Skip to main content

Antibiotic choices among healthcare professionals for enterococcal bacteremia with patterns of resistance and risk factors of mortality, in settings of poor antibiotic stewardship program — a five-year retrospective cohort study



Enterococcal bacteremia has become prevalent in the recent decade, especially in hospitalized patients. Moreover, the rise in resistance patterns against antibiotic drugs regarding enterococci infection, such as cephalosporins, ampicillin and vancomycin, is prevailing. The major driving force behind this is the incongruous use of antibiotics with a minor contribution from environmental stressors which calls for vigilant and prudent administration of evidence-based antibiotics.


A retrospective study was conducted from January 1 2017 until December 31 2021, at the tertiary care center, Dr Ziauddin Hospital in Karachi, Pakistan.


Our research revealed ampicillin resistance in 87 (63.5%), with an estimated 25 (18.8%) mortality. Male gender 19 (76%) and vancomycin resistance 13 (52%) were associated with increased mortality. Furthermore, appropriate antibiotic therapy reduced the risk of death compared with inappropriate and excessive use of antibiotics 10 (40%) vs. 15 (60%) vs. 20 (80%) respectively. Targeted therapy with amoxicillin/clavulanic acid was associated with lower mortality 1 (4%) and higher discharge rates 34 (32.1%). On Kaplan-Meier survival, targeted therapy with amoxicillin/clavulanic acid was associated with shorter hospital stays and prolonged survival. UTI was found as the most common source of enterococcal bacteremia 57 (41.6%), followed by respiratory 21 (15.3%) and intra-abdominal 13 (9.5%). In 26 (19%) patients, no identifiable source of infection was found.


Vancomycin resistance and male gender were found independent risk factors for mortality. The use of inappropriate antibiotics significantly increases mortality in these patients. The appropriate antibiotic therapy reduces the risk of death. Furthermore, overuse of antibiotics didn’t reduce mortality; instead increased the financial burden and chances of developing multi-drug resistant strains of other organisms by increasing hospital stays of patients.

Peer Review reports


Hospitalized patients are becoming more susceptible to enterococcal infections [1, 2]. Enterococci are a regular part of human flora but can cause infections if the host’s immune system is weakened [3]. Enterococci has become the third or fourth most frequent reason for bloodstream infection (BSI) in the last decade [1, 2, 4]. Clinical enterococcal infections are becoming increasingly resistant to vancomycin, with 14 to 25% of all enterococcal isolates in North American hospitals resistant to the antibiotic [4,5,6]. Enterococci species have been recognized as formidable pathogens because of the high fatality rate linked with enterococcal BSI [7,8,9,10,11,12]. All enterococci are intrinsically resistant to cephalosporins, and the frequency of ampicillin and vancomycin resistance is on the rise in many countries worldwide. Which complicates the treatment for enterococcal BSI. Synergistic drug resistance has become more widespread [9, 13].

The infamous Enterococci species, E. faecalis and E. faecium, are commonly mistaken for one another and treated therein. E. faecium BSI, has been linked to BSI in a more critically ill population of patients, has greater rates of antibiotic resistance, and is linked to greater mortality than E. faecalis BSI [7, 8, 14, 15]. BSI of enterococcal origin is frequently linked to infections such as those of the intra-abdominal region, endovascular area, and urinary passage [7, 14, 16,17,18,19,20,21,22]. In previous non-selected observational cohort studies, senile age, male gender, hepatic illness, renal derangement, diabetes, hematopoietic transplant, cancer, and previous antibiotic treatment have all been linked to the acquisition of BSI [7, 8, 14, 21, 23].

In several extensive cohort studies, inadequate and late antibiotic administration has been linked to increased mortality [24]. Antibiotic treatment in enterococcal bacteremia is a contentious topic; a few trials have indicated no reduction in mortality with proper antibiotic therapy [25, 26]. Prospective investigations, on the other hand, have shown that adequate antibiotic treatment improves outcomes for both high-level gentamicin-resistant (HLGR) Enterococci species and Vancomycin-Resistant Enterococci (VRE) [15, 27].

Previous studies have grouped several risk factors likely to increase the chances of VRE infection into three brackets: antibiotic use, host elements, and certain hospital constituents. Other surveys in hospital settings have linked VRE infection with lengthened hospital stays, immunocompromised states/neutropenia, steroid users, renal function derangements, increased exposure to antibiotics, especially vancomycin and 3rd generation cephalosporins, and indwelling urinary catheterization. However, Intensive Care Unit (ICU) patients who are critically ill and have limited treatment options are at tremendous peril of acquiring a VRE infection [28].

The goal of this research was to identify enterococcal bloodstream infection resistance patterns and take into consideration additional known and suspected risk factors. Furthermore, the goal was also to look into the antibiotic prescription practices of doctors in settings with poor/inefficient antibiotic stewardship and their impact on outcomes of enterococcal bloodstream infections.

Materials and methods

Study design and population

All cases of enterococcal BSI in the adult population at Dr Ziauddin Hospital, a tertiary care multidisciplinary hospital accommodating 300 beds, were retrospectively collected. As a result, eligibility was granted to all patients at our hospital who have tested positive for Enterococcal species in a blood culture between January 1, 2017, and December 31, 2021.

Exclusion criteria

Cases excluded from the study were patients under 16, those with incomplete medical records, and patients with polymicrobial bacteremia including non-enterococci or other site infection within three days of the blood culture with Enterococci spp.

Recognition and susceptibility testing

Blood cultures were conducted via the BD/BACTEC/9000 system. Isolates were identified using conventional biochemical studies. According to Clinical and Laboratory Standards Institute (CLSI) guidelines, susceptibility testing for E. species was conducted via Mueller Hinton Agar (MHA) medium employing a modified Kirby-Bauer disc diffusion technique [29].

Operational definitions

Enterococcal Bloodstream Infection; is defined as the seclusion of Enterococci strains in one or more samples of blood culture [9, 12, 15, 26, 30].

Fever; is defined as an elevation in body temperature greater than 37.5 °C using an axillary thermometer [31].

Appropriate antibiotic treatment; is defined as having all of the following features (i) starting antibiotics within 24 h of the positive blood culture; (ii) the spectrum of antibiotics administered covered the Enterococci spp. susceptibility and was an approved treatment for the enterococcal disease; (iii) the dosage was sufficient; (iv) no absolute contraindications or relevant interactions with other drugs; and (v) antibiotics were continued for a minimum of six days.

Inappropriate antibiotic treatment; is defined as having all of the following features (i) a delay in starting antibiotics past the day blood culture results were positive; (ii) the spectrum of antibiotics administered did not cover Enterococci spp. Susceptibility was not an accepted treatment modality for enterococcal infection; (iii) the dosage was inadequate; (iv) antibiotics were continued for less than five days.

Excessive antibiotic treatment; is defined as (i) starting more than one adequate antibiotic treatment for enterococcal infections; (ii) starting antibiotics that are not an acceptable treatment for enterococcal infection besides antibiotics covering enterococcal infection.

Empiric antibiotic; is defined as the use of antibiotics any time before and 24 h after this blood culture was drawn or before preliminary microbiologic data was available.

Prescribed antibiotic; is defined as the use of antibiotics that covered enterococcal species according to the reported drug sensitivity pattern.

Data collection procedure

A skilled team of researchers examined the medical data to extract demographic profiles and information on hospitalization, such as dates, length of stay, ward, comorbidities, concurrent infections, patient diagnoses, and clinical outcomes. Also, the usage of indwelling catheters, the vital status, the recommended antibiotic, the dosage, and the number of treatment days were all noted.

Data on the clinical and microbiological aspects were kept. Moreover, information on clinical traits and the number of positive blood cultures was logged. In addition to the blood culture sample, biochemical data were gathered and analyzed on the same day. The patient charts were reviewed to identify the infection’s likely source. Outcomes were further compared based on empiric and prescribed antibiotics (antibiotics advised after isolation of enterococcal species). Results were further compared for appropriate, inappropriate, and overuse of antibiotics. We also compared outcomes according to the sensitivity patterns of enterococci. The author used the terms E and P for empirical and prescribed antibiotics, respectively. Similarly, frequencies and percentages were noted for the consumption trends of empiric and prescribed antibiotics. The structured proforma was used to enter all the data.

Statistical analysis

Participants’ baseline characteristics were compared for laboratory parameters, existing comorbidities, and signs and symptoms. Continuous variables were compared using the student t-test (standard) or the Mann–Whitney U-test (non-parametric). We calculated frequencies and percentages for categorical variables and compared them using Fisher’s exact test or Pearson’s Chi-square test. Survival analysis was done using the Kaplan-Meier curve. In addition, the results were calculated using both univariate and multivariate analysis (multivariate logistic regression). Logistic regression included variables from univariate analysis with a p-value less than 0.05. Given that there was no demise, the author did not include P-amox in the logistic regression. The data were analyzed with IBM SPSS Version 26, and a P-value < 0.05 was judged statistically significant.


A total of 137 patients were included in this study Fig. 1.

Fig. 1
figure 1

Flow diagram of patients included in the study

Of these, the male/female ratio was roughly the same, with males accounting for 75 (55.5%) and females 62 (44.5%), respectively Table 1. Death was more commonly seen in males with a significant p-value. Although fever was widely observed in surviving patients, there was no statistical significance. The most common comorbid illnesses were hypertension, diabetes, and ischemic heart disease. There was no mortality difference in comorbid conditions. Mortality was significantly higher in patients who needed intensive care unit admission and mechanical ventilation. The most common source of infection was identified as the urinary tract, found in 57 (41.6%). Other common sources included the respiratory tract, found in 21 (15.3%); the intra-abdominal, found in 13 (9.5%); and the pelvic, found in 11 (8%). In 26 (9%) cases, no obvious source of infection was identified. There was no significant mortality difference in the sources of infection. Mortality was lower in enterococci sensitive to beta-lactams and vancomycin, although the difference was insignificant. Similarly, mortality was lower in enterococci resistant to beta-lactams but sensitive to vancomycin with statistically significant p values. However, mortality was highest, with a significant p-value in enterococci resistant to linezolid.

Table 1 Demographics of patients with Enterococcal bacteremia

Using appropriate antibiotics was associated with significantly lower mortality, while inappropriate antibiotic use was associated with significantly higher mortality. Overused antibiotics were again associated with higher mortality, but there was no statistical significance.

The median (IQR) of laboratory values was correlated with the termination of the patient Table 2. The hemoglobin values in the non-survivors were greater than those in survivors, with a significant p-value of 0.003. Similarly, total bilirubin and creatinine were higher in non-survivors than in survivors, with a significant p-value of.017 and a p-value of.030, respectively.

Table 2 Laboratory parameters with survival outcome in Enterococcal bacteremia patients

Different trends of the empiric regimen were used empirically, and these regimens were compared with non-survival outcome Table 3. The most common empiric therapy included ceftriaxone, a combination of a carbapenem and vancomycin, amoxicillin/clavulanic acid, and a combination of carbapenem and linezolid. Patients who received E-amoxicillin/clavulanic acid had significantly lower mortality, while those who received a combination of an E-carbapenem with E-vancomycin had the highest mortality.

Table 3 Empiric regimen with non-survival outcome in Enterococcal bacteremia patients

As for prescribed antibiotics are concerned, amoxicillin/clavulanic acid was the most commonly used antibiotic 36 (26.3%), followed by combinations of Carbapenem + Vancomycin or Linezolid 17 (12.4%) each, and linezolid prescribed in 16 (11.7%) Table 4. When comparing mortality after cultures reported sensitivity patterns, mortality was highest in patients receiving P-vancomycin with a significant p-value, followed by a combination of P-carbapenems with P-vancomycin and P-colistin. Compared to these, mortality was lowest in P-amoxicillin/clavulanic acid.

Table 4 Prescribed antibiotics with survival outcome in Enterococcal bacteremia patients

In the multivariate analysis Table 5, only gender and vancomycin resistance were significantly associated with mortality.

Table 5 Multivariate analysis in Enterococcal bacteremia patients

According to the Kaplan-Meier survival analysis, patients who received P-amoxicillin/clavulanic acid were discharged earlier (6.32 vs. 11.13 days; Log Rank P = 0.005) (Fig. 2). Similarly, comparing time from admission to death, patients who received P-amoxicillin/clavulanic acid had higher survival, although there was no significant statistical difference (21 vs. 11.22 days; Log Rank P = 0.336). There was no statistical significance here as only one patient receiving P-amoxicillin/clavulanic acid did not survive.

Fig. 2
figure 2

Kaplan-Meier survival of P-amoxicillin/clavulanic acid in Enterococcal Bacteremia patients; (A) Time from admission to discharge; (B) Time from admission to death

P—amox Prescribed amoxicillin/clavulanic acid

Contrary to that, the survival of patients who received P-Vancomycin remained similar regarding admission to death (11.20 vs. 11.93 days; Log Rank P = 0.886). Similarly, no significant difference was seen in hospital stay, from admission to discharge (11.17 vs. 9.12 days; Log Rank P 0.335).

On the other hand, patients who received P-linezolid survived slightly longer but with no statistical significance when compared from admission to death (13.0 vs. 11.26 days; Log Rank P 0.734). While from admission to discharge, patients who received P-linezolid were discharged home late (12.60 vs. 8.36 days; Log Rank P 0.050). Using survival analysis on appropriate vs. inappropriate antibiotics; it was found that there was no significant difference in overall survival (11.10 vs. 12.0 days; Log Rank P = 0.923). While overuse of antibiotics significantly increases hospital stay from admission to discharge (11.95 vs. 6.14 days; Log Rank P < 0.001).

According to the unadjusted Cox regression model, patients in the P-vancomycin group had a slightly higher risk of death, although the difference was not statistically significant (HR 1.060, 95% CI 0.463–2.424; P 0.891). Similarly, no difference was seen for ICU admission or mechanical ventilation (HR 1.140, 95% CI: 0.541–2.405; P 0.730, HR 1.387, 95% CI: 0.443–4.346; P 0.574, respectively). Using Cox regression on P-amoxicillin/clavulanic acid, there was no statistical difference from admission to death and mechanical ventilation (HR 0.420, 95% CI: 0.055–3.221; P 0.404, HR 2.371, 95% CI: 0.284–19.776; P 0.425, respectively). Using the Cox regression model, the hazard of death was higher in the P-linezolid group (HR 1.183; 95% CI 0.428–3.269; P 0.747). Similarly, ICU admission and mechanical ventilation hazards were higher in patients receiving P-linezolid (HR 1.180; 95% CI 0.481-2,899; P 0.718; HR 1.405; 95% CI 0.50-3.944; P 0.519, respectively).


The study’s key finding was that vancomycin resistance and male gender were independent risk factors for mortality. While the use of inappropriate antibiotics increases mortality, the appropriate use of antibiotics significantly reduces mortality. However, excessive antibiotic use lengthens hospital stays without significantly affecting mortality.

Enterococci have appeared as sources of significant nosocomial and community-acquired illnesses in the past ten years. They were listed as the United States’ second-most prevalent source of hospital-acquired illnesses. Furthermore, enterococci are reported to be the third most pervasive organism in healthcare-associated bloodstream infection in the United States [5].

Multiple kinds of research in Asia have documented Enterococci spp. as the fourth most frequent microorganism causing BSI [32]. A systemic analysis also labelled it the third most common gram-positive bacteria in driving community-acquired BSI in Asia and Southeast Asia [33]. Unfortunately, BSI of bacterial and fungal etiology involves more than 200,000 people annually in the United States and is a vital source of morbidity and mortality globally [4].

Over the years, Enterococci have developed resistance to several antibiotics owing to three significant factors: [1] excessive administration of broad-spectrum antibiotics such as penicillin and cephalosporins, which results in the growth of gram-negative intestinal bacterial flora; [2] specific strains adapting and circulating the facets of antibiotic resistance; and [3] innate resistance to some frequently prescribed antibiotics [34]. But its ability to cause disease is strongly linked to the development of VRE and other features of multi-drug resistance (MDR) [35].

This study reported UTI as the most common source of enterococcal BSI, which is similar to findings by McBride et al. [14]. from New Zealand, where most cases of enterococcal bacteremia (52/205, 25.3%) originated in the genitourinary system, a frequency lower than reported in this study. The second most prevalent diagnosis for the cause of bacteremia was an unidentified source (21.5%) [14]. However, the unknown source remains almost identical between the findings of McBride et al. and this review. Similarly, in a study by Caballero-Granado, the most common source of enterococcal BSI was reported as intra-abdominal, followed by intravascular catheters and the urinary tract [10]. Although in their study, 39% of patients had no identifiable source of bacteremia [10]. Our findings are consistent with Ceci et al. [36], who reported the urinary tract as the most common source of enterococcal bacteremia found in 36.4% of patients, followed by vascular catheters and cutaneous infections. However, almost half of the patients (48.5%) in their study had no obvious source of infection. Lark et al. [37] noticed bacteremia that is with no documented origin to a less frequent extent (7.0%); the catheters were associated with 47.0% of the cases, whereas infections of the urinary tract had a smaller frequency (11.0%) after intra-abdominal sites, respiratory infections, and the skin or soft-tissue infections. Nevertheless, a prior investigation in Argentina found a much higher frequency (42.0%) of bacteremia of unknown cause, subsequently followed by respiratory, urinary, cutaneous, and abdominal origin [38].

Conventionally, antibiotics, mainly cell wall inhibitors coupled with aminoglycosides, treat enterococci-related infections [39]. However, the inborn robust nature of Enterococci manifests an atypical capability to confer resistance to multiple categories of medication, including macrolides, β-lactams, tetracyclines, aminoglycosides and fluoroquinolones [39]. Hence, one of the most burdensome tasks for today’s physicians regarding Enterococcal infections is the treatment since these organisms either possess innate resistance or are collectively less susceptible to most antibacterial drugs [40].

Collectively, the current review is established to account for the drift of antibiotic resistance in enterococci over 5 years and the association of inappropriate antibiotic regimens with mortality in enterococcal bacteremia in a tertiary care hospital in Pakistan. Our analysis of enterococcal isolates showed profound ampicillin resistance (78.8%), and less than a quarter were resistant to vancomycin (16.8%), out of which 15.3% had both ampicillin and vancomycin resistance. In comparison, a study conducted in Rawalpindi, Pakistan, in 2012 reported the frequency of VRE to be 11.57% [41]. Furthermore, another study done in Karachi, Pakistan, found that the frequency of VRE was relatively low at just 0.9% [42]. Considering the studies mentioned earlier, a general upward trend is noted in the prevalence of VRE in Pakistan. Our findings support the growing trend of antibiotic resistance among enterococci, as reported in the literature. For example, research on the regional resistance pattern of enterococci found that resistance to vancomycin and ampicillin grew from 14% to 21% in 1997 to 17% and 24% in 1999 (increases of 1% each year) [5]. Another source of worry is the advent of glycopeptide resistance in Latin America, initially found in 1998 at a relatively low incidence (1%) but nearly doubled to 2% in the subsequent year [5]. McBride et al. reported resistance to amoxicillin in 69.0% (20/29) of E. faecium isolates [14]. However, there were no vancomycin-resistant enterococci [14]. Additionally, it was observed that studies from many countries, as well as Pakistan, produced conflicting findings for instance, a study in Eastern India showed all Enterococci isolates to be vancomycin and linezolid sensitive [43]. Moreover, a review conducted in Iran showed that resistance to erythromycin, ampicillin, ciprofloxacin, gentamicin, and vancomycin fluctuated between 2001 and 2016, with vancomycin showing a negligible increase in resistance, while erythromycin and ampicillin showed decreasing trends in resistance [44].

One of the key findings of this study was that approximately one-fourth of the patients (26.3%) had received inappropriate antibiotics. These findings are comparatively lower than the study by Napolitano et al. [45], who reported higher use of inappropriate antibiotics (34.2%). Due to the various study criteria, medical settings, and participant characteristics, it is impossible to compare this inappropriateness rate with earlier studies carried out in Pakistan and other nations. However, despite these variations, greater rates were discovered in two earlier studies, where 33% of antibiotics in a Swiss tertiary care hospital [46] and 32.7% of prescriptions in Australian emergency rooms were deemed inappropriate [47]. Similarly, slightly higher rates of inappropriate prescriptions have been noted in a Dutch university hospital (29.3%) [48].

In contrast, a previous study in the same region discovered much higher rates in medical, surgical, and intensive care units, ranging from 53.8 to 79.8% [49]. These findings imply that there is space for improving adherence to antibiotic prescribing guidelines by putting efficient initiatives into practice. Antibiotic stewardship programs (ASP) are well known to have a favorable effect on antibiotic use. They may enhance hospitalization outcomes, such as a decrease in infectious diseases brought on by multidrug-resistant microorganisms, lengths of stay, readmission rates, and patients’ disability and mortality [50,51,52,53]. Another major finding of this study was the overuse of antibiotics. Despite positive cultures with enterococci, after excluding other co-infections, 64.2% of patients were prescribed extra antibiotics with either dual coverage for enterococci or mainly prescribing antibiotics for polymicrobial bacteremia including non-enterococcal infections. The results of a Pakistani multicenter survey on antibiotic stewardship revealed that patients also influence physicians’ prescriptions by compelling them to include an antibiotic to achieve the quickest cure [54]. This finding was similar to studies from Sri Lanka and the United Kingdom [55, 56] that demonstrated how patients influenced physicians to prescribe antibiotics even when they were unnecessary. Without a doubt, the results of the culture and sensitivity tests should be used to guide antibiotic selection. Unfortunately, doctors are forced to overprescribe broad-spectrum antibiotics due to delays in the release of microbiology reports, a lack of confidence on the part of doctors in laboratory results, the limited availability of antibiotics in hospitals, the influence of patients and their families on doctors’ prescriptions, the absence of an efficient program for the stewardship of antibiotics, the fear of losing patients, and the poor financial situation of patients.

Our study gathered isolates, treated empirically with 17 different representative drugs, followed by targeted therapy on the arrival of the sensitivity report. It was noticed that patients who received appropriate empirical treatment were associated with better survival outcomes, regardless of other risk factors for mortality. Mortality in this review was reported at 18.2%, a finding almost identical to McBride et al.‘s conclusions, who noted that the crude 7- and 30-day death rates in their patient group were 13 and 25%, respectively [14]. Others have found crude death rates ranging from 13 to 68% for enterococcal bacteremia [10, 25]. It has been postulated that a significant portion of this mortality is related to causes other than bacteremia, with attributable death rates ranging from 2 to 43% [10]. Suppli et al. observed high enterococcal bacteremia death rates of 26% [57]; Danish research revealed low bacteremia mortality rates of 18% at 30 days and 25% at 90 days [58]. In 398 cases of enterococcal bacteremia, Vergis et al. [15] discovered a 14-day death rate of 19%. In another study, mortality was found to be 37% in enterococcal bacteremia, where the severity of illness and age were independently associated with mortality [26].

Similarly, 39% mortality has been found in another study [59]. According to our findings, the most important variables related to death included gender, the necessity for ICU admission and mechanical ventilation, improper antibiotic administration, using carbapenem and vancomycin alone or in combination, and the isolation of VRE. There is substantial debate about whether vancomycin resistance is a reliable indicator of death in enterococcal bacteremia. According to two studies, VRE infection is not independently related to mortality when illness severity is considered during multivariate analysis [60, 61]. Vancomycin resistance, on the other hand, was discovered to be a standalone predictor of death by another group, which used the presence of shock as a sign of disease severity [12]. In addition, we found that patients with VRE had a much greater fatality rate than those with Vancomycin-Sensitive Enterococci (VSE) in our study, which included a small cohort of patients with VRE bacteremia.

The fact that mortality was significantly decreased when P-amox was given to patients was a key finding of this study. This could be explained by the fact that only a small portion of the patients in this group were critically ill. P-amox was used in just one patient who required invasive ventilatory support and a small number of patients who required ICU admission. P-vanco, on the other hand, was utilised more frequently in patients who required invasive mechanical ventilation and ICU admission. Therefore, to determine whether the use of amoxicillin/clavulanic acid truly contributes to the survival rate, a randomized comparative trial with matched patient backgrounds is necessary, and this study alone does not provide a clear answer.

There are several limitations to this study. First, we didn’t classify the enterococci as health-care-associated or community-acquired. As undoubtedly, infections acquired in healthcare settings are associated with poorer outcomes. Second is the nature of the study and single-centre experience with smaller sample size. Third, due to limited resources, enterococci were not differentiated into faecalis or faecium species, which may have resulted in study bias. Fourth, due to the lack of a control group, we cannot investigate the attributable mortality or correlate the results to those of bacteremia caused by other organisms. The main strengths of this study included being the first in the region to directly report the antibiotic choices made by physicians for treating enterococcal BSI.

In reality, the best way to counteract antibiotic resistance is by properly administering antibiotics and recognizing these diseases to prevent their occurrence rather than inventing new drugs. Therefore, the first and foremost action is to caution doctors against haphazardly using antibiotics like vancomycin [39].


The clinical importance and burden of enterococcal bloodstream infections should be considered. Vancomycin resistance and gender were found to be independent risk factors for mortality. The use of inappropriate antibiotics significantly increases mortality in these patients. The use of amoxicillin/clavulanic acid is associated with a reduction in mortality, increased hospital discharge rates, and reduced hospital stay. Therefore, to determine whether the use of amoxicillin/clavulanic acid truly contributes to the survival rate, a randomized comparative trial with matched patient backgrounds is necessary, and this study alone does not provide a clear answer. Furthermore, overuse of antibiotics didn’t reduce mortality; instead, it increased the financial burden and chances of developing multi-drug-resistant strains of other organisms by increasing patients’ hospital stays.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


  1. Emori TG, Gaynes RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev. 1993;6(4):428–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Jones RN, Marshall SA, Pfaller MA, Wilke WW, Hollis RJ, Erwin ME, et al. Nosocomial enterococcal blood stream infections in the SCOPE Program: antimicrobial resistance, species occurrence, molecular testing results, and laboratory testing accuracy. SCOPE Hospital Study Group. Diagn Microbiol Infect Dis. 1997;29(2):95–102.

    CAS  PubMed  Google Scholar 

  3. Moellering RC. Jr. Emergence of Enterococcus as a significant pathogen. Clin Infect Dis. 1992;14(6):1173–6.

    PubMed  Google Scholar 

  4. Pfaller MA, Jones RN, Doern GV, Kugler K. Bacterial pathogens isolated from patients with bloodstream infection: frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY antimicrobial surveillance program (United States and Canada, 1997). Antimicrob Agents Chemother. 1998;42(7):1762–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Low DE, Keller N, Barth A, Jones RN. Clinical prevalence, antimicrobial susceptibility, and geographic resistance patterns of enterococci: results from the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis. 2001;32(Suppl 2):133–45.

    Google Scholar 

  6. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med. 2000;342(10):710–21.

    CAS  PubMed  Google Scholar 

  7. Noskin GA, Peterson LR, Warren JR. Enterococcus faecium and Enterococcus faecalis bacteremia: acquisition and outcome. Clin Infect Dis. 1995;20(2):296–301.

    CAS  PubMed  Google Scholar 

  8. Patterson JE, Sweeney AH, Simms M, Carley N, Mangi R, Sabetta J, et al. An analysis of 110 serious enterococcal infections. Epidemiology, antibiotic susceptibility, and outcome. Med (Baltim). 1995;74(4):191–200.

    CAS  Google Scholar 

  9. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. 2005;41(3):327–33.

    PubMed  Google Scholar 

  10. Caballero-Granado FJ, Becerril B, Cuberos L, Bernabeu M, Cisneros JM, Pachón J. Attributable mortality rate and duration of hospital stay associated with enterococcal bacteremia. Clin Infect Dis. 2001;32(4):587–94.

    CAS  PubMed  Google Scholar 

  11. Edmond MB, Ober JF, Weinbaum DL, Pfaller MA, Hwang T, Sanford MD, et al. Vancomycin-resistant Enterococcus faecium bacteremia: risk factors for infection. Clin Infect Dis. 1995;20(5):1126–33.

    CAS  PubMed  Google Scholar 

  12. Linden PK, Pasculle AW, Manez R, Kramer DJ, Fung JJ, Pinna AD, et al. Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clin Infect Dis. 1996;22(4):663–70.

    CAS  PubMed  Google Scholar 

  13. Woodford N, Livermore DM. Infections caused by Gram-positive bacteria: a review of the global challenge. J Infect. 2009;59(Suppl 1):4–16.

    Google Scholar 

  14. McBride SJ, Upton A, Roberts SA. Clinical characteristics and outcomes of patients with vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium bacteraemia–a five-year retrospective review. Eur J Clin Microbiol Infect Dis. 2010;29(1):107–14.

    CAS  PubMed  Google Scholar 

  15. Vergis EN, Hayden MK, Chow JW, Snydman DR, Zervos MJ, Linden PK, et al. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study. Ann Intern Med. 2001;135(7):484–92.

    CAS  PubMed  Google Scholar 

  16. Pien BC, Sundaram P, Raoof N, Costa SF, Mirrett S, Woods CW, et al. The clinical and prognostic importance of positive blood cultures in adults. Am J Med. 2010;123(9):819–28.

    PubMed  Google Scholar 

  17. Lewis CM, Zervos MJ. Clinical manifestations of enterococcal infection. Eur J Clin Microbiol Infect Dis. 1990;9(2):111–7.

    CAS  PubMed  Google Scholar 

  18. Barie PS, Christou NV, Dellinger EP, Rout WR, Stone HH, Waymack JP. Pathogenicity of the enterococcus in surgical infections. Ann Surg. 1990;212(2):155–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hoge CW, Adams J, Buchanan B, Sears SD. Enterococcal bacteremia: to treat or not to treat, a reappraisal. Rev Infect Dis. 1991;13(4):600–5.

    CAS  PubMed  Google Scholar 

  20. Garrison RN, Fry DE, Berberich S, Polk HC. Jr. Enterococcal bacteremia: clinical implications and determinants of death. Ann Surg. 1982;196(1):43–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gray J, Marsh PJ, Stewart D, Pedler SJ. Enterococcal bacteraemia: a prospective study of 125 episodes. J Hosp Infect. 1994;27(3):179–86.

    CAS  PubMed  Google Scholar 

  22. Graninger W, Ragette R. Nosocomial bacteremia due to Enterococcus faecalis without endocarditis. Clin Infect Dis. 1992;15(1):49–57.

    CAS  PubMed  Google Scholar 

  23. Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ. Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care. 2003;26(11):2977–82.

    PubMed  Google Scholar 

  24. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244(5):379–86.

    CAS  PubMed  Google Scholar 

  25. Bryan CS, Reynolds KL, Brown JJ. Mortality associated with enterococcal bacteremia. Surg Gynecol Obstet. 1985;160(6):557–61.

    CAS  PubMed  Google Scholar 

  26. Lautenbach E, Bilker WB, Brennan PJ. Enterococcal bacteremia: risk factors for vancomycin resistance and predictors of mortality. Infect Control Hosp Epidemiol. 1999;20(5):318–23.

    CAS  PubMed  Google Scholar 

  27. Vergis EN, Shankar N, Chow JW, Hayden MK, Snydman DR, Zervos MJ, et al. Association between the presence of enterococcal virulence factors gelatinase, hemolysin, and enterococcal surface protein and mortality among patients with bacteremia due to Enterococcus faecalis. Clin Infect Dis. 2002;35(5):570–5.

    CAS  PubMed  Google Scholar 

  28. Tripathi A, Shukla SK, Singh A, Prasad KN. Prevalence, outcome and risk factor associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium at a Tertiary Care Hospital in Northern India. Indian J Med Microbiol. 2016;34(1):38–45.

    CAS  PubMed  Google Scholar 

  29. Humphries R, Bobenchik AM, Hindler JA, Schuetz AN. Overview of changes to the Clinical and Laboratory Standards Institute Performance Standards for Antimicrobial susceptibility testing, M100, 31st Edition. J Clin Microbiol. 2021;59(12):e0021321.

    PubMed  Google Scholar 

  30. Garbutt JM, Ventrapragada M, Littenberg B, Mundy LM. Association between resistance to vancomycin and death in cases of Enterococcus faecium bacteremia. Clin Infect Dis. 2000;30(3):466–72.

    CAS  PubMed  Google Scholar 

  31. Lee DG, Kim SH, Kim SY, Kim CJ, Park WB, Song YG, et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea. Korean J Intern Med. 2011;26(2):220–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dai Z, Chen LY, Cai MJ, Yao YH, Zhu JH, Fang LL, et al. Clinical characteristics and microbiology of nosocomial enterococcal bloodstream infections in a tertiary-level hospital: a retrospective study, 2007–2019. J Hosp Infect. 2022;122:203–10.

    CAS  PubMed  Google Scholar 

  33. Zhang Y, Du M, Chang Y, Chen L-a, Zhang Q. Incidence, clinical characteristics, and outcomes of nosocomial Enterococcus spp. bloodstream infections in a tertiary-care hospital in Beijing, China: a four-year retrospective study. Antimicrob Resist Infect Control. 2017;6(1):73.

    PubMed  PubMed Central  Google Scholar 

  34. Mancuso G, Midiri A, Gerace E, Biondo C. Bacterial antibiotic resistance: the most critical pathogens. Pathogens. 2021;10(10).

  35. Chatterjee A, Johnson CN, Luong P, Hullahalli K, McBride SW, Schubert AM et al. Bacteriophage resistance alters antibiotic-mediated intestinal expansion of Enterococci. Infect Immun. 2019;87(6).

  36. Ceci M, Delpech G, Sparo M, Mezzina V, Sánchez Bruni S, Baldaccini B. Clinical and microbiological features of bacteremia caused by Enterococcus faecalis. J Infect Developing Ctries. 2015;9(11):1195–203.

    CAS  Google Scholar 

  37. Lark RL, Chenoweth C, Saint S, Zemencuk JK, Lipsky BA, Plorde JJ. Four year prospective evaluation of nosocomial bacteremia: epidemiology, microbiology, and patient outcome. Diagn Microbiol Infect Dis. 2000;38(3):131–40.

    CAS  PubMed  Google Scholar 

  38. Artico MJ, Rocchi M, Gasparotto A, Ocaña Carrizo V, Navarro M, Mollo V, et al. [Community-acquired bacteremia in adult patients attending the emergency service of a teaching hospital]. Rev Argent Microbiol. 2012;44(1):10–5.

    PubMed  Google Scholar 


    Google Scholar 

  40. Kristich CJ, Rice LB, Arias CA. Enterococcal infection—treatment and antibiotic resistance. In: Gilmore MS, Clewell DB, Ike Y, Shankar N, editors. Enterococci: from commensals to leading causes of drug resistant infection. Boston: Massachusetts Eye and Ear Infirmary; 2014.

    Google Scholar 

  41. Babar N, Usman J, Munir T, Gill MM, Anjum R, Gilani M, et al. Frequency and antibiogram of vancomycin resistant enterococcus in a tertiary care hospital. J Coll Physicians Surg Pak. 2014;24(1):27–9.

    PubMed  Google Scholar 

  42. Abdulla FE, Abdulla EM. Antibiotic options for Enterococcus Faecalis Infections. Antibiotic options for Enterococcus Faecalis Infections. 2006;22(3):286–90.

    Google Scholar 

  43. Chakraborty A, Pal NK, Sarkar S, Gupta MS. Antibiotic resistance pattern of Enterococci isolates from nosocomial infections in a tertiary care hospital in Eastern India. J Nat Sci Biol Med. 2015;6(2):394–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Asadollahi P, Razavi S, Asadollahi K, Pourshafie MR, Talebi M. Rise of antibiotic resistance in clinical enterococcal isolates during 2001–2016 in Iran: a review. New Microbes New Infect. 2018;26:92–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Napolitano F, Pelullo CP, Lamberti M, Donnarumma G, Di Giuseppe G. Antimicrobial Prescribing Practices in Hospital Settings in Italy: a retrospective study. Antibiotics. 2023;12(2):218.

    PubMed  PubMed Central  Google Scholar 

  46. Gürtler N, Erba A, Giehl C, Tschudin-Sutter S, Bassetti S, Osthoff M. Appropriateness of antimicrobial prescribing in a swiss tertiary care hospital: a repeated point prevalence survey. Swiss Med Wkly. 2019;149(4142):w20135–w.

    PubMed  Google Scholar 

  47. Denny KJ, Gartside JG, Alcorn K, Cross JW, Maloney S, Keijzers G. Appropriateness of antibiotic prescribing in the emergency department. J Antimicrob Chemother. 2019;74(2):515–20.

    CAS  PubMed  Google Scholar 

  48. Akhloufi H, Streefkerk R, Melles D, de Steenwinkel J, Schurink C, Verkooijen R, et al. Point prevalence of appropriate antimicrobial therapy in a dutch university hospital. Eur J Clin Microbiol Infect Dis. 2015;34:1631–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Macera M, Calò F, Onorato L, Di Caprio G, Monari C, Russo A, et al. Inappropriateness of antibiotic prescribing in medical, surgical and intensive care units: results of a multicentre observational study. Life. 2021;11(6):475.

    PubMed  PubMed Central  Google Scholar 

  50. Davey P, Brown E, Charani E, Fenelon L, Gould IM, Holmes A et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane database of systematic reviews. 2013(4).

  51. van den Bosch CM, Hulscher ME, Akkermans RP, Wille J, Geerlings SE, Prins JM. Appropriate antibiotic use reduces length of hospital stay. J Antimicrob Chemother. 2017;72(3):923–32.

    PubMed  Google Scholar 

  52. Nathwani D, Varghese D, Stephens J, Ansari W, Martin S, Charbonneau C. Value of hospital antimicrobial stewardship programs [ASPs]: a systematic review. Antimicrob Resist Infect Control. 2019;8:1–13.

    Google Scholar 

  53. Wang H, Wang H, Yu X, Zhou H, Li B, Chen G, et al. Impact of antimicrobial stewardship managed by clinical pharmacists on antibiotic use and drug resistance in a chinese hospital, 2010–2016: a retrospective observational study. BMJ open. 2019;9(8):e026072.

    PubMed  PubMed Central  Google Scholar 

  54. Atif M, Ihsan B, Malik I, Ahmad N, Saleem Z, Sehar A, et al. Antibiotic stewardship program in Pakistan: a multicenter qualitative study exploring medical doctors’ knowledge, perception and practices. BMC Infect Dis. 2021;21(1):374.

    PubMed  PubMed Central  Google Scholar 

  55. Tillekeratne LG, Bodinayake CK, Dabrera T, Nagahawatte A, Arachchi WK, Sooriyaarachchi A, et al. Antibiotic overuse for acute respiratory tract infections in Sri Lanka: a qualitative study of outpatients and their physicians. BMC Fam Pract. 2017;18(1):1–10.

    Google Scholar 

  56. Fletcher-Lartey S, Yee M, Gaarslev C, Khan R. Why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patient expectations: a mixed methods study. BMJ Open. 2016;6(10):e012244.

    PubMed  PubMed Central  Google Scholar 

  57. Suppli M, Aabenhus R, Harboe ZB, Andersen LP, Tvede M, Jensen JUS. Mortality in enterococcal bloodstream infections increases with inappropriate antimicrobial therapy. Clin Microbiol Infect. 2011;17(7):1078–83.

    CAS  PubMed  Google Scholar 

  58. Freundlich M, Thomsen RW, Pedersen L, West H, Schønheyder HC. Aminoglycosides therapy in patients with bacteraemia. Ugeskr Laeger. 2008;170(6):457–60.

    PubMed  Google Scholar 

  59. Bryan C, Reynolds K, Brown J. Mortality associated with enterococcal bacteremia. Surg Gynecol Obstet. 1985;160(6):557–61.

    CAS  PubMed  Google Scholar 

  60. Stroud L, Edwards J, Danzing L, Culver D, Gaynes R. Risk factors for mortality associated with enterococcal bloodstream infections. Infect Control Hosp Epidemiol. 1996;17(9):576–80.

    CAS  PubMed  Google Scholar 

  61. Shay DK, Maloney SA, Montecalvo M, Banerjee S, Wormser GP, Arduino MJ, et al. Epidemiology and mortality risk of vancomycin-resistant enterococcal bloodstream infections. J Infect Dis. 1995;172(4):993–1000.

    CAS  PubMed  Google Scholar 

Download references


Not applicable.


There is no funding body for this research.

Author information

Authors and Affiliations



Jamil Muqtadir Bhatti: Conceptualization, writing original draft; Yameena Noman Khan & Ali Mala: Writing Reviewing and editing; Ayesha Farooq Alam: Data curation, software; Syed Ali Raza: Visualisation, resources; FNU Sameeullah: Validation, methodology; Irshad Batool Abro: Formal analysis, supervision, project administration.

Corresponding author

Correspondence to Jamil Muqtadir Bhatti.

Ethics declarations

Ethics approval and consent to participate

All experiments have been performed in accordance with the Declaration of Helsinki and the research has been approved by Dr. Ziauddin university ethical review committee on March 11, 2022. Written informed consent was waived by Dr. Ziauddin university ethical review committee.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhatti, J.M., Raza, S.A., Alam, A.F. et al. Antibiotic choices among healthcare professionals for enterococcal bacteremia with patterns of resistance and risk factors of mortality, in settings of poor antibiotic stewardship program — a five-year retrospective cohort study. BMC Infect Dis 23, 514 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: