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. 2023 Jun 23;18(6):e0283417. doi: 10.1371/journal.pone.0283417

Essential components of a definition for early antibiotic treatment failure: A scoping review

Hiroyoshi Iwata 1,2,*, Makoto Kaneko 3, Takuya Aoki 4, Koji Endo 5, Yuki Nagai 6, Kenji Kanto 7, Masahiro Yao 8, Shuhei Hamada 9,10
Editor: Ali Amanati11
PMCID: PMC10289306  PMID: 37352330

Abstract

Background

Despite the broad global use of antibiotics, there is no established definition of early antibiotic treatment failure (EATF) to aid clinical evaluation of treatment, which leads to inconsistent assessments of drug effectiveness.

Aim

This scoping review aims to identify common components of EATF definitions by synthesizing studies mentioning EATF and its relevant thesaurus matches.

Design

Scoping review

Methods

This scoping review was conducted following the PRISMA Scoping review guidelines. A systematic literature search was conducted using MEDLINE (PubMed), CENTRAL, CINAHL, and Web of Science, as well as a manual Google search. Search terms were EATF and its thesaurus matches. After removing duplications, candidate studies were screened by title and abstract prior to full text searches, and quality analysis was performed on eligible studies using the Critical Appraisal Skills Programme. From each eligible study, the timing of evaluation, basic components, and detailed information for each definition of EATF were collected. The components of each definition for EATF were then summarized and counted, and finally the most common essential components were identified.

Results

Our systematic literature search found 2,472 candidate studies. After title and abstract screening, full text search and quality assessment, 61 studies, including 56 original studies and five reviews, were eligible for our analysis. Of these 56 original studies, 43 mentioned the timing of EATF evaluation 72 hours after the start of treatment with antibiotics. From these 43 studies, the most common indicators of EATF were extracted, among which a set of essential components for a definition of EATF were identified: mortality, vital signs, fever, symptoms, and additional treatment.

Conclusions

Our scoping review uncovered five essential factors for EATF. Further study is needed to evaluate the validity of our findings.

Introduction

Antibiotics are administered with high frequency worldwide [1], but there is no established clinical standard definition for early antibiotic treatment failure (EATF) with criteria for assessing effectiveness in the early treatment phase [2, 3]. In most cases of infectious disease treatment, decisions about whether to continue, change, or discontinue antibiotics are made based on the individual clinician’s personal criteria and discretion. Moreover, there are many cases in which it is difficult for clinicians to determine the clinical effectiveness of antibiotics. A finding of EATF can help prevent long-term use of unnecessary antibiotics, thereby reducing the risk of developing multidrug-resistant bacteria. In clinical research, EATF may also be warranted as an outcome of antibiotic treatment in observational or randomized controlled studies.

It is difficult to evaluate whether additional treatment succeeded or failed based on mortality alone. Some other outcomes of antibiotic treatment, such as hospital duration, are not applicable for early-stage evaluation. In the early stage of bacterial infectious disease, patients can experience critical events, including: shock, requiring vasopressors, and intubation for mechanical ventilation, in addition to death. Thus, a standardized set of criteria for evaluating early-stage antibiotic treatment effectiveness would have clinical utility.

There are several reports mentioning EATF. In 2009, Sánchez García published a review of "Early antibiotic treatment failure" [2]. However, that study did not conduct a systematic literature search, and over ten years has passed since it was published. There are other novel articles which mention "early antibiotic treatment failure" or its thesaurus matches, as described below. Bassetti et al. (2020) conducted a systematic review focused on the impact of appropriate versus inappropriate initial antibiotics therapy (IAT) [4]. Although EATF and IAT have some overlap, the IAT literature does not always refer to early-stage evaluation. To the best of our knowledge, the definitions of both EATF and IAT lack standardization and are still evolving. Recently, Rac et al. (2020) proposed a set of "early clinical failure criteria" composed of systolic blood pressure, heart rate, respiratory rate, altered mental status and white blood cell count [5]. However, this study investigated the criteria as a predictive variable of 28-day mortality, and did not present the evidence on which the criteria were based or an assessment of their validity.

Therefore, a scoping review was conducted in order to clarify the key components of EATF definitions based on the results of a systematic search of literature mentioning EATF and its thesaurus matches [6].

Methods

Search strategy and types of sources

Our protocol was registered with the Open Science Framework (OSF) on February 28th, 2022 [7]. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews (PRISMA-ScR) and JBI Manual for Evidence Synthesis [8, 9]. (S1 Table) Our search covered all peer-reviewed publications published from January 1st, 1980 to February 28th, 2022. This is because the articles mentioning EATF in the Sánchez García EATF review article were from early 21st Century [2]. The search used Medline (PubMed), CENTRAL, CINAHL, Web of Science, and also performed a manual Google search. Our search terms are shown in S2 Table. Whenever possible, MeSH terms and keywords were used to increase the chances of finding relevant studies. The search strategy, including all identified keywords and index terms, was adapted for each included database. A librarian at the Jikei University School of Medicine supported the systematic literature search. The manual Google search also included literature cited in the eligible articles. Searches were not limited by language.

Eligible publications

Any type of publication was included if it presented a conceptual definition of EATF or its thesaurus matches. This scoping review considered various study designs including randomized controlled trials, non-randomized controlled trials, before and after studies, interrupted time-series studies, prospective and retrospective cohort studies, case-control studies, cross-sectional studies, and case series studies. In addition, systematic reviews that meet the inclusion criteria were considered. Opinion and text papers, as well as research letters were also considered for inclusion. In contrast, case reports and animal studies were excluded.

Participants/Study outcome

Our scoping review conducted a search targeting participants or studies whose outcome was EATF or its thesaurus matches.

Inclusion and exclusion criteria

Studies presenting clear definitions for EATF or its thesaurus matches were included if evaluations were performed no later than seven days after admission or bacteremia onset or initiation of antibiotics treatment, among bacterial infection patients [2]. Because the definition of EATF is still evolving and there is overlap between EATF and "initial antibiotic treatment failure" (IATF), IATF studies were also included if their definition criteria mention outcomes no later than seven days after admission or bacteremia onset or initiation of antibiotics treatment. Finally, treatment success and its thesaurus matches, such as clinical response, were also included as a proxy for treatment failure.

