soto-Febres F, Castillo-Córdova R, Zárate-Tantaleán M, et al. Impact of adding a rapid PCR-based blood culture identification panel to the antimicrobial stewardship program of patients with febrile neutropenia in a Peruvian referral hospital. Antibiotics (Basel). 2023; 12. Epub 20230324. doi: 10.3390/antibiotics12040648 , PubMed Central PMCID: PMC10135419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Satlin MJ, Chen L, Gomez-Simmonds A, Marino J, Weston G, Bhowmick T, et al. Impact of a rapid molecular test for Klebsiella pneumoniae carbapenemase and ceftazidime-avibactam use on outcomes after bacteremia caused by carbapenem-resistant Enterobacterales. Clin Infect Dis. 2022; 75: 2066–2075. doi: 10.1093/cid/ciac354 , PubMed Central PMCID: PMC10200298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Schumann J, Johanns U, Ahmad-Nejad P, Ghebremedhin B, Woebker G. The impact of the Film Array-based detection of microbial pathogens from positive blood culture vials on the time to optimal antimicrobial regimen in intensive care units of the helios university clinic Wuppertal, Germany. J Clin Med. 2021; 10. Epub 20211215. doi: 10.3390/jcm10245880 , PubMed Central PMCID: PMC8704407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Senok A, Dabal LA, Alfaresi M, Habous M, Celiloglu H, Bashiri S, et al. Clinical impact of the BioFire blood culture identification 2 panel in adult patients with bloodstream infection: A multicentre observational study in the United Arab Emirates. Diagnostics (Basel). 2023; 13. Epub 20230721. doi: 10.3390/diagnostics13142433 , PubMed Central PMCID: PMC10378530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Sparks R, Balgahom R, Janto C, Polkinghorne A, Branley J. Evaluation of the BioFire Blood Culture Identification 2 panel and impact on patient management and antimicrobial stewardship. Pathology. 2021; 53: 889–895. Epub 20210611. doi: 10.1016/j.pathol.2021.02.016 . [DOI] [PubMed] [Google Scholar]
  • 13.Verroken A, Despas N, Rodriguez-Villalobos H, Laterre PF. The impact of a rapid molecular identification test on positive blood cultures from critically ill with bacteremia: A pre-post intervention study. PLOS ONE. 2019; 14: e0223122. Epub 20190926. doi: 10.1371/journal.pone.0223122 , PubMed Central PMCID: PMC6762135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Bae JY, Bae J, So MK, Choi HJ, Lee M. The impact of the rapid blood culture identification panel on antibiotic treatment and clinical outcomes in bloodstream infections, particularly those associated with multidrug-resistant micro-organisms. Diagnostics (Basel). 2023; 13. Epub 20231122. doi: 10.3390/diagnostics13233504 , PubMed Central PMCID: PMC10706406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.De Angelis G, Paggi R, Lowery TJ, Snyder JL, Menchinelli G, Sanguinetti M, et al. Direct testing for KPC-mediated carbapenem resistance from blood samples using a T2 magnetic resonance based assay. Antibiotics (Basel). 2021; 10. Epub 20210806. doi: 10.3390/antibiotics10080950 , PubMed Central PMCID: PMC8388919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control. 2007; 35(Suppl 2): S165–S193. doi: 10.1016/j.ajic.2007.10.006 [DOI] [PubMed] [Google Scholar]
  • 17.Kakiuchi S, Livorsi DJ, Perencevich EN, Diekema DJ, Ince D, Prasidthrathsint K, et al. Days of antibiotic spectrum coverage: A novel metric for inpatient antibiotic consumption. Clin Infect Dis. 2022; 75: 567–576. doi: 10.1093/cid/ciab1034 . [DOI] [PubMed] [Google Scholar]
