JAC Advance Access originally published online on August 4, 2006
Journal of Antimicrobial Chemotherapy 2006 58(4):853-856; doi:10.1093/jac/dkl316
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Emergence of multidrug-resistant Gram-negative bacteria during selective decontamination of the digestive tract on an intensive care unit
1 Academic Medical Center, Department of Medical Microbiology Amsterdam, The Netherlands 2 VU University Medical Center, Medical Microbiology and Infection Control Amsterdam, The Netherlands 3 Academic Medical Center, Department of Intensive Care Amsterdam, The Netherlands
*Corresponding author. Academic Medical Center, Department of Medical Microbiology, L1-244, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31-20-5665714; Fax: +31-20-5669745; E-mail: b.duim{at}amc.uva.nl
Received 29 March 2006; returned 23 June 2006; revised 6 July 2006; accepted 12 July 2006
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Abstract |
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Objectives: During treatment with selective decontamination of the digestive tract (SDD), four multidrug-resistant (MDR) strains, three different Escherichia coli and one Klebsiella pneumoniae, were isolated from four patients not known as carriers of such MDR strains before their admission to the intensive care unit (ICU) in the Academic Medical Center (AMC) in Amsterdam. These isolates were extended-spectrum ß-lactamase (ESBL)-positive. We investigated whether this was due to interspecies transfer of resistance genes.
Methods: The MDR strains were typed by amplified fragment length polymorphism (AFLP) analysis. The plasmids from these strains were characterized by restriction fragment length polymorphism and the resistance genes were characterized by PCR and sequence analysis.
Results: The strains were genetically unrelated and contained identical plasmids with ESBL genes.
Conclusions: We identified an outbreak of plasmid-mediated ESBL genes during SDD treatment in the ICU. The use of third-generation cephalosporins in SDD is associated with the emergence of ESBLs. We conclude that identification of emerging MDR Gram-negative bacteria and recognition of resistance plasmid transfer during SDD treatment are crucial for optimal application of this regimen in ICUs.
Keywords: ESBLs , SDD , intensive care , resistance
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Introduction |
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Antimicrobial resistance is a complex and dynamic problem, which leads to excess morbidity, mortality and costs in many clinical settings. A strong association between the use of antibiotics and the emergence of antibiotic resistance has been demonstrated.1 The prevalence of resistance is highest where antibiotic use is high, especially in intensive care units (ICUs).2 Therefore, infection control measures to limit the emergence of antibiotic resistance are important issues in intensive care medicine. Selective decontamination of the digestive tract (SDD) is a prophylactic regimen that was introduced in intensive care medicine in 1984.3 The purpose of SDD is to eliminate potentially pathogenic aerobic microorganisms from the digestive tract without harming the anaerobic flora.4 SDD classically consists of oropharyngeal administration of non-absorbable antimicrobial agents that are active against most Gram-negative bacteria and fungi and decontamination of the rest of the gastrointestinal tract by local administration of the same antibiotics, combined during the first 3–4 days with a parenteral antibiotic to prevent early infections.4
We describe the emergence of four different strains of multidrug-resistant (MDR) Gram-negative bacteria (three Escherichia coli and one Klebsiella pneumoniae) at our ICU. These strains were isolated from patients not carrying these MDR bacteria before their treatment with SDD antimicrobials at the ICU. We investigated whether the isolates carried different resistance genes, indicating independent acquisition, or identical ESBL genes, which may result from horizontal transfer. We provide evidence that these strains harboured the same resistance plasmid, which carried identical extended-spectrum ß-lactamase (ESBL) genes.
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Methods |
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Bacterial strains and SDD
Four MDR Gram-negative bacterial strains (three E. coli and one K. pneumoniae) were isolated from four patients between August and December 2004, treated from the first day of admission until their discharge with SDD in the ICU (Table 1). These MDR Gram-negatives were isolated within a period of 5–8 days of treatment with SDD agents; there was no other antimicrobial therapy during the period of isolation.
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The SDD regimen in our ICU consisted of application four times daily of approximately 0.5 g of an oral paste, containing 2% polymyxin E, 2% tobramycin and 2% amphotericin B, to the buccal cavity. Patients also received 100 mg of polymyxin E, 80 mg of tobramycin and 500 mg of amphotericin B through the gastric tube.5
Cefotaxime 1000 mg four times daily was given intravenously throughout the first 4 days. For surveillance purposes, cultures from rectal swabs, throat swabs and sputum were taken at admission and twice weekly during the stay on the ICU. These were cultured on Columbia agar with tobramycin 4 mg/L for detection of tobramycin-resistant Gram-negative bacteria. All ICU patients with an expected duration of artificial ventilation of >48 h or an anticipated length of stay on the ICU of >72 h were treated with SDD from the first day of admission until discharge from the ICU.
The antimicrobial susceptibility tests in this study were done according to the NCCLS guidelines by the disc diffusion method. The Gram-negative bacteria were screened for ESBL production by the disc diffusion method on Mueller-Hinton agar plates with cefotaxime- and ceftazidime-containing discs (Rosco, Taastrup, Denmark). The double disc synergy test, with discs containing amoxicillin + clavulanate, cefotaxime, ceftazidime and cefepime,6 was used for the confirmation of ESBL production.
Molecular typing
The three MDR E. coli isolates were typed by amplified fragment length polymorphism (AFLP) of genomic DNA. Plasmids were isolated with the QIAgen Plasmid Midi Kit (QIAGEN, Westburg B.V., The Netherlands). Identity of the plasmids was investigated by restriction fragment length polymorphism (RFLP) patterns obtained by digestion with EcoRI and 1.0% agarose Tris-borate-EDTA gel electrophoresis. The plasmids were used for PCR and sequence analysis of ß-lactamase genes as described previously.7
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Results |
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The four strains were ESBL-positive, intermediately susceptible to polymyxin E and resistant to the following antibiotics: tobramycin, gentamicin and ciprofloxacin (Table 1). AFLP analysis confirmed that the three MDR E. coli isolates represented three different strains (Figure 1a). Plasmids from all four strains had identical EcoRI RFLP patterns (Figure 1b). PCR and sequence analysis showed that all four strains harboured identical combinations of ESBL genes: CTX-M-15 and SHV-5.
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Discussion |
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According to our information, this is the first description of infection by different bacterial strains carrying identical plasmids and ESBL genes during treatment with SDD antimicrobials wherein cefotaxime is included.
Besides the considerable inactivation of polymyxin E by faeces,8 the intermediate susceptibility to polymyxin E, the tobramycin resistance and the production of ESBLs explain the survival of these strains during the SDD regimen used in our ICU. Our results show that these four different MDR strains that were isolated from four different patients, who were treated with SDD antimicrobials for >4 days, contained the same plasmid with an identical ESBL gene (Figure 1 and Table 1).
In the routine surveillance cultures, obtained from these patients before SDD, the MDR Gram-negatives were not detected. This leaves three possibilities: (i) these strains were present below the detection level, and subsequently increased in numbers, above the detection level, during SDD therapy; (ii) the patients acquired the strains carrying the resistance plasmid; or (iii) the strains, already present in the patients, acquired the resistance plasmid. The identity of the resistance plasmids may suggest one of the latter two scenarios, although there are no data available on the presence of this resistance plasmid in the community. Any of the possibilities suggest a correlation between the treatment with the SDD antimicrobials and the emergence of these ESBL-producing Gram-negative bacterial strains.
The patients, from whom these MDR strains were isolated, were placed in isolation till their discharge from the ICU. During this period the SDD treatment was continued. The implications of this outbreak were serious, as patient IV was treated for 6 weeks for presumed osteomyelitis of the sternum after cardiac surgery due to infection caused by this MDR E. coli. Fortunately, there were no invasive infections with these strains observed in the other three patients.
At present, cefotaxime is the most common systemic antibiotic used in SDD regimens.9 The use of third-generation cephalosporins is associated with emergence and increase in the prevalence of ESBLs.10 However, in all studies that evaluated the SDD wherein cefotaxime is used, there was no optimal screening of ESBLs.9 Gram-negative bacterial infections in ICUs are associated with increased mortality.11 Therefore, for optimal evaluation of the SDD regimen in ICUs, screening for ESBLs should be included.
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None to declare.
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Acknowledgements |
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We thank L. Spanjaard and the members of the infection control unit of the AMC for their support in collecting these data.
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References |
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1 Husni RN, Goldstein LS, Arroliga AC, et al. (1999) Risk factors for an outbreak of multi-drug-resistant Acinetobacter nosocomial pneumonia among intubated patients. Chest 115:1378–82.
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Chen HY, Yuan M, Ibrahim-Elmagboul IB, et al. (1995) National survey of susceptibility to antimicrobials amongst clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother 35:521–34.
3 Stoutenbeek CP, van Saene HK, Miranda DR, et al. (1984) The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med 10:185–92.[CrossRef][Web of Science][Medline]
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Bonten MJ, Kullberg BJ, van Dalen R, et al. (2000) Selective digestive decontamination in patients in intensive care. The Dutch Working Group on Antibiotic Policy. J Antimicrob Chemother 46:351–62.
5 de Jonge E, Schultz MJ, Spanjaard L, et al. (2003) Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 362:1011–6.[CrossRef][Web of Science][Medline]
6 Livermore DM and Brown DF. (2001) Detection of beta-lactamase-mediated resistance. J Antimicrob Chemother 48:Suppl 1, 59–64.[Abstract]
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Al Naiemi N, Duim B, Savelkoul PH, et al. (2005) Widespread transfer of resistance genes between bacterial species in an intensive care unit: implications for hospital epidemiology. J Clin Microbiol 43:4862–4.
8 van Saene JJ, van Saene HK, Stoutenbeek CP, et al. (1985) Influence of faeces on the activity of antimicrobial agents used for decontamination of the alimentary canal. Scand J Infect Dis 17:295–300.[Web of Science][Medline]
9 de Jonge E. (2005) Effects of selective decontamination of digestive tract on mortality and antibiotic resistance in the intensive-care unit. Curr Opin Crit Care 11:144–9.[CrossRef][Web of Science][Medline]
10
Patterson JE. (2001) Antibiotic utilization: is there an effect on antimicrobial resistance? Chest 119:426S–30S.
11 Luiten EJ, Hop WC, Lange JF, et al. (1995) Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 222:57–65.[Web of Science][Medline]
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