Our exclusion criteria were: 1) studies whose target disease was not a bacterial infection, 2) studies whose target disease’s standard treatment is not antibiotics, 3) studies whose target disease is resistant to common antibiotics, leading to a heightened risk of recurrence, such as Mycobacterium including tuberculosis, Helicobacter, and Clostridium difficile, 4) studies whose participants were pediatric patients or outpatients, 5) studies covering only oral treatment, 6) studies not reporting a clear definition of EATF or IATF, and 7) studies not reporting the timing of their evaluations, or whose evaluations were conducted more than seven days after admission or bacteremia onset or initiation of antibiotics treatment.

Literature search, data extraction process and quality assessment

After combining literature search results and removing duplications, two independent teams [HI] and [KE, SY] performed the first screening using titles and abstracts. Next, HI, KE and MK performed full text reviews. Discrepancies of inclusion or exclusion were resolved by all authors. After choosing candidates with two independent teams, we [YN, KK, SH] independently performed quality analysis using the Critical Appraisals Skill Programme (CASP) [10, 11]. TA audited the whole process from an objective viewpoint. EndNote X9.3.3 was used to sort the literature and remove duplications.

Data presentation and identification of common components of EATF definitions

After the literature search and quality assessment, the definitions of EATF were compiled in a table. The most frequently used timing of EATF assessment was identified from among the eligible studies, excluding reviews. Next, because different timing of evaluation is likely to result in different events constituting failure, the investigation was narrowed to studies reporting the most frequent timing of evaluation. Among the eligible studies, excluding reviews, using the most frequently reported timing for EATF assessment, common components which comprise EATF definitions were identified. Finally, the common essential components of a definition for EATF were summarized.

The components were divided into several categories: mortality, symptoms, vital signs, body temperature, disease-specific changes, radiographic changes, persistent positive blood culture, need of additional treatment including new antibiotics and intubation for mechanical ventilation and vasopressors, new onset of other disease, source control (drainage or operation), intensive care unit (ICU) admission, readmission, and recurrence of the original disease. While body temperature (fever) is itself a vital sign, high fever alone can be an indispensable clinical factor [12]. Hence, vital signs and body temperature are listed separately. Common elements of the definitions for EATF found in eligible studies which measured EATF at the most frequent timing were then summarized.

Results

Our study flow chart is shown in Fig 1. Our systematic literature search produced 2472 potentially eligible studies. Sixteen articles were added through a manual search on Google and Google Scholar. After removing duplications, 2,088 studies were screened by title and abstract, after which 168 studies were deemed appropriate for the full text assessment. In the full text assessment, 107 studies were found to be ineligible for the following reasons: no EATF definition (46), no definition of early phase outcome (48), not bacterial disease (6), pediatrics study (3), case report (2), unavailable in domestic library network (2). After the full-text assessment, 56 studies were eligible for the qualitative assessment using the CASP to assess the risk of bias and applicability, in addition to which five review articles were included. Finally, 61 studies, including the five reviews, were eligible for our analysis. The references of the eligible studies are shown in S3 Table. No authors were contacted.

Fig 1. PRISMA literature search flowchart.

Fig 1

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The characteristics of the eligible studies (ID 1–61) and their EATF components are summarized in Table 1. The first mention of EATF was found in a study published in 1994. All included studies were written in English, except Wang et al. (2014) [13], which was written in Chinese. The most common countries of publication were Sweden, South Korea, and the United States. The most common research target disease was pneumonia (including community-acquired pneumonia and ventilator-associated pneumonia), followed by urinary tract infection. Common EATF thesaurus matches included clinical success, clinical response, clinical failure, initial treatment failure, and early treatment failure. Eight studies reporting infections which may need additional source control were identified, including complicated skin and skin-structure infection, complicated urinary tract infection, acute appendicitis, intra-abdominal infection, and diverticular abscess. However, because these infections can be successfully treated with antibiotics, these eight studies were not excluded from our analysis.

Table 1. Characteristics of eligible studies and components of definitions for early antibiotics treatment failure.

Study ID Author Outcome name Year Language Country Disease 48 hours 72 hours Day 4 Day 5 Day 7 Type
1 Erjavec et al. Response rate 1994 English Netherlands Various ○ original
2 Bosi et al. Success, failure 1999 English Italy Various ○ original
3 Arancibia et al. Failure 2000 English Spain Pneumonia (community-acquired pneumonia) ○ original
4 Ioanas et al. Nonresponse 2004 English Spain Pneumonia (intensive care unit–acquired pneumonia) ○ original
5 Menendez et al. Early treatment failure 2004 English Spain Pneumonia (community-acquired pneumonia) ○ original
6 Edelsberg et al. Treatment failure 2008 English United States Complicated skin and skin-structure infections* ○ ○ original
7 Bruns et al. Early clinical failure 2009 English Netherlands Pneumonia (community-acquired pneumonia) ○ original
8 Mitja et al. Early mortality 2009 English Spain Listeriosis ○ ○ original
9 Shindo et al. Initial treatment failure 2009 English Japan Pneumonia (health-care-associated pneumonia) ○ ○ ○ original
10 Cheng et al. Clinical response 2010 English Taiwan Gram negative bacterial infections ○ original
11 Tumbarello et al. Treatment failure, initial response to treatment 2010 English Italy Bacteremia (bloodstream infections) ○ original
12 Vogelaers et al. Clinical response 2010 English Germany Severe nosocomial infections ○ original
13 Yakar et al. Antibiotic failure 2010 English Turkey Spontaneous bacterial peritonitis ○ original
14 Jeon et al. Initial treatment failure 2011 English Korea Pneumonia ○ ○ ○ original
15 Stojadinovic et al. Early clinical failure 2011 English Serbia Kidney Infections ○ original
16 Waltner-Toews et al. Early clinical response 2011 English United States Bacteremia (bloodstream infections) ○ ○ ○ ○ original
17 Eckburg et al. Clinical response 2012 English Various (Africa, Asia, Eastern Europe, Western Europe, Latin America, and the United States) Pneumonia (community-acquired pneumonia) ○ original
18 Janisch et al. Failure 2012 English Germany Various ○ original
19 O’Neal et al. Treatment failure 2012 English United States Bacteremia ○ original
20 Ott et al. Treatment failure 2012 English Germany Pneumonia ○ original
21 Berger et al. Initial treatment failure 2013 English United States Complicated skin and skin-structure infections* ○ original
22 Kang et al. Unfavorable treatment response 2013 English Korea Bacteremia ○ original
23 Maruyama et al. Initial treatment failure 2013 English Japan Pneumonia ○ ○ ○ ○ ○ original
24 Robinson et al. Treatment response 2014 English United States Pneumonia (community-acquired pneumonia) ○ original
25 Saverio et al. Short-term efficacy of antibiotic treatment, failure 2014 English Italy Acute Appendicitis* ○ original
26 Wang et al. Early treatment failure 2014 Chinese China Pneumonia (community-acquired pneumonia) ○ original
27 Wie et al. Early clinical success, early clinical failure 2014 English South Korea Urinary tract infection (Pyelonephritis) ○ original
28 Wie et al. Early clinical success, early clinical failure 2014 English South Korea Urinary tract infection (Pyelonephritis) ○ original
29 Chong et al. Failure of initial antibiotic therapy 2015 English South Korea Intra-abdominal infections ○ original
30 Elagili et al. Treatment failure 2015 English United States Diverticular abscess* ○ original
31 Lodise et al. Clinical response 2015 English United States Pneumonia (community-acquired pneumonia) ○ ○ ○ ○ ○ original
32 Torres et al. Early treatment failure 2015 English Spain Pneumonia (community-acquired pneumonia) ○ original
33 Hsieh et al. Early clinical failure 2016 English Taiwan Bacteremia ○ original
34 Jääskeläinen et al. Treatment failure 2016 English Finland, Sweden Complicated skin and skin-structure infections* ○ original
35 Merli et al. Treatment failure 2016 English Italy Health-care-associated infections among cirrhosis patients ○ original
36 Park et al. Clinical success, clinical failure 2016 English South Korea Urinary tract infection (Pyelonephritis) ○ original
37 Ramirez et al. Clinical response 2016 English Spain Pneumonia (ventilator-associated pneumonia) ○ original
38 Babich et al. Clinical failure 2017 English Israel Urinary tract infection (Catheter-Associated) ○ original
39 Ceccato et al. Early treatment failure 2017 English Spain Pneumonia (community-acquired pneumonia) ○ ○ original
40 Ereshefsky et al. Clinical cure 2017 English United States Serious nosocomial infections ○ original
41 Lee et al. Clinical response 2017 English Taiwan Bacteremia ○ original
42 Ruiz-Ramos et al. Treatment failure, clinical response 2017 English Spain Pneumonia (ventilator-associated pneumonia) ○ original
43 Trupka et al. Early failure 2017 English United States Pneumonia (ventilator-associated pneumonia) ○ original
44 El-Sokkary et al. Clinical response 2018 English Egypt Pneumonia (community-acquired pneumonia) ○ ○ original
45 Karve et al. Success, failure, intermediate 2018 English Brazil, France, Italy, Russia, Spain Urinary tract infections (complicated urinary tract infection) * ○ original
46 Nie et al. Treatment failure 2018 English China Pneumonia (community-acquired pneumonia) ○ ○ ○ ○ original
47 Eliakim-Raz et al. Treatment failure 2019 English 20 countries in Europe and the Middle East Urinary tract infection (complicated urinary tract infection) * ○ ○ original
48 Kim SH et al. Treatment failure, clinical treatment success 2019 English South Korea Urinary tract infection (Pyelonephritis) ○ original
49 Peeters et al. Initial treatment failure, treatment success, treatment failure 2019 English Brazil, France, Italy, Russia, Spain Intra-abdominal infection* ○ original
50 Wongsurakiat et al. Early treatment failure 2019 English Thailand Pneumonia (community-acquired pneumonia) ○ ○ original
51 Al-Hasan et al. Early treatment failure 2020 English United States Bacteremia (gram-negative bloodstream infections) ○ original
52 Kim YJ et al. Early clinical response 2020 English South Korea Urinary tract infection ○ original
53 Rac et al. Early clinical failure 2020 English United States Bacteremia (gram-negative bloodstream infections) ○ ○ original
54 Shimoni et al. Response to antibiotic therapy 2020 English Israel Urinary tract infection ○ original
55 Herrmann et al. Early treatment response 2021 English Germany Bacteremia (Bloodstream Infections) ○ original
56 Mun et al. Early antibiotic treatment failure 2021 English South Korea Bacteremia ○ original
57 Garcia-Vidal et al. Early failure 2009 English Review article Pneumonia (community-acquired pneumonia) ○ Review article
58 Sánchez García M Early antibiotic treatment failure 2009 English Review article Various Review article
59 Cao et al. Failed initial therapy 2018 English Review article Pneumonia (community-acquired pneumonia) ○ Review article
60 Bassetti et al. Treatment failure 2020 English Review article Various (severe bacterial infections) Review article
61 Ceccato et al. Clinical response 2022 English Review article Pneumonia (ventilator-associated pneumonia) ○ Review article
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○; Applicable

* Target disease may need infection control.

Eligible studies used varying definitions for EATF and evaluations were performed at various times. Aside from the five review studies, of the 56 other eligible studies, 43 mentioned EATF evaluation at 72 hours after the initiation of antibiotics treatment, suggesting that the most common timing for evaluating EATF is 72 hours.

Next, the components of the EATF definitions were extracted. (Table 2) Major components of definitions for EATF were found to be mortality, symptoms, vital signs, fever, and need of additional treatment.

Table 2. Components of definitions for early antibiotics treatment failure evaluated 72 hours after antibiotics treatment.

