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Defense against infections

Last update 17-7-2009

On Selective Intestinal Decontamination

What is Selective Intestinal Decontamination?

Selective Intestinal Decontamination (SID) is a treatment approach to prevent or even treat infections in patients with a decreased resistance against infections. The decreased resistance can be caused for example by irradiation treatment, severe burning, some forms of cancer (leukemia). SID can also be used in preparation of massive surgery, such as liver transplants.
The causative microbes most often involved in infections in immunocompromised patients are the gram negatives and yeasts such as Candida species.

The alternative approach, often chosen without thinking or out of habit, is Total Intestinal Decontamination (TID). Here broad spectrum antimicrobials are used that kill most of the microorganisms in the gut.

Why use Selective Intestinal Decontamination?

Selective Intestinal Decontamination is more effective than conventional treatments, which is important for the immunocompromised patient. For patients with a normally functioning defense against infections SID is too expensive as it requires high doses of antibiotics that are not normally used and frequent culturing to check its effects. The latter requires a well equipped hospital laboratory on hand.

How does the normal defense against infections work (summary)?

The main components of the defense against infections

As can be read extensively elsewhere in this site, the defense against infections is built in four layers of defense:

  1. Microflora dynamics and inter microorganism chemical warfare
  2. The Innate defense system
  3. The Ideotype defense system
  4. The Adaptive defense system

In an immunocompromised patient the adaptive defense system is (severely) reduced in its role. Consequently if a potential pathogen manages to attach to the gut wall and penetrate it, limited or no defenses remain to resist it multiplying and invading the body. In order to attach to the gut wall the potential pathogen must be present in sufficiently high numbers.
A key role to prevent this can be found in the microflora that line the gut wall, compete for food and space and attempt to kill each other with defensins. This role is also called the colonization resistance. If through the use of broad spectrum antibiotics the microflora in the gut is reduced, this line of defense also is weakened. This has two effects:

  1. a reduced competition for food and reduced chemical warfare so it is easier for potential pathogens to grow in to high numbers
  2. a reduced competition for space along the gut wall, so adherence to the gut wall is easier

Consequently the risk of rampant penetration and growth of potential pathogens is significantly increased.

SID compared to the normal situation

The following images were created in the 1980s to explain the difference in the defense against infections between the normal situation and SID.

Normal CR SID

The leftmost figure shows the defense against infections in its normal state, with the colonization resistance, defensin based defense in the mucosa and ideotype and adaptive defense layers as "defense apparatus".
In the rightmost figure the "defense apparatus is reduced in its ability. This is compensated by the used of SID adding strengthening the colonization resistance defense layer and preventing potential pathogens from colonizing the intestinal lumen and growing to sufficient numbers to become dangerous.

Why is Selective Intestinal Decontamination a better approach?

There are two ways to prevent potential pathogens to invade an immunocompromised patient:

  1. Use antibiotics to kill all microorganisms named Total Intestinal Decontamination (TID)(and hope none of them is resistant to that antibiotic, as in that case these resistant strains will grow out to high numbers which may imply their translocation). Yeasts and fungi may for example escape TID. Also, specially in hospitals and around animal farms, multi resistant strains can be present and easily picked up
  2. Use Selective Intestine Decontamination to attack the potential pathogens only while carefully not harming the normal non-pathogen microflora

So for immunocompromised patients SID is a better approach because the risk of one or more invasions with resistant potential pathogens is significantly reduced.
Please remember that resistance is to defensins and developing resistance against new defensins is a normal microorganism capability. They have had billions of years of chemical warfare to perfect that art. There are three ways for resistance to develop or be acquired:

  1. Essential (naturally inherited) resistant to an antimicrobial agent
  2. Developed (induced and manmade) resistance to an antimicrobial agent
  3. Acquired (genetic transmission or -transformation) resistance to a (induced or manmade) antimicrobial agent

How does Selective Intestinal Decontamination work?