  • 18.Savage TJ, Rao S, Joerger J, Ozonoff A, McAdam AJ, Sandora TJ. Predictive value of direct disk diffusion testing from positive blood cultures in a Children’s Hospital and its utility in antimicrobial stewardship. J Clin Microbiol. 2021; 59. Epub 20210519. doi: 10.1128/JCM.02445-20 , PubMed Central PMCID: PMC8316030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kim D, Yoon EJ, Hong JS, Choi MH, Kim HS, Kim YR, et al. Major bloodstream infection-causing bacterial pathogens and their antimicrobial resistance in South Korea, 2017–2019: Phase I report from kor-GLASS. Front Microbiol. 2021; 12: 799084. Epub 20220106. doi: 10.3389/fmicb.2021.799084 , PubMed Central PMCID: PMC8770956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.National Institute of Health. Antimicrobial resistance in human 2024. [Cited 2024 29 Jun]. Available from: https://www.nih.go.kr/nohas/en/statistics/selectARStatisticsMainTab.do?systemName=Kor_GLASS.
  • 21.Ponyon J, Kerdsin A, Preeprem T, Ungcharoen R. Risk factors of infections due to multidrug-resistant Gram-negative bacteria in a community hospital in rural Thailand. Trop Med Infect Dis. 2022; 7. Epub 20221023. doi: 10.3390/tropicalmed7110328 , PubMed Central PMCID: PMC9692927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Santoro A, Franceschini E, Meschiari M, Menozzi M, Zona S, Venturelli C, et al. Epidemiology and risk factors associated with mortality in consecutive patients with bacterial bloodstream infection: Impact of MDR and XDR bacteria. Open Forum Infect Dis. 2020; 7: ofaa461. Epub 20200930. doi: 10.1093/ofid/ofaa461 , PubMed Central PMCID: PMC7652098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Paniagua-García M, Bravo-Ferrer JM, Pérez-Galera S, Kostyanev T, de Kraker MEA, Feifel J, et al. Attributable mortality of infections caused by carbapenem-resistant Enterobacterales: Results from a prospective, multinational case-control-control matched cohorts study (EURECA). Clin Microbiol Infect. 2024; 30: 223–230. doi: 10.1016/j.cmi.2023.11.008 . [DOI] [PubMed] [Google Scholar]
  • 24.Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, et al. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis. 2017; 64: 257–264. Epub 20161109. doi: 10.1093/cid/ciw741 , PubMed Central PMCID: PMC5241781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Zhou R, Fang X, Zhang J, Zheng X, Shangguan S, Chen S, et al. Impact of carbapenem resistance on mortality in patients infected with Enterobacteriaceae: A systematic review and meta-analysis. BMJ Open. 2021; 11: e054971. Epub 20211214. doi: 10.1136/bmjopen-2021-054971 , PubMed Central PMCID: PMC8672018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Jokinen E, Laine J, Huttunen R, Rahikka P, Huhtala H, Vuento R, et al. Comparison of outcome and clinical characteristics of bacteremia caused by methicillin-resistant, penicillin-resistant and penicillin-susceptible Staphylococcus aureus strains. Infect Dis (Lond). 2017; 49: 493–500. Epub 20170228. doi: 10.1080/23744235.2017.1292046 . [DOI] [PubMed] [Google Scholar]
  • 27.Hemapanpairoa J, Changpradub D, Thunyaharn S, Santimaleeworagun W. Does vancomycin resistance increase mortality? Clinical outcomes and predictive factors for mortality in patients with Enterococcus faecium infections. Antibiotics (Basel). 2021; 10. Epub 20210122. doi: 10.3390/antibiotics10020105 , PubMed Central PMCID: PMC7911214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Huh K, Chung DR, Ha YE, Ko JH, Huh HJ, Lee NY, et al. Impact of vancomycin resistance in Enterococcus faecium bloodstream infection on mortality: A retrospective analysis of nationwide surveillance data. Int J Infect Dis. 2023; 134: 8–14. Epub 20230511. doi: 10.1016/j.ijid.2023.04.411 . [DOI] [PubMed] [Google Scholar]
