Luciano Silvestri

Prevention of MRSA pneumonia by oral vancomycin decontamination: a randomised trial

This study was undertaken to assess whether oropharyngeal vancomycin may control oropharyngeal carriage and lower airway infection due to methicillin‐resistant Staphylococcus aureus (MRSA) acquired in the intensive care unit (ICU). Secondary endpoints were the emergence of vancomycin-resistant enterococci, vancomycin-intermediate S. aureus and vancomycin consumption. A total of 84 patients, admitted to a medical/surgical ICU and mechanically ventilated for >72 h, were randomly assigned to control (n=42) or test (n=42) group. Both groups received the protocol of selective decontamination of the digestive tract, including polymyxin E, tobramycin and amphotericin B. Patients in the test group received 0.5 g of a 4% vancomycin gel at 6‐h intervals in the oropharynx. Lower airway infections due to MRSA acquired on the ICU were reduced in the test group, as was oropharyngeal carriage. Neither vancomycin-resistant enterococci nor vancomycin-intermediate S. aureus were isolated from either surveillance or diagnostic samples during the study period. The vancomycin costs were lower in the test group. This study demonstrates that oropharyngeal vancomycin, which controls intensive care unit‐acquired lower airway infections and secondary carriage due to methicillin-resistant Staphylococcus aureus, is cost-effective and safe in terms of vancomycin-resistant enterococci and vancomycin-intermediate Staphylococcus aureus.

Impact of selective decontamination of the digestive tract on fungal carriage and infection: systematic review of randomized controlled trials

ObjectiveTo determine the impact of the antifungal component of selective decontamination of the digestive tract on fungal carriage, infection and fungaemia.DesignMeta-analysis of randomized controlled trials of selective decontamination of the digestive tractStudy selectionData sources included Medline, Embase, Cochrane Register of Controlled Trials, previous meta-analyses, personal communications and conference proceedings, without restriction of language or publication status. All randomized trials were selected that compared oropharyngeal and/or intestinal administration of antifungals amphotericin B or nystatin, as part of selective decontamination protocol, with no treatment in the controls. There were 42 randomized controlled trials with a total of 6,075 critically ill patients.MethodsThree reviewers independently applied selection criteria, performed quality assessment and extracted the data. The main outcome measures were patients with fungal carriage, patients with fungal infections and patients with fungaemia. Odds ratios were pooled with the random effect model.Measurements and resultsEnteral antifungals significantly reduced fungal carriage (odds ratio 0.32, 95% confidence interval 0.19–0.53) and overall fungal infections (0.30, 0.17–0.53). Fungaemia was not significantly reduced in the treatment group (0.89, 0.16–4.95).ConclusionsAntifungals, as part of selective decontamination of the digestive tract, reduce fungal carriage and infection but not fungaemia in critically ill patients and may justify the inclusion of an antifungal component in the decontamination protocol.

Survival benefit of the full selective digestive decontamination regimen

PURPOSE We assessed the impact of the full protocol of selective decontamination of the digestive tract (SDD) using parenteral and enteral antimicrobials on mortality. MATERIALS AND METHODS A systematic review was performed searching MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, previous meta-analyses, and conferences proceedings. We included all randomized controlled trials (RCTs) comparing the full protocol of SDD, including oropharyngeal and intestinal administration of antibiotics combined with the parenteral component, with no treatment or placebo. The primary end points were overall mortality, mortality attributable to infection, early, and late mortality. RESULTS Twenty-one RCTs on 4902 patients were included. Overall mortality was significantly reduced (odds ratio [OR], 0.71; 95% confidence interval [CI]; 0.61-0.82; P < .001). There was a nonsignificant reduction in infection-related mortality (6 RCTs; OR, 0.40; 95% CI, 0.10-1.59; P = .19) and early mortality (4 RCTs; OR, 0.64; 95% CI, 0.34-1.19; P = 0.16), and a significant reduction in late mortality (5 RCTs; OR, 0.56; 95% CI, 0.40-0.77; P < .001). The subgroup analysis showed a significant mortality reduction in successfully decontaminated patients (OR, 0.58; 95% CI, 0.45-0.77; P < .001), and when parenteral and enteral antimicrobials were administered to every patient receiving treatment in the intensive care unit (OR, 0.59; 95% CI, 0.42-0.82; P < .001). CONCLUSIONS The findings strongly indicated that the full protocol of SDD reduces mortality in critically ill patients, in particular when successful decontamination is obtained. Eighteen patients should be treated with SDD to prevent one death.

