Prevention of Infection Using Selective Decontami-nation of the Digestive Tract

Prevention of Infection Using Selective Decontami- nation of the Digestive Tract

L. S

, S. K

, A. G

Rationale of Infection Prevention by Selective Decontami- nation of the Digestive Tract

The rationale for preventing infections using selective decontamination of the digestive tract (SDD) is based on the observation that 15 potentially pathogenic micro-organisms (PPMs) cause the three types of infection in the intensive care unit (ICU). The majority of ICU infections are “early” primary endogenous (Table 1). These require immediate adequate parenteral antibiotics in order to control incubating [1, 2] or treat established infections on admission to the ICU. Enteral antibiotics are administered into the throat and gut on admission to the unit to control acquisition, secondary carriage, and subsequent secondary endogenous infections that occur late, in general after 1 week of treatment on the ICU. Strict implementation of hygiene measures is required to control exogenous infection that may occur at any time during the treatment on the ICU. Finally, surveillance cultures of throat and rectum are an integral part of the strategy of SDD to mon- itor the efficacy of the protocol.

Table 1.Classification of infection occurring in the intensive care unit (ICU) using carria- ge (PPM potentially pathogenic micro-organism, AGNB aerobic Gram-negative bacilli, MRSA methicillin-resistant Staphylococcus aureus)

Type of infection PPM Timing Frequency (%)

Primary endogenous 6 normal and “Early” within About 55%

8 abnormal AGNB the 1st week MRSA

Secondary endogenous 8 abnormal AGNB “Late” after About 30%

MRSA the 1st week

Exogenous 8 abnormal AGNB Any time during About 15%

MRSA treatment on ICU

What Is SDD?

SDD is a maneuver designed to convert the “abnormal” carrier state (see Chapter 2) into the “normal” carrier state using non-absorbable antimicrobials.

The practice of SDD has four fundamental features termed the classical Stoutenbeek’s tetralogy [3, 4] (Fig. 1, Table 2).

Fig. 1.The Stoutenbeek’s tetralogy of selective decontamination of the digestive tract (SDD) and the type of infection prevented/controlled by each component. (PPM potentially patho- genic microorganism, ICU intensive care unit) (from Silvestri L, Lenhart FP, Fox MA (2001) Prevention of intensive care unit infections. Curr Anaesth Crit Care 12:35-40, with permission)

1. enteral antimicrobials given throughout the treatment on ICU, in combina- tion with

2. parenteral antibiotics given immediately on admission for 4 days 3. hand hygiene throughout the treatment on ICU

4. surveillance cultures of throat and rectum on admission and twice weekly thereafter

This strategy selectively targets the 15 PPMs and the high-level pathogens, such as Streptococcus pyogenes, which contribute to mortality. By design, SDD does not target low-level pathogens, including anaerobes, viridans streptococ- ci, enterococci, and coagulase-negative staphylococci as, in general, they only cause morbidity. The most-important feature of SDD is the enteral administra- tion of non-absorbable polymyxin E/tobramycin to eradicate the abnormal aer- obic Gram-negative bacilli (AGNB). This results in decontamination of the digestive tract. Critically ill patients are unable to clear these pathogens due to their underlying disease. Intestinal overgrowth with AGNB causes systemic immunoparalysis [4]. Enteral polymyxin E/tobramycin promotes recovery of systemic immunity [4] and prevention or eradication of abnormal AGNB in the throat and gut, and effectively controls aspiration and translocation of these

Target PPM and antimicrobials Total daily dose (4x daily)

