Factors associated with successful completion of outpatient parenteral antibiotic therapy in an area with a high prevalence of multidrug-resistant bacteria: 30-day hospital admission and mortality rates

Thais Cristina Garbelini Salles; Santiago Grau Cerrato; Tatiana Fiscina Santana; Eduardo Alexandrino Medeiros

doi:10.1371/journal.pone.0241595

Peer Review History

Original SubmissionJune 14, 2020
21 Sep 2020 Decision Letter - Francesco Di Gennaro, Editor PONE-D-20-18208 Factors associated with successful completion of outpatient parenteral antibiotic therapy in an area with a high prevalence of multidrug-resistant bacteria: 30-day hospital admission and mortality rates PLOS ONE Dear Dr.ssa Salles, 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 Nov 05 2020 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. 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Please clarify what date range the patient medical records were originally recorded and what date(s) you accessed the medical records. 4.Thank you for stating the following in the Financial Disclosure section: [This work was granted to the corresponding author, T.C.G.S. and was supported by the Hospital Epidemiology Research Group of the Federal University of São Paulo, registered with the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development), URL http://www.cnpq.br/. No role was played in the study design, data collection, analysis, decision to publish or preparation of the manuscript.]. We note that one or more of the authors are employed by a commercial company: UnitedHealth Group Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: PLOS ONE Full Tittle: Factors associated with successful completion of outpatient parenteral antibiotic therapy in an area with a high prevalence of multidrug-resistant bacteria: 30-day hospital admission and mortality rates Manuscript Number: PONE-D-20-18208 Article Type: Research Article Corresponding Author: Thais Cristina Garbelini Salles, M.D. Universidade Federal de São Paulo – UNIFESP. Sao Paulo, SP BRAZIL QUESTIONS/SUGGESTIONS ● PATIENTS AND METHODS: ❖ Does the fact that a patient is assigned the antibiotic in the Santa Helena/Amil United Health Group network or at the patient's home, respond to any special criteria? ❖ It is important to know who administered the antibiotic at home: the nursing staff, the patients or their caregiver. How was the visiting schedule of nursing staff at the patient's home? What was the method of administration of the antibiotic? Was it by gravity or by the use of an elastomeric or electronic pump? Could be the type of administration of the antibiotic related to a higher mortality rate or a higher hospital admission? ❖ LINE 102, “The variables were evaluated prospectively to determine factors related to hospital admission”. Reading the article, the conclusion reached is that the study is retrospective, based on a later analysis of a group of data extracted from daily clinical practice. Could the authors clarify this point? ● RESULTS: ❖ Do the authors dispose of Charlson’s Index of the patients?, Could the Charlson index be related to a higher mortality rate or to a higher hospital admission? ❖ If data were available, it would be important to know what the referring department of the patients (medical specialties, surgical specialties, emergency department) was. Was the referring department of patients associated with greater therapeutic failure, mortality or hospital admission? In case that patients had been previously admitted to the hospital, ¿what was the average stay in conventional hospitalization? What was the duration of the antibiotic treatment during the conventional hospitalization? If the requested data were included, the methods section should also be modified. ❖ Another piece of information to provide, if available, would be to classify pneumonia according to FINE or CURB-65 severity index. Have FINE or CURB-65 any relationship with mortality or hospital admission? ❖ What other antibiotics were used besides ceftriaxone? Is any antibiotic associated with a higher percentage of hospital admissions or mortality? ❖ Line 142, “of the MDR bacteria, 13 (92,9%) were carbapenem-resistant K.pneumoniae…” What type of carbapenamase did the authors find? What antibiotics did they use in those cases? ● DISCUSSION: ❖ In recent years, Hospital at home (HaH) programs have spread throughout all the world. In these programs, medical and nursing staff administer hospital-level care at patient’s homes avoiding admission to a hospital ward. OPAT is one of the most frequent modalities in HaH programs with excellent results. I suggest that authors consider and comment about these HaH programs in the discussion section because this would reinforce the importance of medical visits in the OPAT programs. ● COMMENTS TO THE AUTHOR: ❖ The article draws attention to the high mortality of the series (9.4%) and the high percentage of hospital admissions (35.5%) within 30 days after inclusion in the OPAT program in comparison with other studies on OPAT in which clinical control by nurses and medical staff is carried out at the patient's home several times during the admission and with much better results. On the other hand, we must consider that part of the results are explained because study population is elderly and most of the infections are respiratory, so medical visits are essential. ❖ Personally, I think some data is lacking to give it consistency. All new requested data, if available, would greatly complement the information of the population under study and should be emphasized in the discussion of results. Reviewer #2: In this interesting and innovative study, Authors investigated outcome and predictors of failure of outpatient parenteral antibiotic therapy. Interestingly, in this study the infectious diseases specialist consultation within the first 14 days after enrolment in an OPAT program is associated with a lower risk of hospital admission and mortality. Similarly, other important finding is the high efficacy of OPAT in treating community mild/moderate infections. Overall, this work is worth for publication, however some revisions are needed: 1) A more detailed description of comorbidities should be given. For instance, the variable “neoplasia” presented in Table 2 was chosen arbitrarily? What about chronic kidney diseases, diabetes, immunesuppressive therapy etc? All of these factors could be associated with hospital admission 2) A more detailed description of treatment prescribed should be given, especially for multidrug resistant pathogens. Indeed, one of the main risk factors of failure is inappropriate treatment. 3) Mortality was quite low. Does it was associated with the infectious disease? The same description should be given regarding cause of hospital admission, if possible. 4) “The authors found that infection with such strains did not represent a risk factor for mortality or hospital admission” This statement should be better discussed. I suggest to describe more deeply the type of infection caused by MDR bacteria treated with outpatient treatment. ****** 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: No [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. https://doi.org/10.1371/journal.pone.0241595.r001
Revision 1
4 Oct 2020 Author Response 1. In your ethics statement in the Methods section and in the online submission form, please provide additional information about the data used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients or next of kin provided informed written consent to have data from their medical records used in research, please include this information. The ethics committees waived the requirement for informed consent. This information was added in ethics statement and the patient methods section. 2. Please clarify what date range the patient medical records were originally recorded and what date(s) you accessed the medical records. A database was constructed from October 2016 to June 2017 and accessed for the purpose of this study from October 2017 to July 2018. This information was included in the patients and methods section. 3.Thank you for stating the following in the Financial Disclosure section: [This work was granted to the corresponding author, T.C.G.S. and was supported by the Hospital Epidemiology Research Group of the Federal University of São Paulo, registered with the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development), URL http://www.cnpq.br/. No role was played in the study design, data collection, analysis, decision to publish or preparation of the manuscript.]