SID works by using antibiotics that only kill the potential pathogens, 'normal' predominantly anaerobic micro flora unharmed. During SID the anaerobes it can play their role in the defense against potential pathogens and hence infection. This approach of pealing off the potentially pathogenic microbes requires a small spectrum effect of antibiotics applicable for SID.
There are two groups of small spectrum antibiotics:

  1. Antibiotics that have essentially a small spectrum of activity that affect only potential pathogens, are non-absorbable after oral treatment and act inside the intestinal lumen
  2. Antibiotics that are excreted with the intestinal mucus and are rapidly inactivated by 'colon contents'

Regarding the second group (for the purpose of SID) it is sufficient that the mucosa-associated bacteria (i.e. those which live in the mucus layer through which the antibiotic is applied) are killed. If the pathogens are suppressed in the mucus, they can not translocate into the submucosa as a start to cause an infection. If they survive their stay in the colon contents, they cannot persistently colonize the gut as they are no longer seeded from the mucuous layer into the colon contents. Therefore they are gradually removed by 'washout' with the intestinal contents (peristalsis). The latter process takes 4 to 7 days in man.

What kind of antibiotics to use?

Small spectrum antibiotics
Antimicrobials to be used by oral supply which kill bacteria, yeasts and fungi (and Candida spp). This group involves for example Polymyxin, Nystatin and Amphothericin.
Polymycin and Amphotericin B are strongly chemically inactivated by colonic contents. As a result they act predominantly in the colon contents. This implies that high oral doses are required to accomplish an (sufficient) active concentration in the colon. Fortunately, these drugs are practically not absorbed; an important feature as they are strongly nephro-toxic.

Another small spectrum antibiotic that is applicable, is non-toxic and also acts selectively against gram-negatives, is Aztreonam. This drug is well tolerated, non-toxic and practically not absorbed following oral administration (De Vries-Hospers et al. 1984).

Broad spectrum antibiotics: Antimicrobials that are inactivated, in the mucus layer, or closely beyond the mucosal lining in the intestinal contents. Inactivation will make these drugs inactive in the colon contents. Thus antibiotics of this group like quinolones and Trimethoprim, can act only at short distance from mucosa cells. This has been studied in rats (Toorop-Bouma & Van der Waaij 1987).

In cases of SID in which trimethoprim is used, drug-resistance or bad tolerance by the individual treated may exist. This is not or less strongly the case - at least in older children and in adults - when the quinolone group is used. Alternatively the non-absorbable oral tobramycin or polymyxin can be considered for SID (Veringa EM, Van der Waaij D, 1984).

What is meant with inactivation?

Inactivation of antimicrobials appears a normal process that is part of the ongoing chemical warfare. The actual mechanism(s) are yet unknown. Somehow elements of the gut content manage to bind to the antimicrobials and block its antimicrobial function. Consequently as soon as antimicrobial molecules enter the gut contents, be it following ingestion or by excretion through the mucosa, they stop being active.

Microbial survival in the intestinal contents regardless of the presence of antimicrobial substance can be due to chemical binding of the antibiotic. Chemical binding occurs by (a) certain molecule(s) in the gut contents which come from either the host organism or from other microorganisms. These inactivating molecules, that blocks the activity of the antimicrobial molecule, appears 'ubiquitously' present, as it has been found in fecal material of all animal species in which it has been studied, such as in rodents, dogs, pigs, monkeys and man. Examples of anti-microbials that are rapidly inactivated (within the time required for processing in the laboratory) by this substance, are polymyxin, polyene antibiotics. However, also man-made and chemically designed molecules, such as trimethoprim and other man-made molecules such as quinolones like ciprofloxacin and norfloxacin belong to this category that make them very useful for SID. Less complete inactivation by colonic contents occurs in aminoglycoside antibiotics. Less complete inactivation makes them less reliable for `selective intestinal decontamination`.
In the aminoglycoside group, tobramycin is best inactivated and thus applicable for SID.

Please note: inactivation is a must in the intestinal contents, as it prevents the kill of protective bacteria so that the colonization resistance remains intact.

Inactivation can be caused by:

  1. Inactivation by chemical binding
    This type of inactivation is reversible. When feces of an SID treated subject is suspended in an access of diluent (water), these antibiotics - both those of microbial origin and the man-made origin - get reactivated in a matter of minutes. In vivo in the colon this is also the case, as susceptible microorganisms are protected by chemical binding of the antimicrobial in an environment such as the colon contents of higher organisms (Van der Waaij & Nord .2000)
  2. Inactivation by enzymatic breakdown of an antimicrobial by enzymes produced by microorganisms.
    This type of inactivation is irreversible as it results of breakdown of the agent.
    This type of resistance is irreversible as it results of breakdown of the agent. In microorganisms Essential (genetically inherited) resistance to certain antimicrobials concerns in general the absence of binding sites in the attacked organism (host). Sometimes however, the attacked organism is susceptible, but protected by organisms in the environment by chemical binding of the antimicrobial. This is often the case in an environment such as the colon contents in higher organisms.

What are defensins?

Defensins are the group of antimicrobial molecules that are produced by bacteria, by cells that are in contact with the environment (outside world). This is seen in plants as well as in the animal-world.
In man, these antimicrobial molecules are predominantly produced by cells involved in the control of microbes that intend to enter the tissues or are already inside them. Defensins are released by respectively cells of the skin and those lining the oropharyngeal and intestinal mucosa.
This system of colonization control influences the colonization pattern of the mucus membrane and therewith the translocation by potentially pathogenic microbes. Also in the tissues cells involved in the defense such as neutrophils and macrophages, do produce defensins when triggered.
We could regard this process of defensin production as "natural SID" which may exist since the early days of evolution.

Apparently, E.coli is not in the frontline of the actions of defensins or susceptible to defensins of most animals that normally carry E.coli in their intestines.

How to perform Selective Intestinal Decontamination properly

The success of SID depends on eliminating the potential pathogens while not decreasing the colonization resistance and preventing the potential pathogens of learning how to become resistant to the drug used. This requires:

  1. Adequate antimicrobial drug dosing;
  2. Frequent checking by culturing of feces as well as oral and skin swabs for the absence of the target organisms.

Monitoring of the results of SID is particularly important during the first week of SID; After that interval, a decision can be made about the necessity of adjustment of the dose or switching to an other antimicrobial for SID.
In the presence of the SID drug microorganisms cannot become resistant as long as they get rapidly killed. Therefore, adequate dosing implies prescription of sufficiently high doses of one or combinations of SID drugs, (not just prescribe antimicrobial(s).
TThe monitoring of the result of the treatment should be done by frequent culturing of oropharynx swabs and feces for the presence of opportunistic microbes.

It should emphasised at this poit once more, that it may take several days (the washout time from the colon) before feces are free of culturable gram-negatives and the susceptible bacteria.

References

  1. Toorop-Bouma AG, Van der Waaij D: Scan J Inf Dis 1987, 19, 361-367
  2. Van der Waaij and Nord CE: Intern J Antimicrob. Ag. 2000, 16, 191-197
  3. Van der Waaij D and Van der Waaij BD. Epidemiol Infect 1990,105, 237-243
  4. Van der Waaij D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC. J Hyg 1971 69, 405-411
  5. Van der Waaij D. The influence of antibiotics on gut colonization. J Antimicrob Chemotherapy 1986, 18, 155-158
  6. De Vries Hospers, Welling GW, Swabb FA, Van der Waaij D. J Inf Dis 1984, 150, 636-642
  7. Veringa EM, Van der Waaij D 1984, J Antimicrob Chemother 14, 605-612
  8. Jansen G, Weising F, De Vries-Hospers HG, Tonk R, Van der Waaij D. Infection 1992, 20, 355-359
  9. Van der Waaij D, Van der Waaij JM. In: Wostmann BS, Pleasants JR, Pollard M, Teah BA, Wagner M Editors. Germfree Research: Microflora control and its application to biomedical sciences. New York: Alan Liss Inc. 1985
  10. Van der Waaij LA, Messerschmidt O, Van der Waaij D. 1989. Epidem Inf , 102, 93-103