Impact of selective decontamination of the digestive tract on multiple organ dysfunction syndrome: Systematic review of randomized controlled trials

Objective:We examined the impact of selective decontamination of the digestive tract on multiple organ dysfunction syndrome. Data Sources:We searched MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, previous meta-analyses, and meetings proceedings. Study Selection:We included all randomized trials comparing both oropharyngeal and intestinal administration of antibiotics in selective decontamination of the digestive tract with or without a parenteral component, with placebo or standard therapy used in the controls. Data Extraction:Two reviewers independently applied selection criteria, performed quality assessment, and extracted the data. The primary end point was the number of patients with multiple organ dysfunction syndrome developing during intensive care unit stay. Secondary end points were overall mortality and multiple organ dysfunction syndrome-related mortality. Odds ratios were pooled with the random effect model. Data Synthesis:We identified seven randomized trials including 1270 patients. Multiple organ dysfunction syndrome was found in 132 of 637 patients (20.7%) in the selective decontamination of the digestive tract group and in 219 of 633 patients (34.6%) in the control group (odds ratio, 0.50; 95% confidence interval, 0.34–0.74; p < .001). Overall mortality for selective decontamination of the digestive tract vs. control patients was 119 of 637 (18.7%) and 145 of 633 (22.9%), respectively, demonstrating a nonsignificant reduction in the odds of death (odds ratio, 0.82; 95% confidence interval, 0.51–1.32; p = .41). In five studies including 472 patients, multiple organ dysfunction syndrome-related mortality was demonstrated in 31 of 239 (13%) patients in selective decontamination of the digestive tract group and 37 of 233 (15.9%) in the controls (odds ratio, 0.84; 95% confidence interval, 0.48–1.41; p = .54). Conclusions:Selective decontamination of the digestive tract reduces the number of patients with multiple organ dysfunction syndrome. Mortality was not significantly reduced, probably because of the small sample size.

SDD, SOD, or oropharyngeal chlorhexidine to prevent pneumonia and to reduce mortality in ventilated patients: which manoeuvre is evidence-based?

Dear editor: We read with interest the editorial by Segers and de Mol on the prevention of ventilator-associated pneumonia (VAP) after cardiac surgery [1]. We would like to comment on the authors’ statements on the use of selective digestive decontamination (SDD), selective oropharyngeal decontamination (SOD), and oropharyngeal chlorhexidine, as they are based on inaccurate interpretation of the evidence. The authors refer to a large SDD/ SOD study [2] which showed a significant reduction in the odds for mortality of SDD and SOD compared to standard care of 16% (odds ratio [OR] 0.835, 95% confidence interval [CI] 0.72–0.968, P = 0.016) and 14% (OR 0.858, 95% CI 0.739–0.996, P = 0.045), respectively. The reduction in mortality was higher in the SDD group than in the SOD group, albeit not significantly. There are nine randomized controlled trials (RCTs) evaluating the impact of SOD on lower respiratory tract infection and mortality. We performed a metaanalysis of those RCTs showing that SOD significantly reduces lower respiratory tract infections, but not mortality (Table 1). Contrastingly, there is robust evidence from the literature which indicates that the full SDD regimen of parenteral and enteral antimicrobials significantly reduces morbidity, i.e. pneumonia [3] and bloodstream infection [4], and mortality [3, 5]. The authors advocate the use of SOD instead of SDD ‘‘because it does not include widespread systemic prophylaxis with cephalosporins and involves a lower volume of topical antibiotics, thus minimizing the risk of development of antibiotic resistance’’. However, the Dutch study [2] clearly shows that patients with Gram-negative bacteria in rectal swabs resistant to the marker antibiotics are lower with SDD than with SOD. These results confirm that the resistance problem is not a function of intestinally applied volume of antimicrobials, but of systemically administered antibiotics. Remarkably, the use of all systemic antibiotics was higher in the SOD group than in the SDD group. Finally, the Dutch study confirms the findings that SDD does not increase the resistance problem, but actually reduces it [3]. The authors recommend the use of oropharyngeal chlorhexidine in cardiac surgery. Of the five metaanalyses of oropharyngeal chlorhexidine, three demonstrated a significant reduction in pneumonia, but none showed a significant reduction in mortality (see S1 in the Electronic Supplementary Material). The metaanalysis of the only three RCTs of chlorhexidine in cardiac surgery shows that chlorhexidine significantly reduces lower respiratory tract infections (Table 1). However, this result should be cautiously interpreted, as the duration of mechanical ventilation was short, and those studies reported the incidence of nosocomial pneumonia, not that of VAP, e.g. most patients received only few doses of the oral rinsing agent because extubation occurred within 4–12 h after surgery. Again, mortality is not significantly reduced by chlorhexidine. Therefore, although we welcome the authors’ claim of ‘‘prepare and defend’’, we advocate prevention of pneumonia using evidence based medicine (EBM) manoeuvres. SDD is the only EBM manoeuvre which has been shown to significantly reduce severe infections, i.e. pneumonia and bloodstream infection, and mortality, whilst SOD and oropharyngeal chlorhexidine still require further investigation.

The emperor's new clothes: the fairy tale continues

Semirecumbency Drakulovic [5] Mixed 2/43 11/47 van Nieuwenhoven [6] Mixed 13/112 8/109 All studies 15/155 19/156 Subglottic drainage Mahul [7] Mixed 9/70 21/75 Valles [8] Mixed 14/76 25/77 Metz [9] Trauma/surgery 15/25 10/14 Kollef [10] Cardiac 8/160 15/183 Bo [11] Surgery 8/35 15/33 Smulders [12] Mixed 3/75 12/75 Lorente [13] a Mixed 11/140 31/140 All studies 68/581 129/597 Oral antiseptics DeRiso [14] Cardiac 3/173 9/180 Fourrier [15] Medical 5/30 15/30 Houston [16] Cardiac 4/270 9/291 MacNaughton [17] Mixed NR/91 NR/88 Grap [18] Mixed NR/23 NR/11 Fourrier [19] b Mixed 13/114 12/114 Segers [21] Cardiac 45/485 74/469 Seguin [22] Trauma 3/36 12/31 Koeman [20] Mixed 13/127 23/130 Bopp [23] Mixed 0/2 1/3 Tantipong [24] Mixed 5/102 12/105 All studies c 91/1399 167/1353

Un nuevo ensayo clínico con descontaminación digestiva selectiva

De Smet et al han publicado un nuevo ensayo clinico sobre descontaminacion digestiva selectiva (DDS). La DDS fue descrita en los anos ochenta como una tecnica para prevenir la infeccion respiratoria en los enfermos criticos y desde entonces se han realizado 57 ensayos clinicos con asignacion aleatoria. Por lo tanto, es la tecnica mas extensamente evaluada en las unidades de cuidados intensivos (UCI). La mejor estimacion de su efecto en la poblacion general de enfermos criticos es que la administracion del protocolo completo previene una neumonia por cada 5 enfermos tratados y una muerte por cada 21 enfermos tratados. A pesar de estos efectos beneficiosos, no se ha generalizado el uso de DDS porque los expertos aducen, en contra de la evidencia existente, que: a) la reduccion de la mortalidad es heterogenea en los diferentes ensayos clinicos, y b) puede conllevar un aumento de la resistencia antibiotica. De Smet et al presentan los resultados de un ensayo clinico, realizado en 13 centros de los Paises Bajos, que incluye a 6.000 pacientes. Sus objetivos fueron comparar el impacto en la mortalidad y la resistencia antibiotica de la aplicacion del protocolo completo de DDS contra la descontaminacion solo orofaringea —polimixina, tobramicina, anfotericina— y contra placebo.De Smet et al han publicado un nuevo ensayo clínico sobre descontaminación digestiva selectiva (DDS). La DDS fue descrita en los años ochenta como una técnica para prevenir la infección respiratoria en los enfermos críticos y desde entonces se han realizado 57 ensayos clínicos con asignación aleatoria. Por lo tanto, es la técnica más extensamente evaluada en las unidades de cuidados intensivos (UCI). La mejor estimación de su efecto en la población general de enfermos críticos es que la administración del protocolo completo previene una neumonía por cada 5 enfermos tratados y una muerte por cada 21 enfermos tratados. A pesar de estos efectos beneficiosos, no se ha generalizado el uso de DDS porque los expertos aducen, en contra de la evidencia existente, que: a) la reducción de la mortalidad es heterogénea en los diferentes ensayos clínicos, y b) puede conllevar un aumento de la resistencia antibiótica. De Smet et al presentan los resultados de un ensayo clínico, realizado en 13 centros de los Países Bajos, que incluye a 6.000 pacientes. Sus objetivos fueron comparar el impacto en la mortalidad y la resistencia antibiótica de la aplicación del protocolo completo de DDS contra la descontaminación sólo orofaríngea —polimixina, tobramicina, anfotericina— y contra placebo.

Selective decontamination of the digestive tract in critically ill children: systematic review and meta-analysis.

Objective: We examined the impact of selective decontamination of the digestive tract on morbidity and mortality in critically ill children. Data Sources: We searched MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and previous meta-analyses. Study Selection: We included all randomized controlled trials comparing administration of enteral antimicrobials in selective decontamination of the digestive tract with or without a parenteral component with placebo or standard therapy used in the controls. Data Extraction: The primary end point was the number of acquired pneumonias. Secondary end points were number of infections and overall mortality. Odds ratios were pooled with the random effect model. Data Synthesis: Four randomized controlled trials including 335 patients were identified. Pneumonia was diagnosed in five of 170 patients (2.9%) for selective decontamination of the digestive tract and 16 of 165 patients (9.7%) for controls (odds ratio 0.31; 95% confidence interval 0.11–0.87; p = .027). Overall mortality for selective decontamination of the digestive tract was 13 of 170 (7.6%) vs. control, 11 of 165 (6.7%) (odds ratio 1.18; 95% confidence interval 0.50–2.76; p = .70). In three studies (n = 109), infection occurred in ten of 54 (18.5%) patients on selective decontamination of the digestive tract and 24 of 55 (43.6%) in the controls (odds ratio 0.34; 95% confidence interval 0.05–2.18; p = .25). Conclusions: In the four available pediatric randomized controlled trials, selective decontamination of the digestive tract significantly reduced the number of children who developed pneumonia.

Surviving Sepsis Campaign needed consensus to exclude selective decontamination of the digestive tract.