  • 29.Kim HJ, Oh DK, Lim SY, Cho YJ, Park S, Suh GY, et al. Antibiogram of multidrug-resistant bacteria based on sepsis onset location in Korea: A multicenter cohort study. J Korean Med Sci. 2023; 38: e75. Epub 20230313. doi: 10.3346/jkms.2023.38.e75 , PubMed Central PMCID: PMC10010909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Bard JD, Lee F. Why can’t we just use PCR? The Role of Genotypic versus phenotypic Testing for Antimicrobial Resistance Testing. Clin Microbiol Newsl. 2018; 40: 87–95. Epub 20180522. doi: 10.1016/j.clinmicnews.2018.05.003 , PubMed Central PMCID: PMC7132721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Yee R, Dien Bard J, Simner PJ. The genotype-to-phenotype dilemma: How should laboratories approach discordant susceptibility results? J Clin Microbiol. 2021; 59. Epub 20210519. doi: 10.1128/JCM.00138-20 , PubMed Central PMCID: PMC8316082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Simner PJ, Musser KA, Mitchell K, Wise MG, Lewis S, Yee R, et al. Multicenter Evaluation of the Acuitas AMR Gene Panel for Detection of an Extended Panel of Antimicrobial Resistance Genes among Bacterial Isolates. J Clin Microbiol. 2022; 60: e0209821. Epub 20220316. doi: 10.1128/JCM.02098-21 , PubMed Central PMCID: PMC8925887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Brazelton de Cardenas JN, Garner CD, Su Y, Tang L, Hayden RT. Comparative evaluation of assays for broad detection of molecular resistance mechanisms in Enterobacterales isolates. J Clin Microbiol. 2021; 59: e0103321. Epub 20210818. doi: 10.1128/JCM.01033-21 , PubMed Central PMCID: PMC8525580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bi R, Qin T, Fan W, Ma P, Gu B. The emerging problem of linezolid-resistant enterococci. J Glob Antimicrob Resist. 2018; 13: 11–19. Epub 20171031. doi: 10.1016/j.jgar.2017.10.018 . [DOI] [PubMed] [Google Scholar]
  • 35.Linkevicius M, Sandegren L, Andersson DI. Potential of tetracycline resistance proteins to evolve tigecycline resistance. Antimicrob Agents Chemother. 2016; 60: 789–796. Epub 20151123. doi: 10.1128/AAC.02465-15 , PubMed Central PMCID: PMC4750697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Chang KM, Haghamad A, Saunders-Hao P, Shaffer A, Mirsaidi N, Zimilover A, et al. The clinical impact of early detection of ESBL-producing Enterobacterales with PCR-based blood culture assays. Am J Infect Control. 2024; 52: 73–80. Epub 20230806. doi: 10.1016/j.ajic.2023.08.001 . [DOI] [PubMed] [Google Scholar]
  • 37.Bouza E, Onori R, Semiglia-Chong MA, Álvarez-Uría A, Alcalá L, Burillo A. Fast track SSTI management program based on a rapid molecular test (GeneXpert® MRSA/SA SSTI) and antimicrobial stewardship. J Microbiol Immunol Infect. 2020; 53: 328–335. Epub 20180831. doi: 10.1016/j.jmii.2018.07.008 . [DOI] [PubMed] [Google Scholar]
  • 38.Pandolfo AM, Horne R, Jani Y, Reader TW, Bidad N, Brealey D, et al. Intensivists’ beliefs about rapid multiplex molecular diagnostic testing and its potential role in improving prescribing decisions and antimicrobial stewardship: A qualitative study. Antimicrob Resist Infect Control. 2021; 10: 95. Epub 20210629. doi: 10.1186/s13756-021-00961-4 , PubMed Central PMCID: PMC8243627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Donner LM, Campbell WS, Lyden E, Van Schooneveld TC. Assessment of rapid-blood-culture-identification result interpretation and antibiotic prescribing practices. J Clin Microbiol. 2017; 55: 1496–1507. Epub 20170301. doi: 10.1128/JCM.02395-16 , PubMed Central PMCID: PMC5405267. [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Mabel Kamweli Aworh

