Effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant Staphylococcus aureus in a medical/surgical intensive care unit

doi:10.1016/j.jhin.2003.09.021

Journal of Hospital Infection

Volume 56, Issue 3, March 2004, Pages 175-183

https://doi.org/10.1016/j.jhin.2003.09.021 Get rights and content

Abstract

A prospective trial was undertaken to assess the effectiveness and safety of enteral vancomycin in controlling methicillin-resistant Staphylococcus aureus (MRSA) in an endemic setting. Over the 49 month period patients aged >14 years were enrolled, following admission to a medical/surgical intensive care unit (ICU) and expected to require ventilation for three days or more. A total of 799 patients were included in the trial. Period one, 1 July 1996–30 April 1997, (N=140), was observational. During period two, 1 May 1997–30 September 1998, (N=258), surveillance samples were obtained. MRSA carriers were isolated and received enteral vancomycin. During period three, 1 October 1998–31 July 2000, (N=401), all ventilated patients were given selective digestive decontamination (SDD) with polymyxin E, tobramycin, amphotericin B and vancomycin and four days of intravenous cefotaxime. The primary endpoints were: (1) incidence of patients with diagnostic samples positive for MRSA acquired on the ICU; (2) incidence of patients with vancomycin-resistant enterococci (VRE) in surveillance or diagnostic samples; (3) incidence of patients with samples positive for S. aureus with intermediate sensitivity to glycopeptides (GISA). The incidence of patients with MRSA in diagnostic samples were 31%, 14%, and 2% in periods one, two and three, respectively (P<0.001). There was a VRE outbreak involving 13 patients during period three. VRE disappeared with no change in policy. GISA was not detected. These findings support the effectiveness and safety of enteral vancomycin in the control of MRSA.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious diagnostic and epidemiological problem.1., 2. Systemic vancomycin is the first choice for the therapy of invasive infections due to MRSA. It is, however, potentially toxic and there are even growing concerns about the emergence of micro-organisms resistant to vancomycin, such as enterococci (VRE)³ and S. aureus with intermediate sensitivity to glycopeptide (GISA).⁴

The traditional approach to control MRSA includes: (1) screening of nasal MRSA carriers in selected high-risk areas; (2) topical mupirocin to eradicate nasal carriage; (3) hand hygiene and isolation to prevent MRSA transmission;5., 6. (4) systemic vancomycin in case of suspected infection. Despite reports of sporadic success, the prevalence of MRSA is steadily increasing in most countries, which illustrates the failure of this conventional approach.7., 8.

Outbreaks due to multi-resistant Klebsiella spp. have been brought under control using enteral polymyxin combined with neomycin or tobramycin.9., 10. The aim of this approach is the prevention of the carriage and overgrowth of multi-resistant aerobic Gram-negative bacilli (AGNB) in the digestive tract. Enteral polyenes have been used to control outbreaks of yeasts such as Candida parapsilosis resistant to fluconazole.¹¹ The gut is considered to be a major reservoir of potential pathogens resistant to antimicrobials, including MRSA.12., 13., 14., 15., 16.

Enteral vancomycin has been reported to eradicate Clostridium difficile¹⁷ and methicillin-susceptible S. aureus¹⁸ from the gut without any harmful side effects. Consequently, a new protocol using enteral vancomycin to eradicate MRSA carriage was designed, following the successful control of multi-resistant AGNB using enteral polymyxin E/tobramycin and the absence of harmful side effects from enteral vancomycin.

Over four years a prospective study was undertaken to evaluate the effectiveness and safety of this protocol in the control of endemic MRSA.

Section snippets

Patients

Patients expected to require mechanical ventilation for at least three days were enrolled consecutively over a period of 49 months (1 July 19967–31 July 2000). The setting was an adult medical/surgical intensive care unit (ICU) in the University Hospital of Getafe. The study was approved by the Ethical Committee of Clinical Research of the hospital.

Design and interventions

This prospective four-year study comprised three different periods (Table I). Throughout the whole study, high standards of infection control were

Surveillance samples

Surveillance samples of throat and rectal swabs were processed qualitatively and semiquantitatively. Screening samples were not pooled as pooling did not allow the detection of overgrowth. A salt staphylococcal solid agar plate was inoculated using the four-quadrant method combined with brain–heart infusion broth. Each swab was streaked on to the solid medium, then the tip was broken off into 5 mL enrichment broth. The staphylococcal plate was incubated at 35 °C and examined after two nights.

Results

In total 799 patients were enrolled in the study, 140 in period one, 258 in period two and 401 in period three (Table II). There were no significant differences between the three periods, except for the length of stay, which was shorter in period three compared with period one.

The number of patients with imported positive diagnostic samples was eight (5.7%) in period one, nine (3.5%) in period two and 20 (4.9%) in period three. The number of patients with overgrowth in surveillance samples on

Discussion

Five findings emerge from this four-year study of approximately 800 mechanically ventilated patients: (1) enteral vancomycin was effective in reducing the rates of MRSA carriers and MRSA colonization/infection in an ICU where MRSA was endemic; (2) the preventative administration of enteral vancomycin to the population at risk was more effective than the administration of enteral vancomycin to established carriers; (3) there was no emergence of GISA, although a four month VRE outbreak of 13

Acknowledgements

We are grateful to Dr Paul Baines and Ms Nia Taylor for reviewing the manuscript. This study was partially supported with the grant Respira C 03/11 of Fondo de Investigación Sanitaria.

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Selective digestive decontamination (SDD) is a prophylactic strategy aimed at preventing or eradicating the bacterial overgrowth in the intestinal flora that precedes the development of most infections in the ICU. SDD prevents serious infections, reduces mortality, is cost-effective, has no adverse effects, and its short- or long-term use does not show a significant increase in antimicrobial resistance.SDD is one of the most evaluated interventions in critically ill patients, yet its use is not widespread. The aim of this article is to present a narrative review of the most relevant evidence and an update of the pathophysiological concepts of infection control supporting the use of SDD.
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The objective of this systematic review is to assess the effect of selective digestive decontamination (SDD) or non-absorbable enteral antibiotics (EA) on mortality, the incidence of infection and its adverse effects in burn patients.
Systematic review of randomized clinical trials (RCT) or observational studies enrolling burn patients, and comparing SDD or EA prophylaxis with placebo or no treatment. The search includes Pubmed/Medline, EMBASE, WOS, Cochrane Library (1970–2015). Bibliographic references were also reviewed, as well as communications presented at conferences (2012–2015), without language restrictions.
Two reviewers inspected each reference identified by the search independently; the risk of bias was assessed with the Cochrane Collaboration method for RCT and the Newcastle Ottawa Scale for observational studies.
Five RCT and 5 observational studies were identified enrolling a total of 1680 patients. The overall methodological quality of the studies was poor. The pooled effect of RCT using EA was OR: 0.62 (95% CI: 0.20–1.94). The only RCT using SDD reported OR 0.20 (95% CI: 0.09–0.81). The incidence of Enterobacteriaceae bloodstream was lower in cases treated with SDD or EA. The incidence of pneumonia was only reduced in the studies using SDD. None of the studies reported an increase in antibiotic resistance but in one RCT SDD was associated to an increase in methicillin-resistant Staphylococcus aureus infections, that was controlled with enteral vancomycin.
SDD and EA have shown a beneficial effect in burn patients. Both practices are safe. Higher quality RCTs should be conducted to properly assess the efficacy and safety of SDD in this population.
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Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of health care–associated infections. Although the evidence in support of MRSA screening has been promising, a number of questions remain about the effectiveness of active surveillance.
We searched the literature for studies that examined MRSA acquisition, MRSA infection, morbidity, mortality, harms of screening, and resource utilization when screening for MRSA carriage was compared with no screening or with targeted screening. Because of heterogeneity of the data and weaknesses in study design, meta-analysis was not performed. Strength of evidence (SOE) was determined using the system developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group.
One randomized controlled trial and 47 quasi-experimental studies met our inclusion criteria. We focused on the 14 studies that addressed health care–associated outcomes and that attempted to control for confounding and/or secular trends, because those studies had the potential to support causal inferences. With universal screening for MRSA carriage compared with no screening, 2 large quasi-experimental studies found reductions in health care–associated MRSA infection. The SOE for this finding is low. For each of the other screening strategies evaluated, this review found insufficient evidence to determine the comparative effectiveness of screening.
Although there is low SOE that universal screening of hospital patients decreases MRSA infection, there is insufficient evidence to determine the consequences of universal screening or the effectiveness of other screening strategies.
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A methicillin-resistant Staphylococcus aureus (MRSA) outbreak occurred in an advanced emergency medical service center between 2010 and 2011. Our objective was to evaluate the status of the MRSA outbreak, as monitored by molecular analysis. Twenty-eight MRSA strains were isolated from blood samples from 11 patients, from other specimens (pharynx, nasal cavity, etc.) from 12 patients, from two environmental samples, and from the skin, middle nasal meatus, and urine of one patient each from other wards. Pulsed-field gel electrophoresis (PFGE) was performed to evaluate horizontal transmission. Molecular typing by PFGE showed that the 28 MRSA strains presented 7 patterns in total, and that 11 of the MRSA strains had the same PGFE pattern. Unselective use of intranasal mupirocin ointment, MRSA monitoring for new inpatients, and prevention of direct or indirect contact infection were performed. However, the number of inpatients with MRSA did not quickly decrease, and additional molecular typing by PFGE showed that 10 of 19 MRSA strains found (5 of 6 from blood, 5 of 13 from other specimens) were the same as those found previously. Lectures and ward rounds were performed repeatedly, and staff participation in ward rounds was suggested. Finally, the number of inpatients with MRSA significantly decreased more than 6 months after the intervention. Although the MRSA outbreak was thought to have ended, follow-up molecular typing by PFGE showed that horizontal transmission persisted. Our data suggest that various combinations of infection control measures are essential when dealing with an MRSA outbreak, and monitoring by molecular analysis using PFGE is useful to identify the status of the outbreak.
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Citation Excerpt :
Of the 64 studies, the most common country of origin was the Netherlands (18 studies; 28%), but studies were also done in countries with higher baseline prevalences of antimicrobial resistance such as France (ten studies; 16%), Spain (seven studies; 11%), the UK (six studies; 9%), the USA (six studies; 9%), and Germany (five studies; 8%). There were three groups of repeat studies examining different antimicrobial resistance outcomes in the same study populations, including follow-up studies from de Smet and colleagues,12,79,80,82,84–86 Leone and colleagues,66,70,75 and de La Cal and colleagues.71,74 After removal of secondary publications from these datasets, there were a total of 28 852 unique patients; the median number of patients per study was 150 (IQR 76–324), including a median of 76 patients receiving SDD or SOD (IQR 34–146).
Many meta-analyses have shown reductions in infection rates and mortality associated with the use of selective digestive decontamination (SDD) or selective oropharyngeal decontamination (SOD) in intensive care units (ICUs). These interventions have not been widely implemented because of concerns that their use could lead to the development of antimicrobial resistance in pathogens. We aimed to assess the effect of SDD and SOD on antimicrobial resistance rates in patients in ICUs.
We did a systematic review of the effect of SDD and SOD on the rates of colonisation or infection with antimicrobial-resistant pathogens in patients who were critically ill. We searched for studies using Medline, Embase, and Cochrane databases, with no limits by language, date of publication, study design, or study quality. We included all studies of selective decontamination that involved prophylactic application of topical non-absorbable antimicrobials to the stomach or oropharynx of patients in ICUs, with or without additional systemic antimicrobials. We excluded studies of interventions that used only antiseptic or biocide agents such as chlorhexidine, unless antimicrobials were also included in the regimen. We used the Mantel-Haenszel model with random effects to calculate pooled odds ratios.
We analysed 64 unique studies of SDD and SOD in ICUs, of which 47 were randomised controlled trials and 35 included data for the detection of antimicrobial resistance. When comparing data for patients in intervention groups (those who received SDD or SOD) versus data for those in control groups (who received no intervention), we identified no difference in the prevalence of colonisation or infection with Gram-positive antimicrobial-resistant pathogens of interest, including meticillin-resistant Staphylococcus aureus (odds ratio 1·46, 95% CI 0·90–2·37) and vancomycin-resistant enterococci (0·63, 0·39–1·02). Among Gram-negative bacilli, we detected no difference in aminoglycoside-resistance (0·73, 0·51–1·05) or fluoroquinolone-resistance (0·52, 0·16–1·68), but we did detect a reduction in polymyxin-resistant Gram-negative bacilli (0·58, 0·46–0·72) and third-generation cephalosporin-resistant Gram-negative bacilli (0·33, 0·20–0·52) in recipients of selective decontamination compared with those who received no intervention.
We detected no relation between the use of SDD or SOD and the development of antimicrobial-resistance in pathogens in patients in the ICU, suggesting that the perceived risk of long-term harm related to selective decontamination cannot be justified by available data. However, our study indicates that the effect of decontamination on ICU-level antimicrobial resistance rates is understudied. We recommend that future research includes a non-crossover, cluster randomised controlled trial to assess long-term ICU-level changes in resistance rates.
None.
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Effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant Staphylococcus aureus in a medical/surgical intensive care unit

Abstract

Introduction

Section snippets

Patients

Design and interventions

Surveillance samples

Results

Discussion

Acknowledgements

J Hosp Infect

J Hosp Infect

J Hosp Infect

Lancet

Am J Infect Control

Curr Anaesth Crit Care

J Hosp Infect

J Hosp Infect

J Hosp Infect

Am J Infect Control

Revised guidelines for the control of methicillin-resistant Staphylococcus aureus infections in hospitals

J Hosp Infect

Control of endemic methicillin-resistant Staphylococcus aureus: a cost–benefit analysis in an intensive care unit

JAMA

for the glycopeptide-intermediate Staphylococcus aureus working group. Emergence of vancomycin resistance in Staphylococcus aureus

N Engl J Med

Vancomycin-resistant Staphylococcus aureus: perspectives on measures needed for control

Ann Intern Med

Methicillin-resistant Staphylococcus aureus (MRSA): a briefing for acute care hospital and nursing facilities

Infect Control Hosp Epidemiol

Methicillin-resistant Staphylococcus aureus in Europe

Eur J Clin Microbiol Infect Dis

Intestinal decontamination for control of nosocomial multiresistant Gram-negative bacilli

Ann Intern Med

Prospective study of infection, colonisation and carriage of methicillin-resistant Staphylococcus aureus affecting 900 patients

Eur J Clin Microbiol Infect Dis