To the Editor: We thank Dr. MacIntyre for his editorial (1) on our article (2). We have four questions for him. One, we identified more than 15 methodologic errors in the metaanalysis performed by the EvidenceBased-Medicine Task Force on weaning (3). Our article holds no importance if we are wrong about the methodologic errors we identified (2). Dr. MacIntyre does not contend a single one of these errors. He writes “I’m not going to address the methodologic criticisms” (1). Yet, this is the very core of our article. The primary means for correcting scientific error is the dialectic process (4). Avoiding engagement in argument and counter-argument is the antithesis of science (4). We ask Dr. MacIntyre: “If we mistakenly identified some methodologic errors, which ones are they?” (Dr. MacIntyre writes “the methodologic criticisms [are] addressed in accompanying editorial”. But Dr. Marini did not write that we made methodologic errors). Two, Dr. MacIntyre continues, “Rather I will clarify how the McMaster findings were used by the task force to create operational guidelines for clinicians at the bedside.” (1) In this sentence, Dr. MacIntyre implies that the Task Force created clinical guidelines without analyzing the primary data (5). Our questions to Dr. MacIntyre: “Did Task-Force members check for errors in the analyses undertaken by the McMaster group?” (If the Task Force’s primary role was to imprint a seal-of-approval on a metaanalysis conducted by another group, readers should be so informed). Three, Dr. MacIntyre notes their meta-analysis revealed “consistently significant likelihood ratios” (1). But consistency is no guard against systematic error. If a spirometer contains a positive bias, the recorded volumes will overestimate true volume in a “consistent” manner (2). Dr. MacIntyre writes “the task force concluded that the individual likelihood ratios were not sufficiently high enough to drive clinical decision making at the bedside.” (1) We ask Dr. MacIntyre: “Is it wise to drive clinical decisions based on likelihood ratios that involve a series of compounded methodologic errors?” Four, Dr. MacIntyre writes “The guidelines seem to be standing the ‘test of time’ and are continuing to serve as an important tool to reduce iatrogenic delays in mechanical ventilation withdrawal.” (1) We ask Dr. MacIntyre: “If these are not mere assertions, please present the data that warrant your conclusion: that the guidelines are (a) standing the test of time and (b) reducing iatrogenic weaning delays?” We listed more than 15 methodologic errors in the Task Force’s meta-analysis (2). If we are wrong about these, we welcome correction from any member of the Task Force (3, 5). If the methodologic errors cannot be refuted, then what is the validity of the evidence on which the Evidence-Based-Medicine Task Force base their conclusions? The authors have not disclosed any potential conflicts of interest.

Selective decontamination of the digestive tract in burn patients: an evidence-based maneuver that reduces mortality.

We would like to thank Dr. Silvestri et al for their comments on selective decontamination of the digestive tract (SDD) in burn patients. Their detailed review of available data in burn patients will prove informative to burn practitioners throughout the world. We agree that multiple SDD trials have indicated benefit in decreasing ventilator-associated pneumonia incidence and reducing mortality in surgical patients, including burns. We have tried to make that point clear in our guidelines. Despite multiple positive SDD trials conducted in Europe and elsewhere, this practice has gained little support in intensive care units (ICUs) in the United States. We believe the deterrents to widespread acceptance of SDD in North America have been 1) heterogeneity of methods for decontamination, 2) inconsistent results in surgical patient populations, and, most importantly, 3) the fear that it will promote emergence and spread of antimicrobial resistant microorganisms. To better understand the impact of systematic antibiotic administration to large patient cohorts, longitudinal ecological ICU studies are also needed to substantiate the efficacy observed in the reported clinical trials. Interestingly, although the recent Dutch multicenter trial demonstrated a decreased incidence of multiresistant organisms on rectal cultures with SDD, its follow-up ecological study in the 13 participating ICUs now reports a twofold increase in the incidence of antibiotic resistance in the intestinal and the respiratory tracts. These findings are consistent with prior studies, indicating major shifts in the microbial ecology of the ICU with SDD. We, thus, believe that our caution against “the prophylactic use of antibiotics in units with high levels of antibiotic resistance” remains justified in light of the aggregate data. We believe the best way to resolve this controversy and impact practice patterns would be a prospective, randomized trial of SDD in burn ICUs recruited from multiple countries.