. We note that one or more of the authors are employed by a commercial company: UnitedHealth Group 1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. The updated Funding Statement was included in the cover letter with the information that the company United Health Group provided support in the form of salaries for the authors T.C.G.S and E.A.M. and did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products,etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. The updated Funding Statement and Competing Interests Statement was included in the cover letter with the following informations: • “The company United Health Group provided support in the form of salaries for the authors T.C.G.S and E.A.M. and did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.” Review Comments 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: Partly Reviewer #2: Yes ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ________________________________________ 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: Yes ________________________________________ 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 PATIENTS AND METHODS: ❖ Does the fact that a patient is assigned the antibiotic in the Santa Helena/Amil United Health Group network or at the patient's home, respond to any special criteria? Patients who were bedridden and whose family did not have a means of transport to one of the facilities were assigned antimicrobial treatment at home. ❖ It is important to know who administered the antibiotic at home: the nursing staff, the patients or their caregiver. How was the visiting schedule of nursing staff at the patient's home? What was the method of administration of the antibiotic? Was it by gravity or by the use of an elastomeric or electronic pump? Could be the type of administration of the antibiotic related to a higher mortality rate or a higher hospital admission? The antibiotic at home was administered by the nursing staff assigned to visit the patient according to the antimicrobial scheme prescribed. All antibiotics were infused by gravity or in bolus. No analysis was made as to whether the type of infusion was related to higher mortality or hospital admission rates. However, no serious infusion-related adverse events were reported during this study. ❖ LINE 102, “The variables were evaluated prospectively to determine factors related to hospital admission”. Reading the article, the conclusion reached is that the study is retrospective, based on a later analysis of a group of data extracted from daily clinical practice. Could the authors clarify this point? It is a retrospective study but the database was evaluated prospectively from the beginning of the OPAT program on October 2016. ● RESULTS: ❖ Do the authors dispose of Charlson’s Index of the patients?, Could the Charlson index be related to a higher mortality rate or to a higher hospital admission? Information regarding the patient´s Charlson Index was calculated, with a median score was 4 (four). These results were not analysed for the association with mortality or hospital admission rates. ❖ If data were available, it would be important to know what the referring department of the patients (medical specialties, surgical specialties, emergency department) was. Was the referring department of patients associated with greater therapeutic failure, mortality or hospital admission? In case that patients had been previously admitted to the hospital, ¿what was the average stay in conventional hospitalization? What was the duration of the antibiotic treatment during the conventional hospitalization? If the requested data were included, the methods section should also be modified. Information on whether the antibiotic was prescribed in-hospital, at the emergency room, at an outpatient clinic or at a patinet´s home was submitted to a bivariate analysis and no statistically significant result was found concerning hospital admission and death (tables 1 and 3 of the manuscript). Most antibiotics (79,9%) were prescribed during hospitalization and the treatment was concluded as OPAT. In these cases, the average stay in conventional hospitalization or the duration of treatment was not calculated. ❖ Another piece of information to provide, if available, would be to classify pneumonia according to FINE or CURB-65 severity index. Have FINE or CURB-65 any relationship with mortality or hospital admission? Patients with pneumonia were not classified according to FINE or CURB-65 severity indexes. However, as an inclusion criteria, all patients were evaluated for clinical stability and only mild to moderate cases of pneumonia received OPAT. There was no association found between the type of infectious diagnosis and admission or death (tables 3 and 4). ❖ What other antibiotics were used besides ceftriaxone? Is any antibiotic associated with a higher percentage of hospital admissions or mortality? A bivariate analysis of the Student’s t-test was applied to each antibiotic prescribed and the results did not show any influence on hospital admission or mortality, (Tables 1 and 2). The antibiotics evaluated were as follows: ceftriaxone, piperacilin-tazobactam, cefepime, amikacin, meropenem, teicoplanin and vancomycin. Table 1. Bivariate analysis of factors associated with hospital admission among patients enrolled in an outpatient parenteral antimicrobial therapy program (n=276) at facilities within the Santa Helena/Amil UnitedHealth Group network, October 2016 through June 2017 Antibiotic ADMISSION P Yes No Number of antibiotics prescribed Monotherapy (n = 239) 87 (36.4%) 152 (63.6%) 0.430 Combined therapy (n = 37) 11 (29.7%) 26 (70.3%) CEFTRIAXONE No (n = 162) 60 (37.0%) 102 (63.0%) 0.527 Yes (n = 114) 38 (33.3%) 76 (66.7%) PIPERACILIN-TAZOBACTAM No (n = 233) 83 (35.6%) 150 (64.4%) 0.926 Yes (n = 43) 15 (34.9%) 28 (65.1%) CEFEPIME No (n = 238) 81 (34.0%) 157 (66.0%) 0.200 Yes (n = 38) 17 (44.7%) 21 (55.3%) AMIKACIN No (n = 248) 85 (34.3%) 163 (65.7%) 0.203 Yes (n = 28) 13 (46.4%) 15 (53.6%) MEROPENEM No (n = 252) 91 (36.1%) 161 (63.9%) 0.497 Yes (n = 24) 7 (29.2%) 17 (70.8%) TEICOPLANIN No (n = 257) 95 (37.0%) 162 (63.0%) 0.063 Yes (n = 19) 3 (15.8%) 16 (84.2%) VANCOMYCIN No (n = 260) 93 (35.8%) 167 (64.2%) 0.714 Yes (n = 16) 5 (31.3%) 11 (68.8%) Table 2. Bivariate analysis of factors associated with mortality among patients enrolled in an outpatient parenteral antimicrobial therapy program (n=276) at facilities within the Santa Helena/Amil UnitedHealth Group network, October 2016 through June 2017 Antibiotic Death P Yes No Number of antibiotics prescribed Monotherapy (n = 239) 214 (89.5%) 25 (10.5%) 0.133 Combined therapy (n = 37) 36 (97.3%) 1 (2.7%) CEFTRIAXONE No (n = 162) 151 (93.2%) 11 (6.8%) 0.075 Yes (n = 114) 99 (86.8%) 15 (13.2%) PIPERACILIN-TAZOBACTAM No (n = 233) 211 (90.6%) 22 (9.4%) 0.977 Yes (n = 43) 39 (90.7%) 4 (9.3%) CEFEPIME No (n = 238) 215 (90.3%) 23 (9.7%) 0.729 Yes (n = 38) 35 (92.1%) 3 (7.9%) AMIKACIN No (n = 248) 223 (89.9%) 25 (10.1%) 0.264 Yes (n = 28) 27 (96.4%) 1 (3.6%) MEROPENEM No (n = 252) 229 (90.9%) 23 (9.1%) 0.589 Yes (n = 24) 21 (87.5%) 3 (12.5%) TEICOPLANIN No (n = 257) 231 (89.9%) 26 (10.1%) 0.145 Yes (n = 19) 19 (100.0%) 0 (0.0%) VANCOMYCIN No (n = 260) 235 (90.4%) 25 (9.6%) 0.655 Yes (n = 16) 15 (93.8%) 1 (6.3%) ❖ Line 142, “of the MDR bacteria, 13 (92,9%) were carbapenem-resistant K.pneumoniae…” What type of carbapenamase did the authors find? What antibiotics did they use in those cases? The carbapenem-resistant K. pneumoniae samples were not analysed for the type of carbapenemase. These cultures were obtained from urine samples and 69,2% of the patients received microbiologically appropriate treatment with aminoglycosides. ● DISCUSSION: ❖ In recent years, Hospital at home (HaH) programs have spread throughout all the world. In these programs, medical and nursing staff administer hospital-level care at patient’s homes avoiding admission to a hospital ward. OPAT is one of the most frequent modalities in HaH programs with excellent results. I suggest that authors consider and comment about these HaH programs in the discussion section because this would reinforce the importance of medical visits in the OPAT programs. The OPAT programs are internationally recognised as an option for the treatment of a variety of infectious diseases and their use is expected to grow exponentially in the coming years. In Brazil, “hospital at home” programs started in the 1960s and from the 1990s onwards, the concept of home care as a modality evolved, with the inclusion of multi-professional teams. In 2011, the "Best at Home" program was launched by the Public Health System, to allow home care for those with temporary or permanent mobility difficulties. The OPAT programs emerged in the following years and in 2017, the Brazilian Society of Infectious Diseases published national guidelines to promote the expansion of this treatment modality in the country.3 Those characteristics led to the development of the present study. ● COMMENTS TO THE AUTHOR: ❖ The article draws attention to the high mortality of the series (9.4%) and the high percentage of hospital admissions (35.5%) within 30 days after inclusion in the OPAT program in comparison with other studies on OPAT in which clinical control by nurses and medical staff is carried out at the patient's home several times during the admission and with much better results. On the other hand, we must consider that part of the results are explained because study population is elderly and most of the infections are respiratory, so medical visits are essential. ❖ Personally, I think some data is lacking to give it consistency. All new requested data, if available, would greatly complement the information of the population under study and should be emphasized in the discussion of results. It is importante to point out that in an additional analysis that excludes patients on palliative care, the mortality rate is 3.3%; cure or clinical improvement was achieved in 205 patients (85.8%) and treatment failure occurred in 26 (10.9%). In both groups, the absence of a physician office visit was a predictor of hospital admission (P<0.001) and mortality (P=0.006). Reviewer #2: In this interesting and innovative study, Authors investigated outcome and predictors of failure of outpatient parenteral antibiotic therapy. Interestingly, in this study the infectious diseases specialist consultation within the first 14 days after enrolment in an OPAT program is associated with a lower risk of hospital admission and mortality. Similarly, other important finding is the high efficacy of OPAT in treating community mild/moderate infections. Overall, this work is worth for publication, however some revisions are needed: 1) A more detailed description of comorbidities should be given. For instance, the variable “neoplasia” presented in Table 2 was chosen arbitrarily? What about chronic kidney diseases, diabetes, immunesuppressive therapy etc? All of these factors could be associated with hospital admission. The comorbidities studied were not chosen by the author arbitrarily as they were registered according to the medical history of the elligible OPAT patients. All commorbiditites were evaluated as independent variables and submitted to a bivariate analysis. Neoplasia appears in the multivariate analysis as it showed statistical significance (P<0.05) in the bivariate analysis for hospital admission and mortality (Tables 3 and 4). All commorbiditites were classified according to the International Classification of Diseases (ICD). Table 3. Association of hospital admission with comorbidities and diagnosis – bivariate analysis, Santa Helena/Amil UnitedHealth Group network, October 2016 through June 2017 ADMISSION P Yes No Comorbidities (1) Number of Comorbidities None or one (n = 81) 25 (30.9%) 56 (69.1%) 0.357 Two or more (n = 188) 69 (36.7%) 119 (63.3%) Circulatory system disease Yes (n = 202) 69 (34.2%) 133 (65.8%) 0.755 No (n = 69) 25 (36.2%) 44 (63.8%) Nutritional and metabolic endocrine disease Yes (n = 66) 24 (36.4%) 42 (63.6%) 0.742 No (n = 205) 70 (34.1%) 135 (65.9%) Neoplasia Yes (n = 40) 20 (50.0%) 20 (50.0%) 0.028 No (n = 231) 74 (32.0%) 157 (68.0%) Disease of the genitourinary system Yes (n = 31) 14 (45.2%) 17 (54.8%) 0.193 No (n = 240) 80 (33.3%) 160 (66.7%) Respiratory system disease Yes (n = 31) 13 (41.9%) 18 (58.1%) 0.368 No (n = 240) 81 (33.8%) 159 (66.3%) Nervous system disease Yes (n = 10) 4 (40.0%) 6 (60.0%) 0.719 No (n = 261) 90 (34.5%) 171 (65.5%) Infectious diagnosis (2) Pneumonia (n = 114) 36 (31.6%) 78 (68.4%) Urinary infection (n = 97) 39 (40.2%) 58 (59.8%) 0.411 Skin/soft tissue infection (n = 39) 13 (33.3%) 26 (66.7%) (1) The association with other comorbidities was not studied due to the reduced number of cases (2) Other diagnoses were not included due to the reduced number of cases Table 4. Association of death with comorbidities and diagnosis - bivariate analysis, Santa Helena/Amil UnitedHealth Group network, October 2016 through June 2017 DEATH P Yes No Comorbidities (1) Number of Comorbidities None or one (n = 81) 8 (9.9%) 73 (90.1%) 0.829 Two or more (n = 188) 17 (9.0%) 171 (91.0%) Circulatory system disease Yes (n = 202) 19 (9.4%) 183 (90.6%) 0.860 Não (n = 69) 6 (8.7%) 63 (91.3%) Nutritional and metabolic endocrine disease Yes (n = 66) 6 (9.1%) 60 (90.9%) 0.965 Não (n = 205) 19 (9.3%) 186 (90.7%) Neoplasia Yes (n = 40) 7 (17.5%) 33 (82.5%) 0.050 Não (n = 231) 18 (7.8%) 213 (92.2%) Disease of the genitourinary system Yes (n = 31) 5 (16.1%) 26 (83.9%) 0.158 Não (n = 240) 20 (8.3%) 220 (91.7%) Respiratory system disease Yes (n = 31) 3 (9.7%) 28 (90.3%) 0.926 Não (n = 240) 22 (9.2%) 218 (90.8%) Nervous system disease Yes (n = 10) 1 (10.0%) 9 (90.0%) 0.931 Não (n = 261) 24 (9.2%) 237 (90.8%) Infectious diagnosis (2) Pneumonia (n = 114) 13 (11.4%) 101 (88.6%) 0.582 Urinary infection (n = 97) 7 (7.2%) 90 (92.8%) Skin/soft tissue infection (n =39) 4 (10.3%) 35 (89.7%) (1) The association with other comorbidities was not studied due to the reduced number of cases (2) Other diagnoses were not included due to the reduced number of cases 2) A more detailed description of treatment prescribed should be given, especially for multidrug resistant pathogens. Indeed, one of the main risk factors of failure is inappropriate treatment. A bivariate analysis of the Student’s t-test was applied to each antibiotic prescribed and the results did not show any influence on hospital admission or mortality, (Tables 1 and 2 of this review). The antibiotics evaluated were as follows: ceftriaxone, piperacilin-tazobactam, cefepime, amikacin, meropenem, teicoplanin and vancomycin. In order to clarify, the following alteration was made in the manuscript: “Of the multidrug-resistant bacteria isolated, one (7.1%) was vancomycin-resistant Enterococcus faecalis isolated from a culture of a skin secretion sample and 13 (92.9%) were carbapenem-resistant and aminoglycoside-susceptible K. pneumoniae isolated from cultures of urine samples. Most of these latter patients (69,2%) received microbiologically appropriate treatment with either amikacin or gentamicin and 77,8% had an outcome of cure or clinical improvement.” 3) Mortality was quite low. Was it associated with the infectious disease? The same description should be given regarding cause of hospital admission, if possible. Tables 3 and 4 show the association of admission and death to the following infectious diagnosis: pneumonia, urinary infection and skin/soft tissue infection, none of which showed statistical significance in the bivariate analysys. 4) “The authors found that infection with such strains did not represent a risk factor for mortality or hospital admission” This statement should be better discussed. I suggest to describe more deeply the type of infection caused by MDR bacteria treated with outpatient treatment. The following information was added to the manuscript: “The authors found that infection with such strains did not represent a risk factor for mortality or hospital admission, differing from what has been reported in other studies that evaluated those outcomes in patients with multidrug-resistant bacterial infection. 19,20 This difference might be explained by the fact that in this study, most patients with multidrug-resistant isolates had urinary tract infections caused by K. pneumoniae strains that were susceptible to aminoglycosides, which were available for targeted short-term treatment in OPAT.” Attachments Attachment Submitted filename: RESPONSE TO REVIEWERS.docx https://doi.org/10.1371/journal.pone.0241595.r002
19 Oct 2020 Decision Letter - Francesco Di Gennaro, Editor Factors associated with successful completion of outpatient parenteral antibiotic therapy in an area with a high prevalence of multidrug-resistant bacteria: 30-day hospital admission and mortality rates PONE-D-20-18208R1 Dear Dr. Thais Cristina Garbelini Salles 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Francesco Di Gennaro Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors congratulations 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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes 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: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0241595.r003
Formally Accepted
9 Nov 2020 Acceptance Letter - Francesco Di Gennaro, Editor PONE-D-20-18208R1 Factors associated with successful completion of outpatient parenteral antibiotic therapy in an area with a high prevalence of multidrug-resistant bacteria: 30-day hospital admission and mortality rates Dear Dr. Salles: 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 Dr. Francesco Di Gennaro Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241595.r004

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