Vancomycin resistant Enterococci and its associated factors among HIV infected patients on anti-retroviral therapy in Ethiopia

Belayneh Regasa Dadi; Zerihun Solomon; Mheret Tesfaye

doi:10.1371/journal.pone.0251727

. 2021 Jun 24;16(6):e0251727. doi: 10.1371/journal.pone.0251727

Vancomycin resistant Enterococci and its associated factors among HIV infected patients on anti-retroviral therapy in Ethiopia

Belayneh Regasa Dadi ^1,^*, Zerihun Solomon ¹, Mheret Tesfaye ¹

Editor: Iddya Karunasagar²

PMCID: PMC8224944 PMID: 34166383

Abstract

Background

The emergence of vancomycin resistant Enterococci (VRE) has alarmed the global community due to its tendency for colonization of the gastrointestinal tract. Human Immunodeficiency Virus (HIV) patients are colonized by vancomycin resistant Enterococci than other groups. The aim of this study was to determine the incidence of vancomycin resistant Enterococci and its associated factors among HIV infected patients on Anti-Retroviral Therapy (ART).

Methods

Institution based cross sectional study was conducted among HIV infected patients on ART at from June 1 to August 30, 2020. Socio-demographic and clinical data were collected by pre-tested structured questionnaire. Stool sample was collected and processed by standard microbiological techniques. Kirby Bauer Disc diffusion method was used to perform antimicrobial susceptibility testing. Data were entered by Epi data version 4.6.0.2 and analyzed by SPSS version 25. Bivariable and multivariable logistic regression model was used to analyze the association between dependent and independent variables. P-values in the multivariable analysis, adjusted odds ratio (AOR) and 95% confidence interval (CI) were used to determine the strength of association. P-value ≤0.05 was considered as significant.

Results

Enterococci spp was isolated on 123/200 (61.50%) patients. Among these isolates, the incidence of vancomycin resistant Enterococci was 11.4% [95% CI: (6.0–17.0)]. Antimicrobial susceptibility patterns against Enterococci showed highest rate of resistance to ampicillin (69.9%). Multidrug resistances were observed in 49.59% of Enterococci isolates. Study participants who had prior antibioticexposurer more than two weeks [AOR = 7.35; 95% CI: (1.2144.64)] and hospitalization for the last six months [AOR = 5.68; 95% CI: (1.09 29.74)] were significantly associated with vancomycin resistant Enterococci.

Conclusions

In our study high incidence of vancomycin resistant Enterococci was found. Previous exposure to antibiotics for more than two weeks and hospitalization for more than six months were significantly associated with vancomycin resistant Enterococci. The isolated Enterococci had variable degrees of resistance to commonly prescribed antibiotics. Therefore, periodic surveillance on antimicrobial resistance pattern, adhering to rational use of antibiotics and implementing infection prevention protocols may reduce colonization by VRE.

Introduction

A major problem with the Enterococci is they are very resistant to antibiotics and have ability to survive in harsh environments in community and persist in hospital settings [1]. Because of this, they become important in health facility based settings [2]. According to World Health Organization (WHO) report in 2017, vancomycin resistant Enterococci (VRE) is one of the most resistant bacteria in their “Global Priority list of antibiotic-resistant bacteria” [3]. In the same manner, the Center for Disease Control and Prevention (CDC) has classified Enterococci among bacteria with a threat level of serious [4]. Currently, VRE are the cause of one-third and one fifth of all health care associated infections in the United States and in some European countries respectively [5].

VRE are known in causing different enterococcal infections such as infective endocarditis, bacteremia, urinary tract infection, intra-abdominal and pelvic infections, surgical wound infections, and very rarely Central nervous system (CNS) infection. Many of these infections originate from intestinal flora of colonized individuals. VRE have different selection pressures for proliferation and rapid expansion of its resistant populations. Furthermore, few options are left for management of diseases caused by VRE, and hence causing increased mortality on infected individuals. VRE now represent approximately one third of Enterococcus isolates [6–17].

Asymptomatic VRE gut colonization precedes infection with susceptible hosts. Such susceptible hosts are patients who are exposed to multiple and prolonged courses of antimicrobial agents like Human Immunodeficiency virus (HIV) infected individuals, severely ill, hospitalized for long lengths of stay (LOS), living in a long-term care facility, located in close proximity to another colonized or infected patient, or hospitalized in a room previously occupied by a patient colonized with VRE. Colonization is often obtained by vulnerable hosts in an environment with increased rate of patient colonization with VRE [2, 18–26]. The prevalence of VRE was reported in Europe, Asia, Australia, South America and some African countries [1, 5, 24, 26]. However, there is no sufficient data available on the prevalence and risk factors of VRE in developing countries like Ethiopia. Therefore, this study was conducted with the aim of determining the prevalence of vancomycin resistant enterococci and its associated factors among HIV infected patients on Anti-Retroviral Therapy (ART).

Materials and methods

Study design, period and setting

The study was conducted in Arba Minch General Hospital (Arba Minch, Ethiopia) from June 1 to August 30, 2020. The hospital has ART clinic where it provides different services for HIV- infected patients. The total population of Arba Minch town from 2007 central statistical agency (CSA) census report was 74,879, of whom 39,208 were men and 35,671 women [27]. The inclusion criteria was all HIV infected patients on ART during the study period. Exclusion criteria were HIV infected patients who don’t have Parent or guardian assent if they are <18 years old and those HIV infected patients who were critically ill and unable to respond.

Sampling technique

Systematic random sampling technique was used to select the study participants. Based on the 2020 three months (June-August, 2020) data obtained during COVID-19 pandemic from Arba Minch General Hospital ART clinic, N = 366 (N = total number of study participants) HIV infected patients has visited the ART clinic. Assuming the same number of HIV- infected patients for the study period (June-August, 2020) and taking sample size of 200, the k^th value (k = N/n = 366/2002) is found to be 2 [28]. The first one is selected with lottery method from 1^st and 2^nd patients and found to be 2^nd patient. Then every 2^nd patient was included.

Dependent variable was VRE gut colonization and independent variables were: Age, Sex, CD4 count, Level of hemoglobin, Previous antibiotic treatment for >2 weeks, Current visiting status (Inpatient or Outpatient), History of hospitalization in the last six months, Urinary catheterization, Co-morbid conditions (diabetes and renal failure).

Data collection and laboratory processing

A pretested well designed structured questionnaire was used to collect data from the study participants. The questionnaire was designed by reviewing different literatures and prepared in English and Amharic languages.

Upon the arrival of each study participant at ART clinic, written assent/consent was obtained. Socio-demographic and clinical data were collected by two nurses using a pretested well designed structured questionnaire through face-to-face interview. Moreover, recent CD4 count and hemoglobin level of respondents have been taken from ART clinic logbook.

Isolation and identification of Enterococci

Patients were instructed to collect about 2gm of the faecal specimen in a sterile wide-mouth screw capped container labeled with the unique sample number, date, and time of collection. The collected stool specimens were transported to Arba Minch University, College of Medicine and Health Sciences, Microbiology and Parasitology laboratory.

Immediately after delivery, the transported stool specimens was streaked on Bile Esculin Azide agar (BEAA) (Park Scientific Limited, 24 Low Farm Place, Moulton Park, Northampton, NN3 6HY) and incubated for 24 hours at 37°C. Plates were observed for appearance of characteristic growth with brown-black colored colonies in the medium and dark halo centers. Typical characteristic colonies were selected randomly for characterization and presumptive identification of Enterococci by Gram stains, Catalase test, Salt tolerance test and Heat tolerance test [29].

The antimicrobial susceptibility testing was performed using Kirby Bauer disc diffusion method according to Clinical Laboratory Standards Institute guidelines (CLSI) [30]. After a pure colony was obtained, a loop full of bacteria were taken, transferred to a tube containing 5 ml of sterile normal saline (0.85% NaCl) and mixed gently until it formed a homogenous suspension. The turbidity of the suspension was determined by comparison with 0.5 McFarland standards. A sterile swab was dipped into the suspension, and excess suspension was removed by pressing the swab against the wall of the tube. The entire surface of Muller Hinton Agar plate was uniformly flooded with suspensions and allowed to dry for about 3–5 minutes. The antimicrobial impregnated disks were placed by using sterile forceps at least 24 mm away from each other to avoid the overlapping zone of inhibition. The disks were placed on agar plates and allowed to stand for 30 minutes to dissolve the antibiotics in the media [16]. The plates were then inverted and incubated at 37^oc for 16–18 hours and inhibition zone was measured using a ruler.

In the case of vancomycin, the plates were inverted and incubated at 37^oc, and held a full 16–18 hours for accurate detection of resistance. Zones were examined using transmitted light; the presence of a haze or any growth within the zone of inhibition indicates resistance for vancomycin. Grades of susceptibility pattern were recognized as sensitive, intermediate and resistant by comparison of zone of inhibition according to the 2018 CLSI guidelines [30].

Antimicrobial susceptibility patterns of Enterococci were also assessed against the following antibiotic discs: Penicillin (10 IU), Ampicillin (10 μg), Tetracycline (30μg), Doxycycline (30μg), Ciprofloxacin (5μg), Vancomycin (30 μg), Erythromycin (15μg) and Chloramphenicol (30μg). Interpretations of results were made according to CLSI (30). Antibiotics were selected based on CLSI recommendation, local availability (in health facility) and feasibility (cost and method of antimicrobial susceptibility test).

Data quality assurance

A pretest was done on 5% (n = 10) HIV infected individuals. Quality control measures were implementing throughout the entire process of data collection and laboratory work. Training was given for data and sample collectors concerning on the research objective, data collection tools, sample collection procedures, and infection prevention protocols to be taken related with COVID-19 Pandemic. Standard Operating Procedures (SOP) were prepared and implemented strictly. All culture media were prepared following the manufacturer’s instruction and sterility of the culture media was tested by incubating 5% of the batch at 35–37°C overnight for evaluation of possible contamination. Standard control strains E. faecalis ATCC 29212 and Staphylococcus aureus ATCC 25923 were used as a positive control.

Statistical analysis

Data were checked for its completeness, entered by Epi data version 4.6.0.2 software, and analyzed by SPSS version 25. The fitness of the model was checked by Hosmer-Lemeshow goodness of fit test. Bivariable and multivariable logistic regression model was used to analyze the association between dependent and independent variables. Those variables with P-value < 0.25 in bivariate analysis were considered as candidate for further multivariable analysis. P-values in the multivariable analysis, adjusted odds ratio (AOR) and 95% confidence interval (CI) were used to determine the strength of association. P-value <0.05 was considered as statistically significant.

Ethics approval and consent to participate

Ethical clearance was obtained from Institutional Review Board (IRB) of Arba Minch University, College of Medicine and Health Sciences, and letter of permission to conduct the study was written to Arba Minch General Hospital. Official permission from Arba Minch General Hospital and an informed written assent/consent from each study participants (assent of those <18 age group from their family or guardian) were obtained.

All information that identifies study subjects were given code numbers and were kept confidential. The purpose of the study was clearly described to the study participants and the specimens collected from the patients were analyzed for the intended purpose only. For each confirmed resistant case, the responsible clinicians of the patient were informed for appropriate management.

Results

Socio-demographic characteristics of study participants

A total of 200 study participants were enrolled in this study. Among these the ratio of male to female was 1:1. The mean age and standard deviation was 38.68 ± 10.97 ranging from 18–67 years. More than three fourth of the study participants 154 (77.0%) came from urban settings (Table 1).

Table 1. Socio-demographic characteristics of study participants attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (N = 200).

Variables	Frequency	Percentage (%)
Sex
Males	100	50.0
Females	100	50.0
Age
≤20	12	6.0
21–30	30	15.0
31–40	78	39.0
41–50	47	23.5
≥51	33	16.5
Residence
Rural	46	23.0
Urban	154	77.0
Educational Status
Unable to read and write	17	8.5
Able to read and write	42	21.0
Primary (1–8)	62	31.0
Secondary (9–12)	62	31.0
College and above	17	8.5

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Clinical characteristics of study participants

The clinical data showed that majority of the participants 187 (93.5%) were outpatients and 168 (84.0%) of the participants had CD4 count >350. Less than half of the respondents 83 (41.5%) had low hemoglobin level and 94 (47.0%) had history of previous antibiotic use for <2 weeks. Majority of the study participants 174 (87.0%) didn’t have previous history of hospitalization in the last six months and 180 (90.0%) didn’t have history of previous catheterization. Likewise, majority of the respondents 191 (95.5%) and 193 (96.5%) didn’t have Diabetes Mellitus and Renal failure respectively (Table 2).

Table 2. Clinical characteristics of study participants attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (N = 200).

Visiting Status	Frequency	Percentage
Outpatient	187	93.5
Inpatient	13	6.5
CD₄+ Count
≤350	32	16.0
>350	168	84.0
Hemoglobin Level
Low	83	41.5
Normal	111	55.5
High	6	3.0
Previous Antibiotic Treatment
Never	76	38.0
≥2 weeks	30	15.0
<2 weeks	94	47.0
History of hospitalization in the last six months
No	174	87.0
Yes	26	13.0
History of previous catheterization
No	180	90.0
Yes	20	10.0
Comorbid condition (Diabetes)
No	191	95.5
Yes	9	4.5
Comorbid condition (Renal failure)
No	193	96.5
Yes	7	3.5

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Incidence of vancomycin resistant Enterococcus

From the total of 200 study participants, Enterococci species was isolated from123 (61.50%) patients. Among these isolates, 14 (11.4%) were vancomycin resistant (95% CI: 6.0–17.0%).

Antimicrobial resistance profile of isolated Enterococci

Among 123 Enterococci isolates tested for commonly prescribed antimicrobial agents the highest rate of resistance was observed against ampicillin in which more than two thirds 86 (69.9%) of the isolates were resistant (Fig 1).

Multidrug resistances (MDR) were observed in slightly less than half 61 (49.59%) of Enterococci isolates and less than one tenth 11 (8.94%) of the isolates were resistant to all antimicrobials tested. All VRE isolates were MDR (Table 3).

Table 3. Profile of multidrug resistance pattern of VRE isolates among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (n = 14).

Resistance rate	Combination of Antibiotics	No. (%) of isolates tested
R4	G, P, TTC, MAC	14 (100)
R5	(G, P, TTC, MAC) + F	2 (14.28)
R6	(G, P, TTC, MAC) + F+ PH	11 (78.58)

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Key; G-glycopeptides (vancomycin), P-penicillins (ampicillin and/or penicillin), TTC-tetracyclines (tetracycline and/or doxycycline), MAC-macrolides (erythromycin), F-fluoroquinolones (ciprofloxacin), PH-phenicols (chloramphenicol), and R4-R6 Number of categories of antibiotics resistance from 4 to 6, respectively

Factors associated with vancomycin resistant Enterococcus gut colonization

Factors independently associated with VRE gut colonization on bivariable analysis, and fit into a multivariable logistic regression model were sex, visiting status, history of catheterization, previous antibiotics treatment, history of hospitalization in the last six months and presence of Diabetes Mellitus (Tables 4 and 5).

Table 4. Bivariable logistic regression analysis on factors affecting vancomycin resistant Enterococci among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020.

Characteristics	Categories	VRE gut colonization		COR	P-value
Characteristics	Categories	Yes, N (%)	No, N (%)	COR	P-value
Sex	Females	4 (6.8)	55 (93.2)	0.39	0.133^*
Sex	Males	10 (15.6)	54 (84.4)	1
Residence	Urban	11 (11.6)	84 (88.4)	1.09	0.899
Residence	Rural	3 (10.7)	25 (89.3)	1
Visiting status	Inpatient	3 (30.0)	7 (70.0)	3.97	0.069^*
Visiting status	Outpatient	11 (9.7)	102 (90.3)	1
CD4 count	≤350	2 (11.8)	15 (88.2)	1.04	0.957
CD4 count	>350	12 (11.3)	94 (88.7)	1
Previous Antibiotic Treatment	Never	2 (4.9)	39 (95.1)	1
	≥2 weeks	8 (40.0)	12 (60.0)	13.00	0.003^*
	<2 weeks	4 (6.5)	58 (93.5)	1.34	0.739
History of hospitalization in the last six months	Yes	6 (37.5)	10 (62.5)	7.43	0.002^*
History of hospitalization in the last six months	No	8 (7.5)	99 (92.5)	1
History of previous catheterization	Yes	4 (25.0)	12 (75.0)	3.23	0.078^*
History of previous catheterization	No	10 (9.3)	97 (90.7)	1
Diabetes Mellitus	Yes	2 (28.6)	5 (71.4)	3.48	0.163^*
Diabetes Mellitus	No	12 (10.3)	104 (89.7)	1

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*Variables which passed bivariable logistic regression analysis at cut off value <0.25

Table 5. Multivariable logistic regression analysis on factors affecting vancomycin resistant Enterococci among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020.

Characteristics	Categories	VRE isolates		AOR (95%CI)	P-value
Characteristics	Categories	Yes, N (%)	No, N (%)	AOR (95%CI)	P-value
Sex	Females	4 (6.8)	55 (93.2)	0.27 (0.06–1.25)	0.093
Sex	Males	10 (15.6)	54 (84.4)	1
Visiting status	Inpatient	3 (30.0)	7 (70.0)	1.13 (0.15–8.43)	0.904
Visiting status	Outpatient	11 (9.7)	102 (90.3)	1
Previous Antibiotic Treatment	Never	2 (4.9)	39 (95.1)	1
	≥2 weeks	8 (40.0)	12 (60.0)	7.35 (1.21–44.64)	0.030^**
	<2 weeks	4 (6.5)	58 (93.5)	1.08 (0.17–6.80)	0.936
History of hospitalization in the last six months	Yes	6 (37.5)	10 (62.5)	5.68 (1.09–29.74)	0.040^**
History of hospitalization in the last six months	No	8 (7.5)	99 (92.5)	1
History of previous catheterization	Yes	4 (25.0)	12 (75.0)	1.38 (0.27–7.03)	0.701
History of previous catheterization	No	10 (9.3)	97 (90.7)	1
Diabetes Mellitus	Yes	2 (28.6)	5 (71.4)	1.81 (0.21–15.36)	0.588
Diabetes Mellitus	No	12 (10.3)	104 (89.7)	1

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**Significant in multivariable logistic regression at p-value <0.05

Discussion

The hasty emergence and the increasing incidence of colonization with VRE have become challenging healthcare problems that have caused serious concern to health care providers and health authorities [2]. In the present study, the prevalence of VRE among HIV infected patients was 11.4% (95% CI: 6.0–17.0%). This prevalence rate was consistent with other studies conducted in, West Amhara, Ethiopia (7.7%) [2] Gondar, Northwest Ethiopia (7.8%) [18], where these studies were done on HIV positive patients and also comparable with studies done on HIV status patients not known in Addis Ababa, Ethiopia (6.7%) [31] and South Africa (14.5%) [21]. However, the prevalence of VRE in our study is lower than the report from Ireland (44.1%) [4], Germany (26.1%) [32] Brazil (23.4%) [1], India (19.6%) [33], Saud Arabia (17.3%) [5] and Iraq (46.4%) [17] where these studies were conducted on the population where HIV status not determined. The lower prevalence in the present study might be due to the variation in study settings in which most of the previous countries have been using oral and intravenous vancomycin massively for human diseases [34, 35], and variation in study participants where the previous studies participants were hospitalized patients and critically ill patients in ICU who were frequently exposed to different antibiotics and experienced insertion of external devices like catheter [7]. On the other hand, the prevalence in our study is higher than studies conducted in USA (4.7%) [36], Nigeria (4.07%) [37] and Ethiopia (5.9%) [16]. The gradual increase and clonal expansion in the prevalence of VRE might have contributed to this higher prevalence [32, 38].

Enterococci isolates showed various resistances to the tested antibiotics; namely, 69.9% to ampicillin, 54.5% to penicillin, 49.6% to erythromycin, 59.3% to tetracycline, 28.5% to ciprofloxacin and 21.1% to chloramphenicol. These findings are comparable with studies conducted in India 64.9% [33] and Ethiopia 66.7% [39] for ampicillin; Ethiopia 64.9% [40], 68% [39] for tetracycline; and Brazil 45.7% [1] and Ethiopia 42.7% [9] 53.3% [31] for erythromycin. However, the resistance profiles in our study is lower than previous studies in India for tested antibiotics 75.9% for penicillin, 84.5% for tetracycline, 95.5% for ciprofloxacin, 92.1% for erythromycin and 42.3% for chloramphenicol [33]; Uganda 69.4% [15] and Ethiopia 77.3% [41] for tetracycline; and Iraq (85.7%) [17], Uganda (72%) [15] and Ethiopia 63.2% [41] erythromycin; These lower drug resistance patterns might be due to variations in sample size, methodology and study participants where most of the participants in the previous studies were hospitalized patients who were taking different antibiotics that might have been contributed for emergence of high rate of drug resistance.

On the other hand, the antibiotic resistance profile in our study is higher than studies conducted in Iran 41.2% [42], Brazil 0% [1], Uganda 1.4% [15] and Ethiopia 36% [41] for ampicillin; Brazil 32.6% [1] and Ethiopia 37.7% [2] for tetracycline; and Brazil 10.9% [1] for chloramphenicol. The high drug resistance patterns might be due to overuse or misuse of antibiotics and inappropriate antibiotics prescription which is very common practice in Ethiopia. Additional reasons for high drug resistance might be extensive antibiotics use of antibiotics for agricultural purpose, mutation and gene transfer among bacteria [4].

Moreover, the present study also showed that 49.6% of Enterococci isolates were multidrug resistant. This result is lower than the findings in Iraq (85.7%) [17] and Ethiopia 80.8% [41]. In contrary, the result is higher than the finding in Ethiopia 29.5% [16]. The discrepancy of the result might be due to variation in geographical distribution of strain, trend and frequency of antibiotic prescription, community drug usage practice.

Our study showed that HIV patients who were previously exposed to antibiotics for more than two weeks were seven times more likely to be colonized with VRE as compared with HIV patients who never exposed to antibiotics previously [AOR = 7.35; 95% CI: (1.21–44.64); P- value = 0.030]. This result is in agreement with other studies conducted in Brazil [1], South Korea [43], Egypt [44], and Ethiopia [2]. The reason might be a prior exposure to antibiotics for a prolonged duration can cause VRE colonization due to the fact that the antibiotics exert selective pressure to Enterococci and alter the competing microbial flora in the GI tract allowing VRE to predominate as evidenced by other studies [7, 34].

The present study showed that HIV patients who had history of hospitalization for the last six months were six times more likely to be colonized with VRE as compared with HIV patients who didn’t have history of hospitalization for the last six months [AOR = 5.68; 95% CI: (1.09–29.74); P-value = 0.040]. The finding is consistent with previous studies done in USA [36], South Korea [43] and Ethiopia [2]. The reason might be VRE have been isolated from virtually every object within patient rooms since they are intrinsically resistant to several commonly used antibiotics in hospital and have ability to acquire resistance genes. Besides, they are ubiquitous in their presence and have high survivability on dry surfaces, thereby causing high VRE transmission rates within healthcare facilities [7, 9].

Limitations of the study

The isolated Enterococci were not identified to species level; molecular characterization and MIC were not done due to resource limitation and budget constraints.

Conclusions

In our study high incidence of vancomycin resistant Enterococci was found. Previous exposure to antibiotics for more than two weeks and previous hospitalization for more than six months were significant factors for vancomycin resistant enterococci gut colonization. The study also showed that the isolated Enterococci had variable degrees of resistance to commonly prescribed antibiotics.

Therefore, periodic surveillance on antimicrobial resistance pattern, adhering to rational use of antibiotics and implementing infection prevention protocols may reduce colonization by VRE.

Supporting information

S1 File

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S2 File

(DOCX)

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Acknowledgments

The authors would like to thank those who were involved in this research.

Abbreviations

ART: Anti-Retroviral Therapy
AOR: Adjusted odd ratio
BEAA: Bile Esculin Azide agar
CDC: Center for Disease Control
CI: Confidence Interval
CLSI: Clinical Laboratory Standards Institute guidelines
CSA: Central statistical agency
HAI: Hospital Acquired Infections
HIV: Human Immunodeficiency Virus
MDR: Multi Drug Resistant
SOP: Standard Operating Procedures
VRE: Vancomycin Resistance Enterococcus
WHO: World Health Organization

Data Availability

Ethical restrictions have been imposed on sharing the data underlying this study. Qualified, interested researchers may submit queries related to data access to the corresponding author (belayjanimen@gmail.com) or the authors' Institutional Review Board (contact: Zerihun Zerdo; email: zedozerihun@gmail.com).

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0251727.r001

Decision Letter 0

Iddya Karunasagar

17 Dec 2020

PONE-D-20-34817

Vancomycin resistant enterococci and its associated factors among HIV infected patients on anti-Retro viral therapy in Ethiopia

PLOS ONE

Dear Dr. Regasa Dadi,

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.

Discussion section could focus on interpreting the results rater than repeat the points made in the results section

Please submit your revised manuscript by Jan 28 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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

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

We look forward to receiving your revised manuscript.

Kind regards,

Iddya Karunasagar

Academic Editor

PLOS ONE

Journal Requirements:

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

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

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2. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.
State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”
If any authors received a salary from any of your funders, please state which authors and which funders.
If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

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In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

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We will update your Data Availability statement on your behalf to reflect the information you provide.

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7. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 5 in your text; if accepted, production will need this reference to link the reader to the Table.

8. Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files

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Additional Editor Comments:

The reviewers have commented on the manuscript and raised number of pertinent points that need to be addressed. Discussion section should interpret the results and discuss in the light of current knowledge rather than repeating the results. This applies to Conclusion section abstract too. Please revise the manuscript addressing all reviewer comments.

[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

**********

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

Reviewer #1: 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

**********

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: No

**********

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: 1. The language should be improved.

2. The manuscript presents extensive introduction which can be reduced to two or three paragraphs.

3. Statistical tests should be mentioned in the abstract also.

4. In methodology, some sentences can be eliminated like the section on antimicrobial susceptibility testing.

5. The name of the institute should be masked.

6. Discussion needs to be improved. Rather than stating the facts, the results should be compared and justification (or hypotheses) for any differences should be explored.

7. The disk diffusion test alone was used. Explain why MIC was not estimated and species level identification was not performed.

**********

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

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

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

PLoS One. 2021 Jun 24;16(6):e0251727. doi: 10.1371/journal.pone.0251727.r002

Author response to Decision Letter 0

18 Jan 2021

Point by point response

1. Response to editors

Comment given: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Comment accepted and corrections were made following the guideline and sample template. (Check for tracking documents where changes made accordingly)

Comment given: Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

Response: Comment accepted and questionnaire (both in local language and English) included as additional information.

Comment given: Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

a. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c. If any authors received a salary from any of your funders, please state which authors and which funders.

d. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Response: Comment accepted financial disclosure mentioned in the manuscript “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors received no specific funding for this work” (see page 17 paragraph 1)

Comment given: We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

Response: We have stated that data from this study are available upon request. This is due to Ethical issues (data contain sensitive patient information that cannot be disclosed and can be used for research only). The data can be found upon reasonable request from corresponding author (belayjanimen@gmail.com).

Comment given: PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

Response: Comment accepted.

Comment given: Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

Response: Comment accepted and ethics section moved to Methods section (see page 8 Ethics approval section)

Comment given: We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 5 in your text; if accepted, production will need this reference to link the reader to the Table.

Response: Table 5 is already mentioned on page 11 in line with Table 4 [Table 4 and 5] (on section “Factors associated with vancomycin resistant Enterococcus gut colonization”)

Comment given: Please include your tables as part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files.

Response: Comment accepted and all Tables included in the manuscript (see page 8-12 for Table 1-5)

Comment given: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

Response: Comment accepted.

Comment given: The reviewers have commented on the manuscript and raised number of pertinent points that need to be addressed. Discussion section should interpret the results and discuss in the light of current knowledge rather than repeating the results. This applies to Conclusion section abstract too. Please revise the manuscript addressing all reviewer comments.

Response: Comment accepted and revisions were made according to comment give by reviewers and see the responses given below:-

2. Response to Reviewers

Comment given: The language should be improved.

Response: We tried to amend and also re-write some parts of the manuscript. Check the manuscript again [please check for Abstract, Introduction, Materials and Methods, Result, Discussion, Conclusion and Limitations of the study sections.]

Comment given: The manuscript presents extensive introduction which can be reduced to two or three paragraphs.

Response: Comment accepted and Introduction section reduced to three paragraphs on the manuscript (see page 2)

Comment given: Statistical tests should be mentioned in the abstract also.

Response: Comment accepted and statistical tests added to Abstract section (“Bivariable and multivariable logistic regression model was used to analyze the association between dependent and independent variables. P-values in the multivariable analysis, adjusted odds ratio (AOR) and 95% confidence interval (CI) were used to determine the strength of association. P-value <0.05 was considered as significant.”)

Comment given: In methodology, some sentences can be eliminated like the section on antimicrobial susceptibility testing.

Response: Comment accepted and antimicrobial susceptibility testing deleted (page 4)

Comment given: The name of the institute should be masked.

Response: It is impossible to mask the name of the institute where research was conducted. If we mask the name of the institute where the research is conducted, the research will not be trustworthy to the scientific world.

Comment given: Discussion needs to be improved. Rather than stating the facts, the results should be compared and justification (or hypotheses) for any differences should be explored.

Response: Comment accepted and discussion section revised according to the comments.

Comment given: The disk diffusion test alone was used. Explain why MIC was not estimated and species level identification was not performed.

Response: Due to limitation of resources and budget, species level identification and MIC were not performed (see page 13 “Limitations of the study” section.)

Attachment

Submitted filename: Point by point response.docx

Click here for additional data file.^{(19KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0251727.r003

Decision Letter 1

Iddya Karunasagar

26 Apr 2021

PONE-D-20-34817R1

Vancomycin resistant enterococci and its associated factors among HIV infected patients on anti-Retro viral therapy in Ethiopia

PLOS ONE

Dear Dr. Regasa Dadi,

==============================

Please address comments made directly on the manuscript.

==============================

Please submit your revised manuscript by Jun 10 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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

If 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: http://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,

Iddya Karunasagar

Academic Editor

PLOS ONE

Journal Requirements:

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

Additional Editor Comments (if provided):

The reviewers have made some comments directly on the manuscript. Please address these

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: No

**********

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

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

**********

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

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

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

Reviewer #1: No

Attachment

Submitted filename: PONE-D-20-34817_R1_comments.pdf

Click here for additional data file.^{(5.1MB, pdf)}

PLoS One. 2021 Jun 24;16(6):e0251727. doi: 10.1371/journal.pone.0251727.r004

Author response to Decision Letter 1

28 Apr 2021

Point by point response

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

Response: Comment accepted and corrections were made on all references. (Check for tracking documents where changes were made on reference section, page 15-19)

Comment given: Table 3: G,P,TTC,MAC - all isolates are resistant to these groups. The table is conveying wrong information. .

Response: Comment accepted and correction made on the Table 3. All isolates are resistant to G, P, TTC, MAC 14 (100%); (G, P, TTC, MAC) + F 2 (14.28%) and (G, P, TTC, MAC) + F+ PH 11 (78.58%) (please check Table 3 page 9)

Comment given: It is unclear whether these are the studies conducted on HIV infected patients or not. If not, mention it. (Discussion section on page 11-12 paragraph 1)

Response: Comment accepted and correction made on the manuscript by declaring HIV status of studies done in different area (see page 11-12 paragraph 1 of Discussion section)

Comment given: No italics or upper case for “Enterococci” (page 13 paragraph 2).

Response: Comment accepted and re-written as Enterococci (please check on revised manuscript page 13 paragraph 2)

Comment given: correct as “were not done” on Limitation of study section which was written previously as:- “The isolated Enterococci were not identified to species level; molecular characterization and MIC were done due to resource limitation and budget constraints”

Response: Comment accepted and “were done” changed to “were not done” in limitation of the study section and re-written as “The isolated Enterococci were not identified to species level; molecular characterization and MIC were not done due to resource limitation and budget constraints”

Comment given: Conclusion section paragraph 2 “Therefore periodic surveillance on antimicrobial resistance pattern of Enterococcus species is important for proper treatment, health professionals should strictly follow infection prevention protocols and further studies should be conducted on species identification and molecular characterization of Enterococci” marked as “Not a part of conclusion” by Reviewer

Response: Comment accepted and re-written as “Therefore, periodic surveillance on antimicrobial resistance pattern, adhering to rational use of antibiotics and implementing infection prevention protocols may reduce colonization by VRE” (see page 14 Conclusion section paragraph 2)

Comment given: Figure 1 not necessary as it can be expressed in text.

Response: Comment accepted and Figure 1 is expressed in words in Result section Incidence of vancomycin resistant Enterococcus sub section on page 8

Comment given: Figure 2 change ug symbol

Response: Comment accepted and ug symbol is changed to µg.

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

Reviewer #1: No

Response: Comment accepted and Data availability statement added to page 14 that say “Data cannot be shared publicly because of ethical issues. However the data underlying the results presented in the study are available from corresponding author (belayjanimen@gmail.com) and Institutional Review Board (IRB) committee /Zerihun Zerdo (zedozerihun@gmail.com) on reasonable request.” (please check page 14 Data availability statement section)

Comment given: Remove tables from main text if presented at the end of the manuscript

Response: Tables are submitted in the main text only neither submitted individually nor the end of the manuscript

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PLoS One. doi: 10.1371/journal.pone.0251727.r005

Decision Letter 2

Iddya Karunasagar

3 May 2021

Vancomycin resistant enterococci and its associated factors among HIV infected patients on anti-Retro viral therapy in Ethiopia

PONE-D-20-34817R2

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PLoS One. doi: 10.1371/journal.pone.0251727.r006

Acceptance letter

Iddya Karunasagar

21 May 2021

PONE-D-20-34817R2

Vancomycin resistant Enterococci and its associated factors among HIV infected patients on anti-Retro viral therapy in Ethiopia

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Data Availability Statement

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PERMALINK

Vancomycin resistant Enterococci and its associated factors among HIV infected patients on anti-retroviral therapy in Ethiopia

Belayneh Regasa Dadi

Zerihun Solomon

Mheret Tesfaye

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Materials and methods

Study design, period and setting

Sampling technique

Data collection and laboratory processing

Isolation and identification of Enterococci

Data quality assurance

Statistical analysis

Ethics approval and consent to participate

Results

Socio-demographic characteristics of study participants

Table 1. Socio-demographic characteristics of study participants attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (N = 200).

Clinical characteristics of study participants

Table 2. Clinical characteristics of study participants attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (N = 200).

Incidence of vancomycin resistant Enterococcus

Antimicrobial resistance profile of isolated Enterococci

Fig 1. Antimicrobial resistance patterns of isolated Enterococcus spp among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (n = 123).

Table 3. Profile of multidrug resistance pattern of VRE isolates among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020 (n = 14).

Factors associated with vancomycin resistant Enterococcus gut colonization

Table 4. Bivariable logistic regression analysis on factors affecting vancomycin resistant Enterococci among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020.

Table 5. Multivariable logistic regression analysis on factors affecting vancomycin resistant Enterococci among clients attending ART clinic at Arba Minch General Hospital, Southern Ethiopia October 2020.

Discussion

Limitations of the study

Conclusions

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Iddya Karunasagar

Roles

Author response to Decision Letter 0

Decision Letter 1

Iddya Karunasagar

Roles

Author response to Decision Letter 1

Decision Letter 2

Iddya Karunasagar

Roles

Acceptance letter

Iddya Karunasagar

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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