19 Jun 2024

PONE-D-24-17809Emergence of resistance to last-resort antimicrobials in bacteremia pathogens: A multicenter analysis of bloodstream pathogens in Korea.PLOS ONE

Dear Dr. Park,

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 submit your revised manuscript by Aug 03 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,

Mabel Kamweli Aworh, DVM, MPH, PhD. FCVSN

Academic Editor

PLOS ONE

Journal requirements:

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

1. 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. In the online submission form, you indicated that [Restrictions apply to the availability of the data described in this study, and so are not publicly available. Subsets of datasets generated and analyzed during this study are available from the corresponding author on reasonable request.]. 

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. 

3. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

3. 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

Reviewer #2: No

**********

4. 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

Reviewer #2: Yes

**********

5. 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: Comments and Suggestions for Authors

I read the manuscript with great interest. Here are some comments, which may help the authors to improve the manuscript:

Title: I suggest the “bacteremia pathogen” in the title should be replaced with “bacteremia patients”

Abstract: Please define MDRO at its first mention. This applies to all others throughout the paper.

Methods: For easy understanding, I suggest the methods should be grouped under sub-headings.

For example;

Lines 92 – 104 should be under sub-heading: Study design and procedures

Lines 105 – 119 should be under the sub-heading: Classification of Antibiotic Resistance

Lines 120 – 125 should be under the sub-heading: Statistical analysis

Lines 126 – 133 should be under the sub-heading: Ethical approval

Reviewer #2: REVIEWER’S COMMENTS

Title: Emergence of resistance to last-resort antimicrobials in bacteremia pathogens: A multicenter analysis of bloodstream pathogens in Korea

Summary

This is an important research work which brings to fore the profile of AMR associated with blood stream infection in Seoul, South Korea. It is a retrospective multi-centre study conducted within a year period across three health facilities (two secondary and one tertiary health facility) with the aim of conducting a large-scale analysis that enables adequate review of the microbiological and clinical characteristics of patients diagnosed with bacteremia. The objectives of the study and rationale for the study were well highlighted. The problem statements and gap in knowledge were also well outlined. Reference to previous literature were satisfactory.

The authors described their methods broadly which is worrisome for reproducibility. To summarize, the authors reviewed positive blood culture results to identify bacteria isolates, conducted antimicrobial susceptibility testing and compared the pattern of empirical treatment and tailored treatments with respect to their spectrum of coverage and MDRO. They went further to assess the underlying pathology and in-hospital mortality of the patients. However, there are important questions to answer. The authors conducted this study in only urban hospitals which have implications for generalizability to a more heterogenous population. The study sites should be sufficiently described to put the study in context. The sampling method and study population were not adequately described. The study population appears to be skewed to the elderly based on the median age group despite the fact that bacteremia can occurs in any age group. It is important that the authors clearly outline the inclusion and exclusion criteria of the study population.

Although, the variables of interest were well elucidated, there was no mention of the study instrument which has implications for standardization being a multi-centre study. Were the samples analyzed separately in each facility or pooled to a centre and were there clear Laboratory protocols developed? What were the other quality assurance processes for the laboratory component of this study?

The research findings provide evidence of antimicrobial resistance to last resort antibiotics. Analysis done are mostly descriptive, authors should consider doing some inferential statistics or if done to be reflected in the tables. In addition, given the comparative nature of the study with respect to facilities, statistically significant differences should also be highlighted (asterix) on the tables where available. It is also important that the authors explain how 3397 bacteria isolates were isolated from 3064 blood patients, having mentioned in the methods, that they focused solely on the first organism isolated from each positive blood culture per patient. Figure 1, should add up to 100% for each health facility (showcasing MDROs and non-MDROs even if the MDROs are disaggregated). The variables in figure 2 are best presented using a table to compare the ASC scores between Empirical and Tailored treatment and highlighting the level of statistical significance.

The authors may also wish to review the manuscript for typographical and grammatical errors beginning with the abstract, line 27-28. Also, line 50-57 (The sentence is too long, authors to consider splitting into 2 or 3 sentences). Rephrase sentence in line 77-80. The discussion in line 177-183 is a bit confusing.

Overall, the study findings highlight the need for rapid diagnostic infrastructure with capacity for wide antimicrobial resistance detection in order to reduce the use of empirical antibiotics and enhance timely prescription of tailored treatment which is critical to slow down the emergence of multidrug resistant organisms.

I personally think this is a well written manuscript, the findings are noteworthy and should be used to drive a strong public health response in South Korea to address the issues of antimicrobial resistance. I recommend that the manuscript be published after the outlined corrections are effected.

**********

6. 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: No

Reviewer #2: Yes: DR. JENNY ADONORELI MOMOH

**********

[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.

Attachment

Submitted filename: Emergence of resistance to last-resort antimicrobials.docx

pone.0309969.s002.docx (14.2KB, docx)
PLoS One. 2024 Oct 23;19(10):e0309969. doi: 10.1371/journal.pone.0309969.r002

Author response to Decision Letter 0


11 Jul 2024

July 11, 2024

Dr. Emily Chenette

Editor-in-Chief

PLOS ONE

Dear Dr. Calderaro:

On behalf of the authors, I would like to thank you and the reviewers for the valuable and insightful comments they have provided regarding our submitted manuscript, “Emergence of resistance to last-resort antimicrobials in bacteremia pathogens: A multicenter analysis of bloodstream pathogens in Korea” (manuscript ID: PONE-D-24-17809).

We have carefully reviewed the comments and have revised the manuscript accordingly. Our responses are provided in a point-by-point manner, and changes to the manuscript are shown in yellow highlight, which is also visible through the Track Changes function.

We want to reiterate that this manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these.

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Kuenyoul Park, MD, PhD.

Department of Laboratory Medicine, Sanggye Paik Hospital, School of Medicine, Inje University, 1342, Dongil-ro, Nowon-gu, Seoul 01757, Korea.

Tel: +82-2-950-4898

Fax: +82-2-950-1244

Email: kuenyoul.park@gmail.com

Response to Reviewer 1

Thank you for reviewing our manuscript. We appreciate the reviewer's thorough analysis and comments. We have considered the reviewer's points as much as possible to improve the quality of our research and paper. We have answered each of your points below.

1. Title: I suggest the “bacteremia pathogen” in the title should be replaced with “bacteremia patients”

è Response: Thank you for this insightful suggestion. We have revised the title as follows:

“Emergence of resistance to last-resort antimicrobials in bacteremia pathogens: A multicenter analysis of bloodstream pathogens in Korea” → “Emergence of resistance to last-resort antimicrobials among bacteremia patients: A multicenter analysis of bloodstream pathogens in Korea”

2. Abstract: Please define MDRO at its first mention. This applies to all others throughout the paper.

è Response: Response: Following your suggestion, we defined MDRO at its first mention in the abstract.

“Among these, 949 isolates obtained from 893 patients were classified as multidrug-resistant organisms (MDRO), including 170 imipenem-resistant gram-negative bacteria, 714 methicillin-resistant staphylococci, and 65 vancomycin-resistant enterococci.”

3. Methods: For easy understanding, I suggest the methods should be grouped under sub-headings.

For example;

Lines 92 – 104 should be under sub-heading: Study design and procedures

Lines 105 – 119 should be under the sub-heading: Classification of Antibiotic Resistance

Lines 120 – 125 should be under the sub-heading: Statistical analysis

Lines 126 – 133 should be under the sub-heading: Ethical approval

è Response: Thank you for your helpful suggestion. We added subheadings as recommended.

Response to Reviewer 2

Thank you for reviewing our manuscript. We appreciate the reviewer's thorough analysis and comments. We have carefully considered the reviewer's points and have incorporated them to enhance the quality of our research and paper. Below, we have addressed each of your points.

The authors conducted this study in only urban hospitals which have implications for generalizability to a more heterogeneous population. The study sites should be sufficiently described to put the study in context.

è Response: Thank you for your insightful suggestion. The three participating hospitals in this study are geographically clustered; however, each hospital's characteristics and functional capacity are distinct. Hospital A is a university-affiliated tertiary-care hospital with high patient severity, and hospital P is a secondary-care hospital with a larger volume of oncology patients compared to other secondary-care hospitals. The proportion of cancer among patients enrolled from these two hospitals is approximately 20% as shown in Table 1. While hospital S is also a secondary-care hospital, it is a municipal hospital that carries out public projects and serves patients of various socioeconomic status: elderly patients, who generally have lower income compared to the general population, particularly utilize hospital S due to its affordability. We did attempt to incorporate as much heterogeneity to our study population by including several hospitals with distinct characteristics, yet we also acknowledge that the hospitals are not geographically diverse and added this point as a limitation of our study under “Discussion” as follows:

"Third, the three participating hospitals in this study were geographically clustered, and a single hospital accounted for nearly 60% of the positive blood cultures included in this study, which may also have been a source of selection bias.”

The sampling method and study population were not adequately described. The study population appears to be skewed to the elderly based on the median age group despite the fact that bacteremia can occurs in any age group. It is important that the authors clearly outline the inclusion and exclusion criteria of the study population.

è Response: All hospitalized patients with positive blood cultures during the study period. We clarified the study duration and inclusion/exclusion criteria under “Methods” as follows:

“This retrospective observational study was conducted using the medical records and blood culture results of patients admitted to three distinct hospitals from July 2022 to June 2023: a public secondary hospital (S), a university-affiliated tertiary hospital (A), and a university-affiliated secondary hospital (P). All hospitalized patients with positive blood cultures during the study period were enrolled. Data were collected only for the first organism isolated from positive blood culture of each patient’s duration of admission: in case two or more organisms were simultaneously identified on first blood culture, all were included.”

è We also agree that the age distribution appears skewed toward the elderly population. However, the high median age (72 years) and interquartile age (61 to 82 years) of this study are more likely attributable to the high risk of bacterial infection associated with elderly population (e.g., reduced efficacy of immune system and comorbidities such as diabetes).

Although, the variables of interest were well elucidated, there was no mention of the study instrument which has implications for standardization being a multi-centre study. Were the samples analyzed separately in each facility or pooled to a centre and were there clear Laboratory protocols developed? What were the other quality assurance processes for the laboratory component of this study?

è Response: We clarified the testing process and the quality control policies under “Methods”:

“Bacterial identification and AST were performed in the laboratory of the patient’s admitting hospital. The laboratories of all three participating hospitals were accredited for internal and external quality assurance programs by the Laboratory Medicine Foundation of Korea and Korean Association of External Quality Assessment Service during the study period."

The research findings provide evidence of antimicrobial resistance to last resort antibiotics. Analysis done are mostly descriptive, authors should consider doing some inferential statistics or if done to be reflected in the tables. In addition, given the comparative nature of the study with respect to facilities, statistically significant differences should also be highlighted (asterix) on the tables where available.

è Response: We thank you for sharing this perspective. The demographic and clinical characteristics were compared between the three institutions using the Kruskal-Wallis test for continuous variables and the chi-square or Fisher’s exact test for categorical data. The statistical analysis methods and results were added to the text as follows:

“Comparative analyses of nominal variables were conducted using Pearson's chi-squared test and Fisher's exact test, while continuous variables were analyzed using the Kruskal-Wallis test.”

“The median age of the patients was 72 years (IQR: 61–82 years), 45.9% were female, and there were statistically significant differences in age (p<0.001) and gender (p<0.001) between the institutions.”

“Among the three institutions, the frequency of malignancy as an underlying disease showed statistically significant differences (p<0.001) between the three institutions, being highest in hospital A (20.3%), followed by hospital P (19.5%) and hospital S (3.7%).”

It is also important that the authors explain how 3397 bacteria isolates were isolated from 3064 blood patients, having mentioned in the methods, that they focused solely on the first organism isolated from each positive blood culture per patient.

è Response: If the same bacterial pathogen was repeatedly identified from the same patient within the patient’s admission duration, only the first identification result was retained, and the rest were excluded to avoid repeated inclusion. However, as noted in Table 1, two or more distinct bloodstream pathogens were simultaneously identified from a single patient within a single admission in approximately 8% of the patients, in which case all distinct organisms were included. We clarified this point in “Methods”:

“Data were collected only for the first organism isolated from positive blood culture of each patient’s duration of admission: in case two or more organisms were simultaneously identified on first blood culture, all were included.”

Figure 1, should add up to 100% for each health facility (showcasing MDROs and non-MDROs even if the MDROs are disaggregated).

è Response: We revised Figure 1 as recommended.

The variables in figure 2 are best presented using a table to compare the ASC scores between Empirical and Tailored treatment and highlighting the level of statistical significance.

è Response: We converted Figure 2 into Table 4, and statistical significance were denoted with asterix. We also incorporated these changes in “Results” as follows:

“Interestingly, the proportion of ASC scores ≥ 15, indicating broad- or very broad- spectrum antibiotic coverage, was not significantly different between the MDRO and non-MDRO groups at B0, but significantly decreased in non-MDRO group at R+2 (p<0.001, Table 4).”

The authors may also wish to review the manuscript for typographical and grammatical errors beginning with the abstract, line 27-28.

è Response: Thank you for pointing out this detail. We corrected the error as follows:

“Antibiotic spectrum coverage (ASC) scores were calculated on the day the blood culture was performed (B0) and on two days after the blood culture results were reported obtained (R+2).” → “Antibiotic spectrum coverage (ASC) scores were calculated on the day the blood culture was performed (B0) and on two days after the blood culture results were reported (R+2).”

Also, line 50-57 (The sentence is too long, authors to consider splitting into 2 or 3 sentences).

è Response: We divided the sentence as follows:

“Bacteria harboring resistance to several classes of antimicrobial agents are commonly referred to as multidrug-resistant organisms (MDRO).”

“In 2017, the World Health Organization (WHO) listed several MDRO as “priority pathogens” requiring novel therapeutic agents, including vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant/extended beta-lactamase (ESBL)-producing Enterobacterales.”

Rephrase sentence in line 77-80.

è Response: Thank you for this suggestion. We rephrased this as follows:

“Recently, T2resistance (T2Biosystems, Lexington, MA, USA) has become available for research use and one study reported 84.6% detection rate of carbapenem resistance genes in blood-culture confirmed carbapenem-resistant gram-negative BSI with a turnaround time of 3 to 5 hours” → “Recently, T2resistance (T2Biosystems, Lexington, MA, USA) has become available for research use, and one study reported 84.6% detection rate of carbapenem resistance genes in blood culture-confirmed Gram-negative BSI within 3 to 5 hours.”

The discussion in line 177-183 is a bit confusing.

è Response: We rewrote this as follows in the revised manuscript:

“According to the Global Antimicrobial Resistance and Use Surveillance Program in Korea (Kor-GLASS) data, which collects and annually reports AMR data across nine tertiary hospitals across Korea, there was high prevalence of multidrug-resistance among blood-isolated organisms among large-scale hospitals in Korea. In 2022, susceptibility rate of blood-isolated Staphylococcus aureus to cefoxitin was 54.3%, and susceptibility rate of Enterococcus faecium to vancomycin was 64.9%. Carbepenem susceptibility among blood-isolated Enterobacterales has also steadily declined since 2019 (imipenem-susceptible Escherichia coli and Klebsiella pneumoniae- 99.2% in 2019 to 94.0% in 2022).”

Attachment

Submitted filename: Response_to_Reviewers_BSI_240711.docx

pone.0309969.s003.docx (30.8KB, docx)

Decision Letter 1

Mabel Kamweli Aworh

20 Aug 2024

Emergence of resistance to last-resort antimicrobials in bacteremia patients: A multicenter analysis of bloodstream pathogens in Korea.

PONE-D-24-17809R1

Dear Dr. Park,

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,

Mabel Kamweli Aworh, DVM, MPH, PhD. FCVSN

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

Reviewer #2: 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: (No Response)

Reviewer #2: Yes

**********

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

Reviewer #1: (No Response)

Reviewer #2: 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: (No Response)

Reviewer #2: No

**********

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: (No Response)

Reviewer #2: 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)

Reviewer #2: Title: Title: Emergence of resistance to last-resort antimicrobials in bacteremia pathogens: A multicenter analysis of bloodstream pathogens in Korea

Following the review of the updated manuscript, I think that the authors have to a very great extent addressed the queries raised. They have addressed the issues around heterogeneity of study sites and generalization of study findings. They have also provided more clarity into their methods and laboratory procedures to enable for reproducibility. Further review of their results have been done which now transcends beyond descriptive analysis to include inferential statistics, giving more weight to the findings.

I am satisfied with the current update on the manuscript as the authors have taken the time to address point by point all issues raised. I therefore recommend that the manuscript be published.

**********

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: No

Reviewer #2: No

**********

Acceptance letter

Mabel Kamweli Aworh

23 Aug 2024

PONE-D-24-17809R1

PLOS ONE

Dear Dr. Park,

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

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. Mabel Kamweli Aworh

Academic Editor

PLOS ONE

Associated Data

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

    Supplementary Materials

    S1 Table. Prevalence of microbial isolates in blood cultures across three hospital settings.

    (DOCX)

    pone.0309969.s001.docx (19KB, docx)
    Attachment

    Submitted filename: Emergence of resistance to last-resort antimicrobials.docx

    pone.0309969.s002.docx (14.2KB, docx)
    Attachment

    Submitted filename: Response_to_Reviewers_BSI_240711.docx

    pone.0309969.s003.docx (30.8KB, docx)

    Data Availability Statement

    The availability of the raw data described in this study is restricted by the Institutional Review Boards of three institutions (Seoul Medical Center, seoulmc.irb@gmail.com; Ajou University Hospital, ajouirb@aumc.ac.kr; Sanggye Paik Hospital, spirb@paik.ac.kr) because it contains potentially identifiable patient information and is therefore not publicly available.


    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES