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Risk factors for acquisition of gentamicin-resistant enterococcal infection: a case-controlled study
  1. M Viagappan,
  2. R E Holliman
  1. Department of Medical Microbiology, St George's Hospital & Medical School, Blackshaw Road, London SW17 0QT, UK


    High-level gentamicin-resistant enterococci present problems in the treatment of infected patients, especially as synergy between penicillin and gentamicin is lost. Previous studies have suggested various risk factors for the acquisition of these enterococci. A case-controlled study was performed on 17 patients infected with resistant enterococci and 26 infected with sensitive strains who attended a London hospital. The key risk factors for acquisition of infection with high-level gentamicin-resistant enterococci were found to be prior prolonged antibiotic treatment, use of five or more antibiotics, and the presence of a urinary catheter. It is proposed that infection control measures should be targeted at patients at higher risk. In addition, control of antibiotic usage in a hospital may help to prevent acquisition and spread of these organisms.

    • gentamicin-resistant enterococci
    • enterococcal infection

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    Infection with high-level gentamicin-resistant (HLGR) enterococci is an increasing clinical problem.1 2 Studies from North America suggest nosocomial spread as the major route of acquisition.1 3-5 A number of features, including length of hospital stay and antibiotic usage, have been identified as risk factors for acquisition of these organisms.

    Studies of the epidemiology of HLGR enterococcal infection have not been performed in the UK. A study was undertaken to see if colonisation factors identified in the USA were consistent with infection-related factors in a UK hospital and whether further risk factors could be detected. With the identification of important risk factors, appropriate control measures might be introduced to control the spread of infection with these organisms or prevent their emergence from the outset.


    The study was based on retrospective review of hospital patients' notes.


    The case definition was a patient from whom a blood culture isolate of HLGR enterococcus had been grown and who had documented evidence of a clinical infection attributable to this organism. Patients were identified using the blood culture records kept in the microbiology department of the hospital and from hospital case notes. For each patient with HLGR enterococci isolated from blood cultures and who fitted the case definition, the previous and (where possible) next patient listed in the blood culture isolate book with a gentamicin-sensitive enterococcus were chosen as controls.


    All enterococci isolated from blood cultures were reviewed over a 2-year period. These isolates were retrieved from nutrient agar slopes (Oxoid CM 3) and plated out onto 5% horse blood agar to check for viability and purity prior to antibiotic testing. Definitive identification of organisms used the API 20 STREP system.


    HLGR strains were defined as those with a minimum inhibitory concentration (MIC) of >1000 μg/ml. MIC testing was undertaken using the multi-point inoculation method. Mueller-Hinton agar plates (Oxoid CM337) were prepared and gentamicin incorporated at concentrations of 0.5, 1, 2, 4, 8, 16, and 1000 μg/ml. Plates were also prepared without antibiotic to check for satisfactory bacterial growth. Each isolate was inoculated into brain heart infusion broth (Oxoid CM225) incubated at 37ºC overnight to produce an organism concentration of approximately 107 cfu/ml. An inoculum of this suspension was delivered to the plates by a manual inoculator delivering 1 μl (104 cfu) per spot. The plates were then incubated at 37ºC in air for 24 hours and examined using a magnifying glass to establish the lowest concentration of antibiotic which inhibited growth.


    The notes of all patients with enterococcal infection were reviewed. Patient details were collected according to the protocol of Axelrod et al.4 Information collected on a standard form included location of the patient, microbiological results, clinical details prior to the isolation of enterococci, and type and duration of antibiotic therapy during the current admission and from any referring hospital. The presence of a urinary or vascular catheter at any time during the admission was noted.


    Analysis of findings was performed by comparing clinical and demographic features in patients with sensitive enterococcal infection and those infected with HLGR enterococci. Significance levels were calculated using the EPI Info 5 software package for Epidemiology and Disease surveillance.


    A total of 17 patients infected with HLGR enterococci and 26 patients infected with susceptible strains were identified. A comparison of clinical features between the two groups is presented in table 1.

    Table 1

     Comparison of clinical features in patients infected with enterococci highly resistant or sensitive to gentamicin

    There was no association between infection with HLGR enterococci and sex or length of hospital stay. No increase in HLGR enterococcal infection was found in patients over 60 years old, but a significant number of patients with a sensitive strain were young babies. No one age group appeared to be linked to an increased risk of acquiring resistant enterococci. There was a strong association found between sensitiveenterococcal infection and admission to the special care baby unit, but no HLGR enterococcus was isolated from a child on the special care baby unit.

    An association was detected between HLGR enterococcal infection and the presence of a urinary catheter but not with the presence of intravascular catheters. There was a marked association between HLGR enterococcal infection and previous antibiotic therapy. Most patients with HLGR infection had previous antibiotic treatment. In patients who had not received antibiotics the infection was usually due to sensitive enterococcus. Use of five or more antibiotics and treatment for 14 days or more were both associated with HLGR enterococcal infection. HLGR enterococcal infection was more frequently found with prior cephalosporin therapy but not with penicillin or gentamicin. The cephalosporins used, with one exception, were second or third generation.

    Table 2 gives a summary of clinical details and the suspected source of sepsis. Bacteraemia was mostly associated with sepsis of the gastrointestinal or biliary tract, although line and urinary sources were noted in some cases.

    Table 2

     Clinical details and source of sepsis

    Table 3 gives the full set of known antibiotic sensitivities. Of 28 gentamicin-sensitive isolates, seven were resistant to ampicillin (three E faecalis, threeE faecium, one not speciated). Out of 17 gentamicin-resistant isolates, three were resistant to ampicillin (one each of E faecalis, andE faecium and one not speciated).

    Table 3

     Antibiotic susceptibility findings


    HLGR enterococci can cause difficulties in selecting appropriate therapy when clinical infection is present. The most important example is the loss of synergy between the aminoglycoside and penicillin,6 which presents problems in treating endocarditis. As HLGR enterococci become more common, serious infections such as endocarditis and osteomyelitis caused by them cannot be treated satisfactorily.7-9 Consequently, there is a need to limit the spread of these organisms by appropriate control of infection procedures.

    An important step in controlling the spread of this organism is to identify the risk factors for acquisition and target infection control measures to ‘at risk’ patients, or preferably avoid the risk factors for acquisition from the start. This study demonstrated that patients were more likely to be infected with HLGR enterococci if they had prior antibiotic therapy, if they had received treatment with more than four antibiotics, or if therapy had included a cephalosporin. They were also more likely to be infected if they had a urinary catheter. Patients less likely to be infected with a HLGR enterococci were those who had received no prior antibiotic therapy and babies on the special-care baby unit.

    Previous workers have shown an association between colonisation or infection with HLGR enterococci and hospital stay of 14 days or longer.5 Such an association was not shown in the present study. However, our study was limited to patients with suspected enterococcal infection only and excluded colonisation.

    Control of hospital spread of HLGR enterococci might be achieved by screening for carriage and subsequent isolation of carriers. It is important to decide in advance which group of patients it would be most effective to screen, and it must be clear why screening is being done. The aims of screening and isolation would be to protect the individual patient from infection with resistant enterococci, particularly patients at risk of endocarditis and osteomyelitis where synergistic therapy with a beta-lactam and an aminoglycoside would be used. Additional aims would be to prevent cross-infection of other patients and prevent spread to neighbouring hospitals. Rather than swab all patients, some workers have suggested that it would be a more efficient use of hospital resources to target a high-risk population of patients such as those identified in this and other studies10 as being at enhanced risk for HLGR enterococcal infection.

    Learning points

    • HLGR enterococcal endocarditis or osteomyelitis may fail to respond to conventional combination antibiotic therapy

    • HLGR enterococcal infection is associated with prolonged antibiotic therapy, use of five or more antibiotics and the presence of a urinary catheter

    • infection control measures should seek to control risk factors for the acquisition of HLGR enterococcal infection

    An alternative strategy would be to limit potential risk factors in an attempt to prevent resistance emerging. Such a policy would include strict control of antibiotic usage on the ward and the avoidance of unnecessarily prolonged courses of antibiotics or unnecessary long-term urinary catheterisation. Prospective studies are required to evaluate the relative merits of these procedures.