Study ID Author Outcome Mortality Symptom Vital sign Mental status Fever Laboratory change Radiographic change Need additional therapy Disease specific change Source control (Drainage or operation) New disease onset ICU admission Multiple organ failure Persistent blood culture Readmission Recurrence
1 Erjavec et al. Response rate ○ ○ ○ ○
2 Bosi et al. Success, failure ○ ○
3 Arancibia et al. Failure ○ ○
4 Menendez et al. Early treatment failure ○ ○ ○ ○ ○
5 Ioanas et al. Non response ○ ○ ○ ○ ○
6 Edelsberg et al. Treatment failure ○ ○
7 Mitja et al. Early mortality ○
8 Bruns et al. Early clinical failure ○ ○ ○ ○ ○
9 Shindo et al. Initial treatment failure ○ ○ ○ ○
10 Cheng et al. Clinical response ○ ○ ○
11 Tumbarello et al. Treatment failure, initial response to treatment ○ ○ ○
13 Yakar et al. Antibiotic failure ○ ○ ○
14 Jeon et al. Initial treatment failure ○ ○ ○ ○
16 Waltner-Toews et al. Early clinical response ○ ○ ○ ○
17 Eckburg et al. Clinical response ○ ○ ○ ○
18 Janisch et al. Failure ○
19 O’Neal et al. Treatment failure ○ ○ ○ ○ ○
20 Ott et al. Treatment failure ○
21 Berger et al. Initial treatment failure ○ ○
23 Maruyama et al. Initial treatment failure ○ ○ ○
26 Wang et al. Early treatment failure ○ ○ ○ ○ ○
27 Wie et al. Early clinical success, early clinical failure ○ ○ ○ ○
28 Wie et al. Early clinical success, early clinical failure ○ ○ ○ ○
31 Lodise et al. Clinical response ○ ○ ○
32 Torres et al. Early treatment failure ○ ○ ○
33 Hsieh et al. Early clinical response ○ ○
35 Merli et al. Treatment failure ○ ○ ○
36 Park et al. Clinical success, clinical failure ○ ○
37 Ramirez et al. Clinical response ○ ○ ○ ○
39 Ceccato et al. Early treatment failure ○ ○ ○
41 Lee et al. Clinical response ○ ○
42 Ruiz-Ramos et al. Treatment failure, clinical response ○ ○ ○ ○ ○ ○
44 El-Sokkary et al. Clinical response ○ ○ ○ ○
46 Nie et al. Treatment failure ○ ○ ○
50 Wongsurakiat et al. Early treatment failure ○ ○ ○
51 Al-Hasan et al. Early treatment failure ○ ○ ○ ○ ○ ○
52 Kim YJ et al. Early clinical response ○ ○ ○ ○
53 Rac et al. Early clinical failure ○ ○ ○
54 Shimoni et al. Response to antibiotic therapy
55 Herrmann et al. Early treatment response ○ ○ ○ ○
56 Mun et al. Early antibiotic treatment failure ○ ○ ○ ○
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○; Applicable, ICU; Intensive care unit

Discussion

The present study is a systematic scoping review, covering 56 original studies and five reviews mentioning EATF. The most frequent timing for EATF evaluation was 72 hours after the initiation of antibiotics treatment. Our scoping review identified the five most common EATF components: mortality, vital signs, fever, symptoms, and additional treatment.

EATF is a potentially useful framework for clinicians and researchers in various fields. In clinical practice, EATF can be used to judge the effectiveness of antibiotics. Effective EATF evaluation may help prevent unnecessary changes to broad-spectrum antibiotics, lower the risk of Clostridium difficile colitis, prevent the development of multidrug-resistant bacteria, and improve mortality [14, 15]. EATF can also allow researchers to assess the effectiveness of target antibiotics in clinical research. EATF may also have applications in the assessment of outcomes in antimicrobial drug trials and the establishment of criteria for early discontinuation. Furthermore, the appropriateness of the EATF components depends on the application. For example, the mortality component would be of no value in informing clinical treatment decisions. Moreover, clinical practice may benefit from similar definitions for treatment failure in fungal infections, tuberculosis, and viral diseases such as COVID-19. Further research is needed to establish definitions for early-stage assessment of these conditions. Furthermore, as the concept of EATF continues to be refined, methods for reaching consensus on a definition should be also considered. One possibility is the Delphi method, which facilitates consensus-building and minimizes the influences of potential sources of bias such as conflicts of interest and interpersonal relationships [16].

The common components for defining EATF identified in this study comport with definitions presented in previous reports. Among the five common components, vital signs were the most common components, followed by additional treatment, mortality, fever and symptoms (Table 2). To the authors’ knowledge, the earliest EATF review article was published by Sánchez García (2009) [2]. That article compiled criteria used to diagnose treatment failure in a table. The components identified all match the criteria which he presented. Mun et al. (2021) included EATF in their title and presented a definition for EATF [17]. Their criteria for EATF comprise mortality, vital signs, fever, and additional treatment, which are consistent with our findings.

Among the five common components identified, vital signs, fever, and mortality were measured objectively, while there was some variation in additional treatments and much variation in symptoms. Additional treatments included the use of vasopressors and mechanical ventilation, which are standard advanced medical care for many diseases. However, symptoms depend on the original disease. Furthermore, because responses to antibiotic treatment may be influenced by resistance patterns in specific geographical areas, the results of antibiotics treatment studies may not be generalizable across populations with vastly different levels of resistance. Our systematic literature was conducted without limiting for geographical area, clinical setting, local antibiotic resistance pattern, or language. Future studies of EATF should adjust the definition of symptoms according to the research target and attempt to account for the influence of local antibiotic resistance patterns. Finally, because this study excluded target diseases whose standard treatment is not antibiotics, source control was not included among the factors for analyzing EATF which were identified. If the concept of EATF were expanded to cover all types of bacterial infections, source control would be an indispensable consideration from the perspective of avoiding antibiotic escalation.

Given the most common timing of EATF evaluation uncovered in our study, 72 hours appears to be a generally accepted timeframe. However, various timeframes are used for EATF evaluation among the studies included in our review, and there is no concrete evidence to support evaluation at 72 hours [2]. The Centers for Disease Control and Prevention provides "Core Elements of Hospital Antibiotic Stewardship Programs" which mention antibiotic timeouts at 48–72 hours of treatment to facilitate appropriate antibiotic selection [18, 19]. Rac et al. (2020) mentioned evaluations performed at 72–96 hours, which also largely matches our findings, except for the inclusion of altered mental status and white blood cell count [5].

The present study systematically surveyed existing definitions for EATF. However, EATF remains a nascent concept, and there are several ways in which it may be improved for future application. First, improved rapid diagnostic methods now enable clinicians to quickly find multidrug-resistant organisms in blood cultures. Among the eligible studies discussing bacteremia, there were no differences in definitions for EATF based on whether the involved organism is Gram-positive or Gram-negative. However, responses to antibiotics and clinical courses are often different for Gram-positive and Gram-negative bacteria. Thus, developing different definitions for EATF based on Gram-negative bacteria (especially multidrug-resistant strains) and Gram-positive bacteria may be clinically useful. Second, while bacterial count may influence clinical outcomes in some cases, none of the 61 eligible studies included bacterial count as a factor for EATF. However, Mun et al. (2021) suggests the possibility of bacterial count affecting clinical outcomes and the importance of source control with some organisms [17]. Future studies may evaluate the importance of bacterial count (inoculum effect) and its potential relevance for assessing EATF. Lastly, this study comprehensively collected a diverse set of definitions for EATF from various studies. While each of these has its advantages, such as often being tailored to the target disease, they also have distinct disadvantages, such as being difficult to define based on observation of symptoms or other objective measures, and being difficult to apply to diseases other than the target disease. Therefore, a precise universal definition that can be applied to all types of bacterial infections may be difficult to achieve. Accordingly, the present study attempts to identify the essential components of a definition for EATF, rather than prescribing a definitive formulation.

There are some limitations to our study. First, specific definitions for each component of EATF could not be identified; individual definitions were vague or inconsistent, and none of the five components converged on a unified definition. Further investigation is needed to define the details of each component and evaluate their validity. Next, the literature search was not conducted using EMBASE, due to financial constraints. In order to overcome this limitation, a range of common systematic literature search methods were employed. An experienced research librarian provided assistance with the selection of search terms and formulae, and two independent teams conducted manual searches on Google and Google Scholar. We also searched for all papers referenced in the reviews and articles that were uncovered with mentions of EATF. Further, the definition of EATF falls within the broader concept of treatment failure. For example, if treatment failure is defined as mortality within seven days after treatment initiation, this may also meet the definition of EATF. Therefore, some potentially eligible studies may have been left out of the present review. However, our scoping review aims to identify common components used to define EATF, rather than to synthesize numerical figures as in a meta-analysis. Moreover, there are many vague definitions, particularly for symptoms, among the 56 studies in the present review. However, symptoms should be included as a common component because it appears in more than 40% of the eligible studies. Further, many types of bacterial infections were included, which contributes to heterogeneity among the definitions of EATF. While there is much variety among diseases, the present study assessed common physical changes caused by bacterial infections in the hope that these findings would apply to a range of bacterial diseases. Finally, the protocol for this study was not registered on PROSPERO because scoping reviews are no longer eligible for registration as of as of February 2022 [20]. The protocol was therefore registered with the OSF, as suggested by JBI [9].

Conclusions

Our scoping review identified the common components of EATF: mortality, vital signs, fever, symptoms, and additional therapy, evaluated 72 hours after the initiation of antibiotics treatment. Further studies are needed to define the details of each component of EATF and investigate its validity.

Supporting information

S1 Table. PRISMA checklist.

(DOCX)

Click here for additional data file. (85.2KB, docx)
S2 Table. MEDLINE (PubMed), CENTRAL, CINAHL, Web of Science search terms and results.

(DOCX)

Click here for additional data file. (20.6KB, docx)
S3 Table. Reference list for eligible studies.

(DOCX)

Click here for additional data file. (27.1KB, docx)

Acknowledgments

The authors would like to thank Izumi Osaki at the Academic Information Center of the Jikei University School of Medicine for systematic literature search support, Keisuke Kamada at the Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association’s Department of Mycobacterium Reference and Research for expert advice related to infectious diseases and review and editing of the manuscript, Shinichiro Ueda at the University of Ryukyus for general research advice, and Allen Paul Heffel for writing assistance.

Data Availability

Our protocol data are available from the OSF database: osf.io/d9wa4. DOI 10.17605/OSF.IO/D9WA4.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Ali Amanati

10 Feb 2023

PONE-D-22-31074Essential components of a definition for early antibiotic treatment failure: a scoping review.PLOS ONE

Dear Dr. Hiroyoshi Iwata,

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.

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Ali Amanati

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

Dear authors

Your manuscript [ID Number PONE-D-22-31074] has passed through the review stage and is ‎ready for revision. ‎

Editorial comments

To ensure the Editor and Reviewers can recommend that your revised manuscript is ‎accepted, ‎please pay careful attention to each of the comments posted underneath ‎this email. This way we ‎can avoid future rounds of clarifications and revisions, moving swiftly to ‎a decision.‎

‎1. Please provide a point-by-point response to the the Editor and reviewer's comments

‎2. Please highlight all the amends on your manuscript with yellow colour

‎3. Minor English language correction is needed

‎

Other shortcomings

First of all, early antibiotics treatment response could be interpreted only ‎according to the local antibiotic resistance pattern and the geographical area of ‎the conducted studies. Therefore, the findings of studies obtained in areas with ‎low levels of resistance cannot be generalized for other areas with high levels of ‎resistance (lack of external validity). This was expected to be included in the ‎discussion.

Second, due to the improvement of rapid diagnostic methods in ‎bacterial infections, such as the use of rapid detection methods for multi-‎resistant bacteria in blood cultures, these definitions can be different based on ‎Gram-negative (especially multi-drug resistant Gram-negative) and Gram-‎positive organisms.

Tthird, bacterial infections are also divided based on the ‎bacterial inoculum size and therefore should be considered in the early ‎antibiotic’s treatment failure definition. While urinary tract infections have a ‎low bacterial inoculum size, pneumonia and sepsis have a high bacterial ‎inoculum size, and thus the response to treatment may be different. Overall, for ‎serious bacterial infections more stringent definitions should be considered; ‎however, for milder infections, more flexible definitions may be acceptable. ‎There is no discussion in this regard in the manuscript and it is recommended ‎to improve the discussion section accordingly. Also, if possible, a table can be ‎prepared (based on the definitions of bacterial inoculum size) for more precise ‎comparison.

Although the findings of this study could be helpful there are ‎many shortcomings in the definition, which will make it difficult to reach an ‎accurate definition based on the wide variety of bacterial infections‏.‏

[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

**********

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Reviewer #1: N/A

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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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: Congratulations on the paper. The subject is exciting, and a lot of work to make this review is apparent.

Significant revisions/clarifications:

- Elaborate further about the potential uses of EATF. However, this is not the purpose of the review; discussing the possible uses would be helpful for readers to integrate the concept into their work. Also, clarifying the potential uses even has implications for the components of the definition. For example, the use of EATF as an outcome for RCTs for new antibiotics has essential differences when compared with the use for clinical or antimicrobial stewardship purposes. For the second, component mortality would be of little help.

- From an antimicrobial stewardship point of view, using EATF raises some concerns that should be addressed. For example, analyzing together studies that report infections that need source control and those that typically do not need may create a concept (EATF) that promotes antibiotic escalation when the problem is source control. The authors should separate their findings for infections that typically do not need source control, such as respiratory tract infections and those that usually need source control.

- Elaborate further about future steps to develop this interesting EATF concept and how it can be studied and used in future. Would the authors suggest some consensus procedure to define the concept? Delphi, for example?

Minor revision:

- Page 21, line 223: mortality is misspelt.

Reviewer #2: The manuscript by Hiroyoshi Iwata et al. answers an important definitional question on "Early antibiotics treatment failure" by a systematic review of the literature.

This manuscript is well-written and describes a well-conducted systematic review but deserves rare and formative revisions before possible acceptance for publication.

Italicize "et al." and names of bacteria

Prefer passive forms.

Why didn't the authors use EMBASE? Numbers less than or equal to 12 should be spelled out if appropriate.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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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. 2023 Jun 23;18(6):e0283417. doi: 10.1371/journal.pone.0283417.r002

Author response to Decision Letter 0

3 Mar 2023

Dr. Ali Amanati

Academic Editor, PLOS ONE

March 1, 2023

Dear Dr. Amanati,

On behalf of all of the authors, I would like to sincerely thank you and your team for your comments and suggestions for the improvement of our manuscript. We believe we have been able to apply them in order to constructively refine and strengthen our paper. We respond to the individual comments from both you and the reviewers below.

Regarding our funding, we apologize for the lack of clarity in the financial disclosure which accompanied our initial submission. We have updated our cover letter – sent separately – to include the statement: “The authors received no specific funding for this work,” which correctly characterizes our lack of funding for this study.

Finally, Dr. Keisuke Kamada provided us with some assistance in the revision of this manuscript. He has been added to our acknowledgements section accordingly.

Editor Comments

“First of all, early antibiotics treatment response could be interpreted only ‎according to the local antibiotic resistance pattern and the geographical area of ‎the conducted studies. Therefore, the findings of studies obtained in areas with ‎low levels of resistance cannot be generalized for other areas with high levels of ‎resistance (lack of external validity). This was expected to be included in the ‎discussion.”

Thank you for your sharp opinion. We agree, and we have added the following text to our discussion section.

Line 234

Furthermore, because responses to antibiotic treatment may be influenced by resistance patterns in specific geographical areas, the results of antibiotics treatment studies may not be generalizable across populations with vastly different levels of resistance. Our systematic literature was conducted without limiting for geographical area, clinical setting, local antibiotic resistance pattern, or language. Future studies of EATF should adjust the definition of symptoms according to the research target and attempt to account for the influence of local antibiotic resistance patterns.

“Second, due to the improvement of rapid diagnostic methods in ‎bacterial infections, such as the use of rapid detection methods for multi-‎resistant bacteria in blood cultures, these definitions can be different based on ‎Gram-negative (especially multi-drug resistant Gram-negative) and Gram-‎positive organisms.”

Thank you for your valuable suggestion.

Following your advice, we attempted to assess whether there were any distinctions made between Gram-negative bacteria (especially multidrug-resistant Gram-negative bacteria) and Gram-positive bacteria among the eligible studies. (ID 11,16,19,22,25,33,41,55,56. Tumbarello et al.(2010), Waltner-Toews et al. (2011), O’Neal et al.(2012), Kang et al. (2013), Hsieh et al.(2016), Lee et al.(2017), Herrmann et al. (2021), Mun et al.(2021)). We focused on bacteremia because both Gram-positive and Gram-negative bacteria are approximately equally likely to be the causative pathogen. However, we did not find any such distinctions in the papers included in this study. We therefore suggest the possible utility of such distinctions in future research.

According to your advice, we have added the following sentences in our discussion section.

Line 256

First, improved rapid diagnostic methods now enable clinicians to quickly find multidrug-resistant organisms in blood cultures. Among the eligible studies discussing bacteremia, there were no differences in definitions for EATF based on whether the involved organism is Gram-positive or Gram-negative. However, responses to antibiotics and clinical courses are often different for Gram-positive and Gram-negative bacteria. Thus, developing different definitions for EATF based on Gram-negative bacteria (especially multidrug-resistant strains) and Gram-positive bacteria may be clinically useful.

“Third, bacterial infections are also divided based on the ‎bacterial inoculum size and therefore should be considered in the early ‎antibiotic’s treatment failure definition. While urinary tract infections have a ‎low bacterial inoculum size, pneumonia and sepsis have a high bacterial ‎inoculum size, and thus the response to treatment may be different. Overall, for ‎serious bacterial infections more stringent definitions should be considered; ‎however, for milder infections, more flexible definitions may be acceptable. ‎There is no discussion in this regard in the manuscript and it is recommended ‎o improve the discussion section accordingly. Also, if possible, a table can be ‎prepared (based on the definitions of bacterial inoculum size) for more precise ‎comparison.”

Thank you for your sharp comment.

In order to evaluate the significance of bacterial inoculum in our study, we once again reviewed the EATF definitions in the 61 included studies. However, no study had a definition that directly referred to bacterial inoculum or bacteria count as a factor for EATF.

However, Mun et al. (2021) (ID 56) did suggest the clinical importance of high bacteria count:

"Furthermore, the presence of a high burden may also contribute to an inoculum effect, which attenuates the activity of beta-lactam antibiotics and often requires source control"

Based on your comment, we have added the discussion of this topic below.

Line 262

Second, while bacterial count may influence clinical outcomes in some cases, none of the 61 eligible studies included bacterial count as a factor for EATF. However, Mun et al. (2021) suggests the possibility of bacterial count affecting clinical outcomes and the importance of source control with some organisms. [16] Future studies may evaluate the importance of bacterial count and its potential relevance for assessing EATF.

“Although the findings of this study could be helpful there are ‎many shortcomings in the definition, which will make it difficult to reach an ‎accurate definition based on the wide variety of bacterial infections‏.‏”

We appreciate your point – the variety of bacterial infections is an important limitation to the usefulness of a standard definition for EATF. We have added this to our discussion.

Line 267

Lastly, this study comprehensively collected a diverse set of definitions for EATF from various studies. While each of these has its advantages, such as often being tailored to the target disease, they also have distinct disadvantages, such as being difficult to define based on observation of symptoms or other objective measures, and being difficult to apply to diseases other than the target disease. Therefore, a precise universal definition that can be applied to all types of bacterial infections may be difficult to achieve. Accordingly, the present study attempts to identify the essential components of a definition for EATF, rather than prescribing a definitive formulation.

Reviewer Comments

Reviewer #1

“Congratulations on the paper. The subject is exciting, and a lot of work to make this review is apparent.”

Thank you for your kind words. We appreciate your review of our work.

“- Elaborate further about the potential uses of EATF. However, this is not the purpose of the review; discussing the possible uses would be helpful for readers to integrate the concept into their work. Also, clarifying the potential uses even has implications for the components of the definition. For example, the use of EATF as an outcome for RCTs for new antibiotics has essential differences when compared with the use for clinical or antimicrobial stewardship purposes. For the second, component mortality would be of little help.”

Thank you for your sharp comment.

In addition to discussing potential clinical applications for EATF in the second paragraph of the discussion section, we have added the following sentence. Furthermore, your suggestion reminds us that the appropriateness of the various EATF components depends on the application. For example, the death component would be useless when informing treatment decisions in clinical practice.

Line 212

EATF may also have applications in the assessment of outcomes in antimicrobial drug trials and the establishment of criteria for early discontinuation. Furthermore, the appropriateness of the EATF components depends on the application. For example, the death component would be of no value in informing clinical treatment decisions.

“- From an antimicrobial stewardship point of view, using EATF raises some concerns that should be addressed. For example, analyzing together studies that report infections that need source control and those that typically do not need may create a concept (EATF) that promotes antibiotic escalation when the problem is source control. The authors should separate their findings for infections that typically do not need source control, such as respiratory tract infections and those that usually need source control.”

We appreciate this important consideration.

While we agree that this is an issue which must be considered, we do not believe that this issue affected the contents of our proposed definition for EATF. First, we excluded "studies whose target disease’s standard treatment is not antibiotics," such as necrotizing enteritis requiring immediate operation. Also, we checked for " Source control (Drainage or operation) " in Table 2. Definitions for diseases that may need additional source control treatment may differ from those for diseases that typically do not. We counted the diseases which need souse control again from the table 1.We identified eight studies handling infections which may need additional source control treatment and marked them in Table 1. We considered analyzing two separate groups – studies of infections that need source control and those that typically do not. However, the eight studies, which included complicated skin and skin-structure infections, complicated urinary tract infection, acute appendicitis, intra-abdominal infection, and diverticular abscess, represent various diseases and definitions. Among the eight studies, only Edelsberg et al. (2008) and Berger et al. (2013) mention EATF at 72 hours, and thus were already included in our final assessment (see Table 2); however, the definitions of EATF used by Edelsberg et al. and Berger et al. (2013) did not influence the essential EATF components which we present.

We have added the following discussions of the potential impact of source control on the application of EATF.

Line 198

Eight studies reporting infections which may need additional source control were identified, including complicated skin and skin-structure infection, complicated urinary tract infection, acute appendicitis, intra-abdominal infection, and diverticular abscess. However, because these infections can be successfully treated with antibiotics, these eight studies were not excluded from our analysis.

Line 242

Finally, because this study excluded target diseases whose standard treatment is not antibiotics, source control was not included among the factors for analyzing EATF which we identified. If the concept of EATF were expanded to cover all types of bacterial infections, source control would be an indispensable consideration from the perspective of avoiding antibiotic escalation.

“- Elaborate further about future steps to develop this interesting EATF concept and how it can be studied and used in future. Would the authors suggest some consensus procedure to define the concept? Delphi, for example?”

We agree with your suggestion about seeking consensus using the Delphi method.

We added the description below, and also a new reference (Yoshida M. 2018).

Line 219

Furthermore, as the concept of EATF continues to be refined, methods for reaching consensus on a definition should be also considered. One possibility is the Delphi method, which facilitates consensus-building and minimizes the influences of potential sources of bias such as conflicts of interest and interpersonal relationships.

Reference

Yoshida M. Formulating Consensus for the Development of Clinical Practice Guidelines using the Delphi Method. J Tokyo Wom Med Univ. 2018;88: E35–E37.

“Minor revision:

- Page 21, line 223: mortality is misspelt.”

Thank you for finding this spelling error. It has been corrected.

Reviewer #2

“Italicize "et al." and names of bacteria

Prefer passive forms.

Numbers less than or equal to 12 should be spelled out if appropriate.”

Thank you for these directions. We have italicized “et al.” and names of bacteria, used passive forms where practical, and spelled out numbers less than or equal to 12 as appropriate.

“Why didn't the authors use EMBASE?”

We agree that EMBASE is a useful resource which may have allowed us to uncover additional candidate articles. We have added this as a limitation of our study. (See below.) Because this work received no specific funding, we were limited in terms of the resources at our disposal.

In order to overcome our lack of access to EMBASE, we employed a range of search tools, including manual searches of Google and Google Scholar which were conducted by two independent teams with Dr. Aoki (our third author) overseeing the process. In addition, we sought help from an experienced librarian who helped us to craft search terms and formulas in order to minimize the chances of missing a potentially eligible article. We also conducted manual searches for papers referenced in reviews and other articles mentioning EATF.

Bramer et al. (2017) surveyed combinations of search tools and reported that "[t]he highest scoring database combination without Embase is a combination of MEDLINE, Web of Science, and Google Scholar." We included all of these tools.

As a result, we uncovered approximately 2,500 candidate papers. While it is certainly possible that we missed some potential candidates, for example, because some texts might discuss concepts equivalent to EATF without using any of our search terms, we believe that we uncovered a broad enough range of papers discussing this topic to allow us to examine the conceptual framework of EATF.

Line 280

Next, the literature search was not conducted using EMBASE, due to financial constraints. In order to overcome this limitation, we employed a range of common systematic literature search methods. An experienced research librarian provided assistance with the selection of search terms and formulae, and two independent teams conducted manual searches on Google and Google Scholar. We also searched for all papers referenced in the reviews and articles that were uncovered with mentions of EATF.

Reference

Bramer WM, Rethlefsen ML, Kleijnen J, Franco OH. Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study. Syst Rev. 2017;6: 245.

The authors would like to thank you again for taking the time to review our manuscript. We sincerely hope that you will consider this revised draft favorably and find it acceptable for publication.

Cordially yours,

Hiroyoshi Iwata, MD, MSc, PhD, FACP

Center for Environmental and Health Sciences, Hokkaido University

Kitaku Kita 12 Nishi 7, Sapporo, 060-0812, Hokkaido, Japan

Telephone: +81-11-706-4747

E-mail1: hiwata@cehs.hokudai.ac.jp

E-mail2: hii887@mail.harvard.edu

Attachment

Submitted filename: Rebuttal Letter.docx

Click here for additional data file. (23.3KB, docx)

Decision Letter 1

Ali Amanati

6 Mar 2023

PONE-D-22-31074R1Essential components of a definition for early antibiotic treatment failure: a scoping review.PLOS ONE

Dear Dr. Hiroyoshi Iwata,

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 Apr 20 2023 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 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 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,

Ali Amanati

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear authors

The manuscript's overall presentation improved after amendments and is now ‎more readable‎. I thank the authors for their very detailed ‎replies to my comments.‎

Minor correction is needed:

Line 267: add "(inoculum effect)" after "bacterial count". "Future studies may evaluate the importance of bacterial count (inoculum effect) and its ..."

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. 2023 Jun 23;18(6):e0283417. doi: 10.1371/journal.pone.0283417.r004

Author response to Decision Letter 1

6 Mar 2023

Dr. Ali Amanati

Academic Editor, PLOS ONE

March 6, 2023

Dear Dr. Amanati,

On behalf of all of the authors, I would like to sincerely thank you and your team for your comments and suggestions for the improvement of our manuscript. We have incorporated all of your suggestions, as detailed below.

Comments

#1

The manuscript's overall presentation improved after amendments and is now ‎more readable‎. I thank the authors for their very detailed ‎replies to my comments.‎

Thank you for your support throughout this process.

Minor correction is needed:

Line 267: add "(inoculum effect)" after "bacterial count". "Future studies may evaluate the importance of bacterial count (inoculum effect) and its ..."

Response:

Thank you for your suggestion. We agree, and we have added "(inoculum effect)" after "bacterial count" in the manuscript.

Line 267

Future studies may evaluate the importance of bacterial count (inoculum effect) and its potential relevance for assessing EATF.

#2

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/.

Response:

We appreciate your kind support. Following your instructions, we have made adjustments to "Figure 1" using the PACE tool, and re-uploaded it on the submission page.

The authors would like to thank you again for taking the time to review our manuscript. We sincerely hope that you will consider this revised draft favorably and find it acceptable for publication.

Cordially yours,

Hiroyoshi Iwata, MD, MSc, PhD, FACP

Center for Environmental and Health Sciences, Hokkaido University

Kitaku Kita 12 Nishi 7, Sapporo, 060-0812, Hokkaido, Japan

Telephone: +81-11-706-4747

E-mail1: hiwata@cehs.hokudai.ac.jp

E-mail2: hii887@mail.harvard.edu

Attachment

Submitted filename: Response Letter 0306.docx

Click here for additional data file. (16.5KB, docx)

Decision Letter 2

Ali Amanati

8 Mar 2023

Essential components of a definition for early antibiotic treatment failure: a scoping review.

PONE-D-22-31074R2

Dear Hiroyoshi Iwata,

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.

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Kind regards,

Ali Amanati

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I read the revised manuscript ‎

I have no further comments to add. I thank the authors for their very detailed ‎‎replies to my comments.‎

Reviewers' comments:

Acceptance letter

Ali Amanati

15 Mar 2023

PONE-D-22-31074R2

Essential components of a definition for early antibiotic treatment failure: a scoping review.

Dear Dr. Iwata:

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

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 plosone@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

Professor Ali Amanati

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. PRISMA checklist.

    (DOCX)

    Click here for additional data file. (85.2KB, docx)
    S2 Table. MEDLINE (PubMed), CENTRAL, CINAHL, Web of Science search terms and results.

    (DOCX)

    Click here for additional data file. (20.6KB, docx)
    S3 Table. Reference list for eligible studies.

    (DOCX)

    Click here for additional data file. (27.1KB, docx)
    Attachment

    Submitted filename: Rebuttal Letter.docx

    Click here for additional data file. (23.3KB, docx)
    Attachment

    Submitted filename: Response Letter 0306.docx

    Click here for additional data file. (16.5KB, docx)

    Data Availability Statement

    Our protocol data are available from the OSF database: osf.io/d9wa4. DOI 10.17605/OSF.IO/D9WA4.

    Articles from PLOS ONE are provided here courtesy of PLOS

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