<5 years 5–12 years >12 years 1. enteral antimicrobials

A. oropharynx

AGNB: polymyxin E 2 g of 2% paste/gel

with tobramycin

Yeasts: amphotericin B, 2 g of 2% paste/gel

or nystatin

MRSA: vancomycin 2 g of 4% paste/gel

B. Gut

AGNB: polymyxin E (mg) 100 200 400

with tobramycin (mg) 80 160 320

Yeasts: amphotericin B (mg), 500 1,000 2,000

or nystatin (units) 2x10⁶ 4x10⁶ 8x10⁶

MRSA: vancomycin (mg) 20-40/Kg 20-40/Kg 500/2,000

2. parenteral antimicrobials

cefotaxime (mg) 150/Kg 200/Kg 4,000

3. hygiene

4. surveillance cultures of throat and rectum on admission, Monday, Thursday

PPM, potentially pathogenic micro-oganism; AGNB, aerobic Gram-negative bacilli;

MRSA, methicillin-resistant Staphyloccoccus aureus

micro-organisms into the lower airways and blood, respectively. Enteral antimi- crobials are effective in the control of secondary endogenous infections.

However, the use of enteral antibiotics does not affect primary endogenous and exogenous infections. The second component is the immediate administration of an adequate parenteral antimicrobial to control primary endogenous pneu- monia and septicemia. Cefotaxime has been used in most randomized trials to cover both “community” and “hospital” pathogens. In adding enteral to par- enteral antibiotics, the original pre 1980s antibiotics remain useful, without the development of antimicrobial resistance (Chapter 28). Thirdly, high standards of hygiene are indispensable for reducing hand contamination and subsequent transmission from external sources. Finally, surveillance samples of the throat and rectum are taken on admission and twice weekly thereafter. These are an integral component of the SDD protocol. Knowledge of the carrier state allows the compliance with and efficacy of this prophylactic protocol to be monitored.

Effectiveness of SDD

In total, 54 randomized controlled trials (RCTs) have been undertaken over 20 years of clinical research (Table 3) [5–58]. SDD was actively researched during the 1990s and after a short interval there has been a revival in new randomized

Net, netilmicin; Nor, norfloxacin; Ny, nystatin; O, oropharynx; Oflox, ofloxacin; P, polymyx- in; Pip, piperacillin; T, tobramycin; Van, vancomycin)

Enteral

Author Patients Parenteral AGNB Yeasts S. aureus Site

Abele-Horn et al. [5] Trauma Cefotaxime PT A O, -

Aerdts et al. [6] Mixed Cefotaxime P Nor A O, I

Arnow et al. [7] Liver Cefotaxime/ PG Ny O, I

transplantation ampicillin (2 arms)

Barret et al. [8] Pediatric, Pip/ami/ PT A -, I

burns van (2 arms)

Bergmans et al. [9] Mixed Antibiotics (40%) PG -- Van O, - (2 arms)

Bion et al. [10] Liver Cefotaxime/ PT A O, I

transplantation ampicillin (2 arms) (2 arms)

Blair et al. [11] Mixed Cefotaxime PT A O, I

Boland et al. [12] Trauma Cefotaxime PT Ny O, I

➝ Cont.

Enteral

Author Patients Parenteral AGNB Yeasts S. aureus Site

Bouter et al. [13] Cardiac Flucloxacillin P Neo -- -, I (2 arms)

Brun-Buisson Mixed -- P -- -,I

et al. [14] Neo

Nali

de la Cal et al. [17] Burns Cefotaxime PT A O, I

Cerra et al. [15] Mixed -- Nor Ny -, I

Cockerill et al. [18] Mixed Cefotaxime PG Ny O, I

Ferrer et al. [19] Respiratory Cefotaxime PT A O, I

(2 arms)

Finch et al. [20] Mixed Cefotaxime PG A O, I

Flaherty et al. [21] Cardiac Cefazolin PG Ny O, I

(2 arms)

Gastinne et al. [22] Mixed Antibiotics PT A O,I

(65%)(2 arms)

Gaussorges Mixed Antibiotics PG A Van -, I

et al. [23] (2 arms)

Georges et al. [24] Trauma Amoxycillin P Net A O, I

+clav (2 arms)

Hammond Respiratory Cefotaxime PT A O, I

et al. [25] (2 arms)

Hellinger et al. [26] Liver Ceftizoxime PG Ny O, I

transplantation (2 arms) (2 arms)

Jacobs et al. [27] Neurosurgical Cefotaxime PT A O, I

de Jonge et al. [16] Mixed Cefotaxime PT A O, I

Kerver et al. [28] Mixed Cefotaxime PT A O, I

Korinek et al. [29] Neurosurgical -- PT A Van O,I

Krueger et al. [30] Surgical, Ciprofloxacin PG -- Van O, I trauma

Laggner et al. [31] Mixed Amoxycillin+clav G A O, -

(70%) (2 arms) (2 arms)

➝ Table 3. Cont.

➝ Cont.

Enteral

Author Patients Parenteral AGNB Yeasts S. aureus Site

Lingnau et al. [32] Trauma Ciprofloxacin PT A O, I

(3 arms) P Cipro A O, I

Luiten et al. [33] Pancreatitis Cefotaxime P Nor A O, I

Martinez-Pellus Cardiac -- PT A -, I

et al. [34]

Martinez-Pellus Cardiac -- PT A -, I

et al. [35]

Palomar et al. [36] Mixed Cefotaxime PT A O, I

Pneumatikos Trauma -- PT A O, -

et al. [37]

Pugin et al. [38] Surgical, -- P Neo -- Van O, -

trauma

Quinio et al. [39] Trauma Cefazolin (38%) PG A O, I

(2 arms)

Rayes et al. [40] Liver Ceftriaxone/ PT A -,I

transplant metronidazole (2 arms)

Rocha et al. [41] Medical, Cefotaxime PT A O, I

trauma

Rodriguez-Roldan Mixed -- PT/Net A O, -

et al. [42]

Rolando et al. [43] Liver failure Cefuroxime PT A O, I

Rolando et al. [44] Liver failure Ceftazidime/ PT A O, I

flucloxacillin (2 arms)

(2 arms)

Ruza et al. [45] Pediatric -- PT Ny -, I

Sanchez-Garcia Mixed Ceftriaxone PG A O, I

et al. [46]

Schardey et al. [47] Gastrectomy Cefotaxime PT A Van -, I (2 arms)

➝ Cont.

➝ Table 3. cont.

SDD trials (Fig. 2). The randomized trials not only differ in combining enteral and/or parenteral antimicrobials, they also show large variations in the antimi- crobials used. The classical Stoutenbeek’s tetralogy has been evaluated in 17 RCTs [11, 16, 17, 19, 25, 27, 28, 36, 41, 43, 48-51, 54, 56, 58]. Infection was signif- icantly reduced in all but 12 studies. In those 12 negative studies the reduction was not significant [8, 14, 19, 22, 25, 26, 31, 32, 44, 54, 55, 58]. Only 2 studies showed a significant reduction in mortality following an intention-to-treat basis [16, 30]. The first study included 527 patients, and the reduction in mor- tality was significant with a relative risk of 0.69 [95% confidence interval (CI) 0.51–0.95]. The second study included 924 patients; both ICU [odds ratio (OR) 0.60, 95% CI 0.42–0.82] and hospital (OR 0.71, 95% CI 0.53–0.94) mortality were significantly reduced. In order to quantify the impact of SDD on infection and mortality meta-analysis is required.

➝ Table 3. cont.

Enteral

Author Patients Parenteral AGNB Yeasts S. aureus Site

Smith et al. [48] Pediatric, Cefotaxime/ PT A O, I

liver transplant ampicillin (2 arms)

Stoutenbeek Trauma Cefotaxime PT A O, I

et al. [49] (2 arms)

Stoutenbeek Trauma Cefotaxime PT A O, I

et al. [50]

Tetteroo et al. [51] Esophagectomy Cefotaxime PT A O, I

Ulrich et al. [52] Mixed Trimethoprim P Nor A O, I

Unertl et al. [53] Neurosurgical -- PG A O, I

Verwaest et al. [54] Mixed Cefotaxime PT A O, I

Ofloxacin Oflox A

Wiener et al. [55] Mixed -- PG Ny O, I

Winter et al. [56] Mixed Ceftazidime PT A O, I

Zobel et al. [57] Pediatric, Cefotaxime PG A O, I

Cardiac

Zwaveling et al. [58] Liver Cefotaxime/ PT A O, I

transplantation tobramycin (2 arms)

Meta-Analyses of Randomized Trials of SDD

Nine meta-analyses have been performed on RCTs only (Table 4) [59–67]. The

most rigorous meta-analysis [66] showed that SDD reduces the OR for lower

airway infections to 0.35 (95% CI 0.29–0.41) and mortality to 0.78 (95% CI

0.68–0.89), with a 6% overall mortality reduction from 30% to 24%. In surgical

patients the benefit is even higher, with the risk of lower airway infections

reduced by 81% (OR 0.19, 95% CI 0.15–0.26), bloodstream infections reduced

by 49% (OR 0.51, 95% CI 0.34–0.75), and mortality reduced by 30% (OR 0.70,

95% CI 0.52–0.93) [63]. The reason for this difference in improvement is that

surgical patients are in general younger and do not suffer from chronic under-

lying diseases, whereas medical patients are older and often have incurable con-

ditions such as diabetes, chronic obstructive pulmonary disease, and heart fail-

ure. In the 53rd and latest SDD trial the randomization unit was the ICU and

not the patient, as in all previous trials [16]. This Dutch study of 934 patients is

the largest single study yet undertaken. The primary endpoint was mortality as

opposed to infectious morbidity, and the risk of mortality was significantly

reduced to 0.6 (95% CI 0.4–0.8) in the unit where SDD was administered to all

patients. In contrast, the patient was the “randomization unit” in the previous

52 trials; therefore, half the population was not decontaminated. However, the

likelihood is high that those control patients, albeit not receiving SDD, will still

benefit from the intervention as concurrent patients were subjected to a lower

risk of microbial acquisition and carriage, acquired infection, and infection-

related mortality. This dilution risk due to the control group being present with

decontaminated patients at the same time in the same unit is termed “contam-

Table 4.Nine meta-analyses of randomized trials of SDD

Author Year Studies Patients Endpoints Results

(n) (n)

SDD trialists’ 1993 22 4,142 Odds ratio

group [59] Mortality 0.90 (0.79–1.04)

Parenteral and enteral 0.80 (0.67–0.97) antibiotics

Only enteral antibiotics 1.07 (0.86–1.32)

Pneumonia 0.37 (0.31–0.43)

Parenteral and enteral 0.33 (0.27–0.40) antibiotics

Only enteral antibiotics 0.43 (0.33–0.56)

Kollef [60] 1994 16 2,270 Difference in risk

Mortality 0.019

(-0.016 to 0.054)

Pneumonia 0.145

(0.016–0.174)

Heyland et al. [61] 1994 24 3,312 Relative risk

Mortality 0.87 (0.79–0.97)

Parenteral and enteral 0.81 (0.71–0.95) antibiotics

Only enteral antibiotics 1.00 (0.83–1.19)

Pneumonia 0.46 (0.39–0.56)

Parenteral and enteral 0.48 (0.39–0.60) antibiotics

Only enteral antibiotics 0.49 (0.32–0.59)

D’Amico et al. [62]1998 33 5,727 Odds ratio

Mortality

Parenteral and enteral 0.80 (0.69–0.93) antibiotics

Only enteral antibiotics 1.01 (0.84–1.22) Pneumonia

Parenteral and enteral 0.35 (0.29–0.41) antibiotics

Only enteral antibiotics 0.56 (0.46–0.68) cont.➝

Author Year Studies Patients Endpoints Results

(n) (n)

Nathens 1999 11 Not Odds ratio

et al. [63] mentioned

Mortality

Surgical patients 0.70 (0.52–0.93) Parenteral and enteral 0.60 (0.41–0.88) antibiotics

Only enteral antibiotics 0.86 (0.59–1.45) Non-surgical patients 0.91 (0.71–1.18) Parenteral and enteral 0.75 (0.53–1.06) antibiotics

Only enteral antibiotics 1.14 (0.77–1.68) Pneumonia

Surgical patients 0.19 (0.15–0.26) Non-surgical patients 0.45 (0.33–0.62)

Redman 2001 Not Not Odds ratio

et al. [64] mentioned mentioned

Pneumonia

Parenteral and enteral 0.31 (0.20–0.46) antibiotics

Only enteral antibiotics 0.40 (0.29–0.55)

Silvestri 2003 42 6,263 Odds Ratio

et al. [65] Fungal carriage 0.32 (0.19-0.53)

Fungal infections 0.31 (0.19-0.51)

Fungemia 0.49 (0.13-1.95)

Liberati 2004 36 6,922 Odds ratio

et al.[66] Mortality

Parenteral & enteral antibiotics 0.78 (0.68-0.89) Only enteral antibiotics 0.97 (0.81-1.16) Pneumonia

Parenteral & enteral antibiotics 0.35 (0.29-0.41) Only enteral antibiotics 0.52 (0.43-0.63)

Safdar 2004 4 259 Relative risk

et al.[67] (Liver Infection 0.88 (0.73-1.09)

transpl.) Gram negative infection 0.16 (0.07-0.37)

Mortality 0.82 (0.22-2.45)

➝ Table 4 cont.

ination bias”. The design of the latest trial has avoided this type of bias and may explain the highest reported mortality reduction to date. Translating this infor- mation into pragmatic terms, only 5 ICU patients need to be treated with SDD to prevent 1 case of pneumonia, and 21 ICU patients need to be treated to pre- vent 1 death [66]. The number needed to be treated to prevent 1 death in the lat- est study of de Jonge et al. is 12 [16].

Conclusions and Future Research

SDD is the only evidence-based maneuver that prevents infection and mortali- ty in the critically ill. The target micro-organisms of SDD include the “normal”

PPMs including Streptococcus pneumoniae and methicillin-sensitive

(MRSA), by design, is not covered by the original protocol of SDD, and, hence, seven randomized trials conducted in ICU where MRSA was endemic at the time of the study, showed a trend towards higher MRSA infection rates in patients receiving SDD [17, 19, 22, 25, 32, 54, 55]. These observations suggest that the parenteral and enteral antimicrobials of the SDD protocol, i.e., cefo- taxime, polymyxin, tobramycin, and amphotericin B, select and promote MRSA.

Under these circumstances, SDD requires the addition of oropharyngeal and intestinal vancomycin. Two RCTs show that the addition of vancomycin to SDD is an effective and safe maneuver [68, 69].

The Cochrane Library meta-analysis [66] - the only one that includes the first ever RCT on antimicrobial resistance [16] - reports that SDD does not lead to resistance amongst AGNB but, even better, the addition of enteral polymyxin/tobramycin to the parenteral antimicrobials reduces resistance com- pared with the parenteral antibiotics only. This is in line with a previous RCT demonstrating that enteral antimicrobials control extended spectrum β-lacta- mase producing Klebsiella [14]. Reports claiming resistance are invariably of low level evidence including before-after studies [70]. SDD implemented in two American ICUs with endemic vancomycin resistant enterococci (VRE) did not lead to an increased number of VRE infections [7, 26]. VRE did not emerge in any of the RCTs using enteral vancomycin [9, 23, 29, 30, 38, 47]. Antimicrobial resist- ance, being a long-term issue, has been evaluated in eight SDD studies monitor- ing antimicrobial resistance between 2 and 7 years, and bacterial resistance with SDD has not been a clinical problem [71-78].

A proper analysis of cost-effectiveness has not been performed. A Spanish

Working Party has undertaken a cost-effectiveness analysis of the 54 RCTs and

the nine meta-analyses using the decision tree analytic model [79, 80].

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JAMA 11:282:554–560

SECTION FOUR

I NFECTIONS ON ICU