Selective Digestive and Oropharyngeal Decontamination

in medical and surgical ICU-patients;

An individual patient data meta-analysis

Supplementary material

Supplementaryfigure 1: Flowchart of included studies

Supplementaryfigure 2: Flowchart of patients per analysis

Supplementary table 1. Results of an additional analysis on the effect of SDD and SOD on hospital survival in medical and surgical survivors of the first ICU-admission (two-stage meta-analysis, fixed pooled effect)

Nr. of survivors of the first ICU-admission / Crude hospital mortality / Adjusted analysis (aOR, 95%-CI) A
SDD / SOD / control / SDD vs. control / SOD vs. control / SDD vs. SOD
Overall
(N=12,851) / 641/5,900
10.9% / 524/4,856
10.8% / 233/2,095
11.1% / 1.07 (0.88 – 1.30) / 0.86 (0.69 – 1.10) / 0.98 (0.86 – 1.12)
Medical
(N=7,072)) / 368/3,243
11.3% / 326/2,845
11.5% / 133/939
14.2% / 0.89 (0.68 – 1.17) / 0.73 (0.53 – 1.00) / 0.96 (0.81 – 1.13)
Surgical
(N=5,818)115) / 273/2,656
10.3% / 198/2,011
9.8% / 100/1,151
8.7% / 1.26 (0.95 – 1.67) / 1.07 (0.75 – 1.53) / 1.02 (0.83 – 1.25)
Measure of interaction on multiplicative scale:
Ratio of ORs (95%-CI) surgical vs. medical / 1.36 (0.91 – 2.04)
P=0.13 / 1.48 (0.92 – 2.38)
P=0.11 / 1.04 (0.80 – 1.36)
P=0.77

Legend: aOR, adjusted OR; NNT, number needed to treat; SDD, selective digestive decontamination; SOD, selective oropharyngeal decontamination

Footnote: A, models of multicentre studies were corrected for centre, models of cluster-randomized trials were corrected for age, gender, admission type (medical or surgical) and APACHE II/IV score and - when available - mechanical ventilation on ICU-admission

Supplementary table 2. Rates of individual antibiotic use per ICU-admission day within the study by de Smet et al.

Nr. of included patients per ICU-admission day
day_1* / day_2 / day_3 / day_4 / day_5 / day_6 / day_7 / day_8 / day_9 / day_10
control / 1986 / 1982 / 1942 / 1834 / 1634 / 1448 / 1270 / 1126 / 989 / 899
SOD / 1904 / 1896 / 1853 / 1758 / 1616 / 1454 / 1273 / 1118 / 988 / 874
SDD / 2033 / 2029 / 1988 / 1867 / 1669 / 1496 / 1330 / 1180 / 1030 / 914
Total / 5923 / 5907 / 5783 / 5459 / 4919 / 4398 / 3873 / 3424 / 3007 / 2687
Nr. of patients with systemic antibiotics **
day_1* / day_2 / day_3 / day_4 / day_5 / day_6 / day_7 / day_8 / day_9 / day_10
control / 1087 / 1263 / 1226 / 1142 / 1071 / 984 / 867 / 763 / 673 / 578
SOD / 1012 / 1217 / 1197 / 1151 / 1097 / 992 / 859 / 732 / 627 / 542
SDD / 1354 / 1717 / 1771 / 1685 / 1422 / 1060 / 799 / 645 / 525 / 449
Total / 3453 / 4197 / 4194 / 3978 / 3590 / 3036 / 2525 / 2140 / 1825 / 1569
Proportion of admitted patients with systemic antibiotics (per admission day)
day_1* / day_2 / day_3 / day_4 / day_5 / day_6 / day_7 / day_8 / day_9 / day_10
control / 54,7% / 63,7% / 63,1% / 62,3% / 65,5% / 68,0% / 68,3% / 67,8% / 68,0% / 64,3%
SOD / 53,2% / 64,2% / 64,6% / 65,5% / 67,9% / 68,2% / 67,5% / 65,5% / 63,5% / 62,0%
SDD / 66,6% / 84,6% / 89,1% / 90,3% / 85,2% / 70,9% / 60,1% / 54,7% / 51,0% / 49,1%
Mean(total) / 58,3% / 71,1% / 72,5% / 72,9% / 73,0% / 69,0% / 65,2% / 62,5% / 60,7% / 58,4%
SDD vs. SOD
absolute difference / 13,4% / 20,4% / 24,5% / 24,8% / 17,3% / 2,6% / -7,4% / -10,8% / -12,5% / -12,9%
relativedifference (SDD=ref) / 20,2% / 24,1% / 27,5% / 27,5% / 20,3% / 3,7% / -12,3% / -19,8% / -24,5% / -26,2%
Footnotes
* day_1 = day of ICU-admission
** systemic antibiotics include penicillins, carbapenems, cephalosporins, quinolones, clindamycin, and a selection of other antibiotics (mainly aminoglycosides, tetracyclins, antifungals, macrolides, sulfonamide/trimethoprim, metronidazol, teicoplanin and colistin); definitions conform the priorly reported Table 5 in NEJM 2009 360:1, 20-31.1

Supplementary figure 3. Proportion of patient days with systemic antibioticswithin the study by de Smet et al.

Footnotes

* day_1 = day of ICU-admission

Systemic antibiotics include penicillins, carbapenems, cephalosporins, quinolones, clindamycin, and a selection of other antibiotics (mainly aminoglycosides, tetracyclins, antifungals, macrolides, sulfonamide/trimethoprim, metronidazol, teicoplanin and colistin); definitions conform the priorly reported Table 5 in NEJM 2009 360:1, 20-31. 1

.

Supplementarytable 3. Setting of included studies with regard to antibiotic resistance.

Study
  • Location
  • Inclusion period
  • Nr. of inclusions in original studies
/ Citations and/or numbers from original publications concerning prevalence of antibiotic resistance
Bergmans et al. 20012
  • Maastricht Groningen (NL)
  • 1994 –1996
  • N=226
/ “No vancomycin-resistant enterococci (VRE) were isolated in either hospital before, during, or after the study. No increase in the number of patients colonized or infected with microorganisms resistant to gentamicin was observed during the study. Separate analysis of the resistance patterns of the pathogens causing VAP did not reveal cases of acquired resistance to the antibiotics used in the oropharyngeal paste.”
Krueger et al. 20023
  • Munich & Augsburg (D)
  • 1990 - 1992
  • N=527
/ Nr. of patients colonized with resistant species on admission (surveillance sampling included tracheobronchial, oropharyngeal, and gastric secretions, and rectal swabs)
  • Oxacillin resistant S. aureus: 2/410 (0.5%)
  • Colistin resistant K. pneumoniae/E.coli: 3/410 (0.7%)
  • Colistin resistant P. aeruginosa: 4/410 (1.0%)

De Jonge et al. 20034
  • Amsterdam (NL)
  • 1999-2001
  • N=934
/ Nr. of patients colonized with resistant species at inclusion (surveillance sampling included sputum, throat, rectum, axilla, and wound samples)
  • Ceftazidime or tobramycin resistant P. aeruginosa: 4/868 (0.5%)
  • Imipenem resistant GNB: 2/868 (0.2%)
  • VRE: 10/868 (1.2%)
  • MRSA: 0/868 (0.0%)

Camus et al. 20055
  • Rennes, Brest & Tours (F)
  • 1996 - 1998
  • N=515
/ Nr. of infections with GNB resistant to:
  • Polymyxin: 34 (only GNB with intrinsic resistanceto polymyxins)
  • Tobramycin: 64
  • MRSA: 24 6

De Smet et al. 2009 1
  • 13 hospitals throughout the country (NL)
  • 2004 - 2006
  • N=5,939
/ Results from monthly point prevalence screenings
-“For all pathogen–antibiotic combinations [E. coli, K. pneumoniae, P. aeruginosa, E. cloacae with gentamycin, tobramycin, ciprofloxacin and ceftazidime], the rate of nonsusceptibility was less than 5%”
-“There were no patients with MRSA”
-“Eight patients had VRE”
Oostdijk et al. 2017 7
  • 16 hospitals throughout the country (NL)
  • 2009-2012
  • N=11,997
/ Results from monthly point prevalence screenings (including 3799 patients with a rectal culture and 3714 with a respiratory sample):
Rectal samples
  • HRMO: 377
  • ESBL: 229
  • VRE: 15
  • GNB nonsusceptible to tobramycin or gentamycin: 329
  • GNB nonsusceptible to ciprofloxacin: 301
  • GNB nonsusceptible to colistin: 36
  • GNB nonsusceptible to carbapenems-R: 36
Respiratory samples
  • HRMO: 108
  • ESBL: 48
  • GNB nonsusceptible to tobramycin or gentamycin: 122
  • GNB nonsusceptible to ciprofloxacin: 96
  • GNB nonsusceptible to colistin: 17
  • GNB nonsusceptible to carbapenems-R: 41
Nr. of ICU-acquired bacteraemia with:
  • HRMO: 54
  • ESBL: 13
  • GNB nonsusceptible to tobramycin or gentamycin: 51
  • GNB nonsusceptible to colistin-R: 4
  • VRE: 3
  • MRSA: 2

Legend: D, Germany; ESBL, extend spectrum beta-lactamase; F, France GNB, gram-negative bacteria; HRMO, highly-resistant micro-organism; ICU, intensive care unit; MRSA, methicillin-resistant S. aureus; NL, the Netherlands; VRE, vancomycin-resistant Enterococci

References

1.de Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in ICU patients. The New England journal of medicine 2009; 360(1): 20-31.

2.Bergmans DC, Bonten MJ, Gaillard CA, et al. Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. American journal of respiratory and critical care medicine 2001; 164(3): 382-8.

3.Krueger WA, Lenhart FP, Neeser G, et al. Influence of combined intravenous and topical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortality in critically ill surgical patients: a prospective, stratified, randomized, double-blind, placebo-controlled clinical trial. American journal of respiratory and critical care medicine 2002; 166(8): 1029-37.

4.de Jonge E, Schultz MJ, Spanjaard L, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet (London, England) 2003; 362(9389): 1011-6.

5.Camus C, Bellissant E, Sebille V, et al. Prevention of acquired infections in intubated patients with the combination of two decontamination regimens. Critical care medicine 2005; 33(2): 307-14.

6.Camus C, Sebille V, Legras A, et al. Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients. Infection 2014; 42(3): 493-502.

7.Oostdijk EAN, Kesecioglu J, Schultz MJ, et al. Notice of Retraction and Replacement: Oostdijk et al. Effects of Decontamination of the Oropharynx and Intestinal Tract on Antibiotic Resistance in ICUs: A Randomized Clinical Trial. JAMA. 2014;312(14):1429-1437. Jama 2017; 317(15): 1583-4.