Selective Decontamination of the Digestive Tract: the Role of the Pharmacist

Selective Decontamination of the Digestive Tract:

the Role of the Pharmacist

N.J. R

, A.J. N

, K. P

Introduction

Selective decontamination of the digestive tract (SDD) is a prophylactic strate- gy aimed at preventing both endogenous and exogenous infections in patients admitted to the intensive care unit (ICU) [1]. Endogenous infections in critical- ly ill patients are invariably preceded by oropharyngeal and gastrointestinal carriage of potentially pathogenic micro-organisms (PPMs). “Community” and

“hospital” PPMs (Table 1) carried by the patient upon admission are the causative agents of primary endogenous infections, whilst “hospital” PPMs acquired by the patient during their time on the ICU are responsible for sec- ondary endogenous infections. Exogenous infections are caused by mainly hos- pital PPMs not carried by the patient at all [2].

The causative bacteria for exogenous infections are also acquired on the unit, but are never present in the throat and/or gut flora of patients [3]. For example, long-stay patients, particularly those who receive a tracheostomy on respiratory units, are at high risk of exogenous, lower airway infections.

Purulent lower airway secretions yield a micro-organism that has never been previously carried by the patient in the digestive tract flora, or indeed in their oropharynx. Although both the tracheostomy and the oropharynx are equally accessible for bacterial entry, the tracheostomy tends to be the entry site for bacteria that colonize/infect the lower airways. Within a group of adult ICU patients it has been shown that c. 55% will develop “early” or primary endoge- nous infections, c. 30% will develop secondary endogenous infections, and 15%

will develop exogenous infections.

There are few epidemiological studies on nosocomial infections in pediatric ICU (PICU) [4–8] compared with published studies on neonatal and adult ICU.

Publications demonstrating the benefits of SDD in the PICU are also limited

[9–14]. Two recent meta-analyses, however, have shown the important impact

that SDD has on morbidity and mortality in adult patients. The most rigorous

meta-analysis of the two reviewed 36 randomized SDD trials and concluded that the use of SDD had led to a reduction of lower airway infections and mortality by 65% and 22%, respectively [15]. The second meta-analysis in surgical patients showed that SDD usage led to a reduction in lower airway infection, septicemia, and mortality by 80%, 50%, and 30%, respectively [16]. A recent prospective cohort study on a PICU [17] reported that 61% of their infections were caused by micro-organisms carried by the patients on admission and hence unrelated to the PICU ecology. A low secondary endogenous infection rate of 5% was attrib- uted to the use of SDD and was in line with the results of the two meta-analyses.

In this study the exogenous infection rate was 34% and suggested that transmis- sion via hands was a problem in a busy PICU.

The concept of SDD was introduced in the early 1980s by Stoutenbeek et al.

[18] and was aimed at controlling the three types of infections (i.e., primary endogenous, secondary endogenous, and exogenous infections) caused by both

“community” and “hospital” PPMs, by means of a parenteral antibiotic, a mix- ture of topical non-absorbable antimicrobials, high levels of hygiene, and sur- veillance cultures [19, 20]. Due to the lack of commercially available topical for- mulations, the application of SDD to hospital practice has required a substan- tial input from pharmacists in both the development and extemporaneous preparation of SDD formulations. This article aims to provide the reader with comprehensive information on the pharmaceutical technology involved in the implementation of SDD and how the role of the pharmacist is essential if this concept is to be successfully utilized to reduce carriage, colonization, and infec- tion rates.

Table 1. Potentially pathogenic micro-organisms (PPM) causing infection in intensive care unit (ICU) patients

Previously healthy host Host with severe underlying disease ("community" PPM) ("hospital" PPM)

1. Streptococcus pneumoniae 7. Klebsiella spp.

2. Haemophilus influenzae 8. Proteus spp.

3. Moraxella catarrhalis 9. Morganella spp.

4. Escherichia coli 10. Enterobacter spp.

5. Staphylococcus aureus 11. Citrobacter spp.

6. Candida albicans 12. Serratia spp.

13. Acinetobacter spp.

14. Pseudomonas spp.

The Use of Non-Absorbable Antimicrobials-the PTA Regimen

In healthy individuals host defense mechanisms prevent abnormal carriage in the digestive tract of PPMs, including aerobic gram-negative bacilli (AGNB).

However, if host defense mechanisms are impaired in traumatized and infected patients, e.g., after intubation (impaired cilia), urinary catheterization (sphinc- ter breached), or gut paralysis, carriage can lead to colonization and with immunoparalysis to infection [3]. Micro-organisms present in the oropharynx migrate down to the lower airways causing respiratory tract infections and sub- sequent pneumonia. Those present in the rectum migrate to the urethra and bladder to cause urinary tract infections. Lesions of the head, neck, and thorax can become infected by salivary flora, whilst lesions below the waist are usual- ly infected by fecal flora. Septicemia may follow pneumonia, cystitis, and wound infection by further migration of micro-organisms. Translocation of PPM through the gut mucosal lining may occur, producing systemic infection with- out the stage of colonization [21–23].

SDD aims to convert the abnormal carrier state into normal carriage, using oral, non-absorbable antimicrobials. It is a method of controlling coloniza- tion/infection, moderating the systemic inflammatory response, and containing the spread of multi-resistant micro-organisms. Locally applied oropharyngeal and gastrointestinal antibiotics are directed at eradicating the carriage of PPMs, including Staphylococcus aureus, AGNB, and yeasts [24]. Only the use of non-absorbable antimicrobials can guarantee concentrations in the saliva and feces high enough to selectively abolish the carriage of PPMs [25] without influencing the protective anaerobic flora, thereby decreasing colonization resistance. The ideal regimen should use antimicrobials that are non-toxic, inexpensive, palatable, and microbiologically active in the presence of feces, saliva, or antacids [26, 27]. It should be noted that only a parenteral antibiotic can eradicate colonization and infection; enteral agents only prevent carriage [28, 29]. The most widely used SDD regimen is that of the Groningen group [18]

who devised a protocol using polymyxin E, tobramycin, and amphotericin B applied as an oral paste and suspension to treat both the throat and gut, respec- tively. Hence the antimicrobials of this SDD regimen are often referred to in the literature as “PTA” after the initial letters of polymyxin E, tobramycin, and amphotericin B. In the United Kingdom polymyxin E is known as colistin.

There are 14 potential pathogens (Table 1) that can cause serious infection

and death during a patient’s ICU stay. The rationale behind the use of SDD is to

control the three types of infection due to the 14 potential pathogens [19]. The

combination of polymyxin E and tobramycin is synergistic against Proteus and

Pseudomonas species. It is the most potent anti-pseudomonal combination asso-

ciated with an effective clearance of Pseudomonas from the gut. Emergence of

resistance to polymyxin is rare. Although there are bacteria producing

tobramycin-inactivating enzymes, polymyxin is thought to protect tobramycin from being destroyed by these bacterial enzymes [24]. Tobramycin is the pre- ferred aminoglycoside because it is intrinsically most active against Pseudomonas and is minimally inactivated by saliva and feces [30]. It also has useful activity against Staphylococcus aureus [28]. Both agents absorb endotoxin released by AGNB in the gut. This feature is important because endotoxin can be absorbed from the gut of seriously ill patients producing fever, release of inflammatory mediators, and shock [31]. Amphotericin B is included to prevent overgrowth by yeasts. It is intrinsically the most potent antifungal but there is a high rate of inac- tivation in the gut requiring the use of high doses [32]. By design, the PTA regi- men is inactive against the indigenous flora, such as Streptococcus viridans, ente- rococci, coagulase-negative staphylococci, and anaerobes [28], each of which is necessary for normal physiological gut function.

Indications

In the PICU setting SDD is indicated [33]:

1. In the control of infection—in patients requiring ventilation for more than 3 days SDD reduces the risk of endogenous infections.

2. In the control of inflammation—following cardiac surgery (and particular- ly cardiopulmonary bypass) patients develop the systemic inflammation response syndrome (SIRS), characterized by high levels of cytokines, leuko- cytes, and increased C-reactive protein. Polymyxin E and tobramycin neu- tralize endotoxin and reduce gut overgrowth.

3. To prevent resistance—SDD eradicates multi-resistant micro-organisms detected from surveillance swabs of throat and rectum.

Method of Application

Selective Decontamination of the Oropharynx

SDD gel containing 2% polymyxin, tobramycin, and amphotericin B (PTA) is used. A pea-sized application of gel is evenly smeared in the lower cheeks four times a day. A 5-g tube lasts approximately 5 days.

Selective Decontamination of Gastrointestinal Tract

The antimicrobials are given orally or through the nasogastic tube. When the

patient requires gastric suction, the nasogastric tube is clamped and the suction

is discontinued for 1 h. When the normal anatomy of the gastrointestinal tract is disrupted (gastro or intestinal fistulae or colostomy), each (blind) loop should be separately treated with approximately half of the oral PTA dose in an adequate volume [33]. Doses of the preparations used are shown in Table 2.

Table 2. Doses for selective decontamination of the digestive tract (SDD) [33]

Over 12 years Polymyxin E/colistin 100 mg
3,000,000 units four times daily Tobramycin base 80 mg four times daily

Amphotericin B 500 mg four times daily

SDD gel A pea-sized application four times daily 5-12 years Polymyxin E/Colistin 50 mg
1,500,000 units four times daily

Tobramycin base 40 mg four times daily Amphotericin B 250 mg four times daily

SDD gel A pea-sized application four times daily 1-4 years Polymyxin E/Colistin 25 mg
750,000 units four times daily

Tobramycin base 20 mg four times daily Amphotericin B 100 mg four times daily

SDD gel A pea-sized application four times daily Small infants/ Polymyxin E/Colistin 25 mg
750,000 units four times daily neonates Tobramycin base 20 mg four times daily

Amphotericin B 100 mg four times daily

SDD gel A pea-sized application four times daily The dose administered is dependent on gut volume

To be administered 30 min before feeds and not with feeds

Sucralfate significantly reduces concentrations of colistin, tobramycin, and amphotericin B, therefore separate administration by 2–4 h [34]

Colistin doses in milligrams are specified as colistin base, where 1 mg=30,000 units.

However, colistin should normally be prescribed in units and the appropriate preparation used to give the specified number of units

1 mg tobramycin base is equivalent to 1.5 mg tobramycin sulfate 1 mg colistin base is equivalent to 1.5 mg colistin sulfate

Pharmaceutical Technology

The development of SDD medication has depended upon close collaboration

between pharmacists and microbiologists. For decontamination of the gut in

the unconscious adult and in children, liquid preparations for administration

via a nasogastric tube are required [35]. For decontamination of the orophar-

ynx, formulations covering oral gel and paste, pastilles, and lozenges have been

developed and prepared by hospital and academic pharmacists [36]. Solutions

or suspensions of the three antimicrobials are used for oral and nasogastric

administration [33]. Colonic coated tablets of colistin have also been prepared

for positioned release into the colon [37]. No commercial company has yet shown more than a passing interest in the further development, licensing, or marketing of these preparations, and this may have influenced the rate of devel- opment of the SDD concept.

Since all preparations are made extemporaneously in the hospital pharma- cy or manufacturing units, they are classed as “hospital specials” and as such are unlicensed. In using these unlicensed products in clinical practice, respon- sibility for safety and efficacy lies with the prescriber and responsibility for quality is with the pharmacist. Ideally, to reduce risks to the patient it would be preferable to use medicines that have been appropriately researched and sub- jected to the scrutiny of the medicines licensing process. One other problem with extemporaneous production is that in the United Kingdom pharmacy departments are limited in the quantities of products that they can prepare, unless they have a Manufacturer’s licence (specials) issued by the Medicines Control Agency (MCA).

Because SDD medication is not commercially available or supported by the usual manufacturers’ marketing activity [38], scientific background to the for- mulations (assay, rheology) is limited. To date little work has been undertaken to develop assays for the PTA ingredients, when combined in mixtures or for- mulations for local, oral application. Assays should indicate activity of the con- stituent antimicrobials and therefore a microbiological assay is preferred to techniques such as high-performance liquid chromatography. Suitable micro- organisms must be selected for their resistance to the other PTA components, lack of reversion to sensitivity must be demonstrated, and diffusion from the gel to agar plate must be matched to that of standard antimicrobial solutions.

In spite of commercial apathy, hospital-based research is continuing into areas such as modifications to the gel, the development of colonic positioned release products, and the production of placebo products for trial work. It should be noted, however, that the extemporaneous production of SDD formu- lations does lead to an increase in a hospital pharmacy department’s workload and that involvement in research programs requires a considerable amount of research and development work that would be best met by commercial support.

Choice of Formulation

Oropharynx

In order to abolish carriage of PPMs in the oropharynx a contact time of at least

20 min is required for effective decontamination [30, 36]. Pastes, gels, pastilles,

and lozenges therefore offer advantages over suspensions, aerosols, and oral

rinses, as they have a longer contact time [39]. The ideal formulation for use in

the oropharynx should therefore have a prolonged contact time with the oral mucosa, should release the antimicrobials into the oropharynx throughout the contact period, should be pharmaceutically stable, and should be acceptable to the patient [36].

There are four suitable formulations recommended for use in the orophar- ynx–paste, gel, lozenge, or pastille. It should be noted that the shelf life for these products has been assigned on the basis of in vivo microbiological experience and not by traditional pharmaceutical methodology. For use in our PICU, the majority of these preparations are prepared and supplied to us by a specialist hospital pharmacy manufacturing unit at the Western Infirmary in Glasgow, Scotland.

Paste. A paste has advantages in that it is easy to produce, it has good adhesion to the mucosa, it has a prolonged release of medicament, it is stable, and has a well-proven formula [39] (Table 3). Although the paste is effective in the elim- ination of AGNB, it has several drawbacks. It has an unpleasant taste and appearance and can cause considerable drying of the oral mucosa and it can be difficult to remove, occasionally causing trauma to the mucosa [35]. Because of this it has poor acceptability with patients, staff, and relatives. We restrict the use of the paste to topical applications around tracheostomy and gastrostomy sites, where the adherence and barrier properties of the paste are particularly useful. Application of the topical antimicrobials to tracheostomy sites has been proven to be effective in reducing the exogenous route of colonization [3].

Pastille. The advantages of the pastille are that it can be flavored easily, it has good release characteristics, it is easy to use, and it is acceptable to the con- scious patient (Table 4). Studies in cancer patients have demonstrated that SDD pastilles are effective in eradicating the carriage of AGNB and yeasts, reducing the incidence of radiation mucositis and yeast stomatitis in these patients [40].

Table 3. Formula for SDD paste [39]

Amphotericin B powder 2 g (adjusted for potency)

Tobramycin sulfate USP 2 g

Colistin sulfate BP 2 g

Liquid paraffin 10 g

Orabase paste (ConvaTec) to 100 g

Shelf life: 1 month Do not refrigerate

SDD paste is prepared by mixing each of the antimicrobial powders with 10% w/w liquid paraf-

fin and gradually incorporating Orabase. Vigorous mixing causes the Orabase to crack

Table 4. Formula of SDD pastille [39]

Gelatin 500 g

Glycerol BP 700 g

Sucrose 100 g

Sodium benzoate 4 g

Distilled water 600 ml

Lemon oil 2 ml

Blackcurrant powder 10 g

Amphotericin B powder 15.88 g (adjusted for potency)

Colistin sulfate BP 12.95 g

Tobramycin sulfate USP 12.95 g

To prepare SDD pastilles soak the gelatin and water and heat to melt. Add most of the glycerol and the other ingredients except the antibiotics and mix well. Heat for 30 min and then add the antibiotics, wetting the amphotericin with glycerin

Shelf life: 6 months

Each pastille weighs 1.5 g and contains 12 mg of amphotericin and 10 mg of tobramycin and colistin

The pastille, however, has limited use as it cannot be used in comatose patients, it has a high sugar content, and therefore cannot be used in diabetics, and it is unsuitable for young children [34]. It is difficult to produce, as many hospital pharmacy departments do not have appropriate facilities, and there- fore this preparation needs to be made in a specialized manufacturing unit.

Lozenge. The advantages and disadvantages of the lozenge are very similar to that of the pastille (Table 5). In cancer patients the eradication of AGNB and yeasts by SDD lozenges has been shown by Spijkervet et al. [41] to take up to 3 weeks, therefore comparing poorly with eradication rates of 3–4 days that have been achieved by the use of SDD paste in ICU patients. One explanation for these differing eradication rates would be that patients on the ICU are uncon- scious, permitting proper application of sticky paste, whilst patients with head and neck cancer suck their lozenges four times daily and eat normal, unsteril- ized food. Poor compliance within this group of patients, a lower standard of personal hygiene, and an altered oropharyngeal anatomy may also contribute to the longer eradication times.

Lozenges, when sucked will take approximately 15 min to dissolve in vivo.

Hence they do not achieve the same length of contact time with the buccal

mucosa as the paste or gel, and this is therefore another factor contributing to

poorer eradication rates. These results would suggest a need for new formula-

tions to be developed, in order to allow a more protracted and hence more effective delivery of the antimicrobials to the buccal mucosa of ambulant patients.

Gel. The gel is an improvement on the paste in that it is more palatable, much easier to remove, and does not dry the oropharyngeal mucosa [35] (Table 6).

The efficacy of this formulation appears to be equal to that of the paste [35].

Patient acceptability with the gel is high and therefore compliance is better. The gel is also sugar free. The gel presents problems, however, in that it is difficult to produce and at present its long-term stability is unknown [36].

Gastrointestinal Tract

Decontamination of the gut is not difficult. Most ICU patients have gut stasis, there is good contact time between antimicrobials and organisms and it can be demonstrated by surveillance culture that decontamination of the esophagus, stomach, and small intestine occurs within 3 days [35, 43]. However, in order to clear PPMs from the large intestine there must be gut motility. Due to this con- trolling factor, decontamination of the colon and rectum may therefore be longer and may take up to 7 days. A formulation for use in the gastrointestinal Table 5. Formula for SDD lozenge [42]

Antibiotic mixture

Amphotericin B powder 10 mg

Colistin sulfate BP 2 mg

Tobramycin sulfate USP 1.6 mg

Basic mixture

Citric acid 40 mg

Calcium diphosphate 150 mg

Saccharine 795 mg

Shelf life: 3 months

To prepare SDD lozenges, two powder mixtures are prepared. After sieving of the powders,

the total mixture is mixed in a turbula mixer (90 rpm) for 15 min. The total powder mix-

ture is then moistened with 25 ml of water and thereafter 25 ml of sodium carboxy-

methylcellulose (low viscosity) is added. Further mixing then takes place for 10 min, after

which the moistened powder is dried for a minimum of 4 h at 40°C. The dried mixture is

then mashed through a 0.75-mm sieve and the resultant granulate is then sieved further

through a 0.4-mm sieve in order to eliminate the fine powder. Prior to the final tableting

stage the granulate is mixed with 0.5% magnesium stearate and 2.5% talc, in the turbula

mixer for 2 min

tract should therefore ideally release the antimicrobials in the terminal ileum and provide high concentrations of these antimicrobials in the colon and rec- tum [36]. The product should also be easy to use, acceptable to patients, and have good pharmaceutical stability [36].

To date only oral suspensions and solutions have been used (Tables 7–10).

Although Crome [36] in 1989 suggested that research was progressing into the development of colon-positioned release tablets/capsules for use in conscious patients, this research does not appear to have led to the availability or wide- spread use of these preparations [44]. We have used colonic coated colistin cap- sules only once [37] in conscious, immunocompromised patients who had func- tioning guts. The aim of colonic coated preparations is that they should allow release of the capsule contents at a pH of approximately 7–7.2, resulting in dis- integration in the ascending colon. The resultant local delivery of antibacterial agents into the colon is thought to achieve fecal flora suppression [45] and by bypassing the esophagus and stomach, gastrointestinal side effects, such as nausea and vomiting, should be reduced.

The widespread use of the oral solutions and suspensions in PICU therefore continues. The advantages of these products being that they are stable [39], easy to produce, and can be given via a nasogastric tube, and are therefore suitable to give to an unconscious patient [36]. Problems with poor taste, however, par- Table 6. Formula for SDD gel 2% [39]

Sodium carboxymethylcellulose (Blanose) 10 g

Glycerol BP 60 ml

Methylhydroxybenzoate 600 mg

Concentrated peppermint water BP 10 ml

Distilled water 200 ml

Amphotericin B powder 6 g (adjusted for potency)

Colistin sulfate BP 6 g

Tobramycin sulfate USP 6 g

Shelf life: 1 month Refrigerate

A gel base is prepared from sodium carboxymethylcellulose, propylene glycol, or glycerol and methylhydroxybenzoate solution. Peppermint water is added for flavor; 2% by weight of each of amphotericin B, colistin sulfate, and tobramycin sulfate are stirred into the cold gel base and the resulting SDD gel is packed into aluminium tubes using a syringe and tube to aid filling

Colistin sulfomethate sodium has been used in the gel in some centers where a "stringy"

texture has been noted when using the sulfate. This method involves the use of the com-

mercial powder for injection (Colomycin injection, manufactured by Pharmax)

ticularly of colistin, may decrease compliance in conscious patients. In neonates, vomiting and other gastrointestinal problems have been seen, partic- ularly if concentrated solutions are administered to an empty stomach [46]. The osmolality of amphotericin suspension is high, approximately 2,000 mosmol/l

Table 7. Formula for amphotericin suspension 100 mg/ml [39]

Amphotericin B powder 500 g (adjusted for potency)

Sodium citrate BP 25 g

Sodium carboxymethylcellulose (Blanose) 12.5 g

Veegum K 25 g

Citric acid monohydrate 5.95 g to adjust pH to 5.5

Saccharin solution BPC 7 ml

Lycassin 750 ml

Nipasept 6.5 g

Concentrated peppermint water BP 125 ml

Distilled water to 5,330 g

Shelf life: 6 months

A suspension is prepared with sodium carboxymethylcellulose (Blanose) as suspending and thickening agent, distilled water and Lycassin as the sweetener.Veegum K (hydrated ma- gnesium aluminum silicate) is then added as the anticaking agent. Amphotericin B powder is added gradually to this mixture, stirring after each addition. Nipasept used as a preser- vative is dissolved in the concentrated peppermint water and then added to the suspension.

Peppermint water is added to mask the metallic taste of amphotericin. Finally saccharin so- lution is added to improve palatability and citric acid monohydrate to adjust the pH of the suspension to 5.5. The remaining water is then added to make up to the final weight

Table 8. Formula for colistin oral solution 100 mg base (3 Munits) in 1 ml [37]

Colistin sulfate powder Ph.Eur 15 g

Nipasept sodium powder 150 mg

Orange syrup BP 10 ml

Purified water to 100 ml

1.5 g colistin sulfate
1 g colistin base Shelf life: 1 month

Refrigerate

Colistin for SDD is prescribed as base

The solution is prepared by dissolving colistin sulfate powder in purified water, using oran- ge syrup as flavoring and Nipasept as the preservative

[A commercial preparation of colistin is available (Colomycin) from Forest. It contains

250,000 units of colistin in 5 ml and is stable for 2 weeks when reconstituted]

compared with an osmolality of approximately 430 mosmol/l with a 25 mg/ml colistin solution and 60 mosmol/l with a 20 mg/ml solution of tobramycin sul- fate. Because hyperosmolar medications have been associated with an increased incidence of necrotizing enterocolitis [46], it is recommended that all three PTA ingredients should be diluted in water. Observers have also suggested that PTA may delay gastric emptying/absorption of feeds, and the binding of colistin and tobramycin by food proteins is a factor known to reduce the lethal intestinal antibiotic levels required for eradication of AGNB [29]. This interference with food has been shown to be the reason for SDD failure when oral contaminated feeds were given to a premature neonate [29]. On our PICU we recommend that SDD doses should be administered 30 min before feeds and not with feeds [33].

Although there are a limited number of commercially available products that could be used for SDD, problems with pack sizes, expiry dates, and strengths of the commercial products mean that most ICUs prefer to use extem- poraneously prepared products on their patients. For example, colistin syrup is available commercially at a strength of 250,000 units in 5 ml (Colomycin, Forest). This means that to give a dose of 3,000,000 units (
100 mg) for a patient over 12 years of age, 60 ml would be required per dose, i.e., 240 ml/day.

Table 9. Formula for tobramycin sulfate oral solution 120 mg in 1 ml [37] (containing tobramycin base 80 mg in 1ml)

Tobramycin sulfate powder USP 1,200 mg

Orange syrup BP 1 ml

Preserved distilled water to 10 ml

120 mg tobramycin sulfate
80 mg tobramycin base Shelf life: 2 weeks

Store at room temperature.

Tobramycin for SDD is prescribed as base

A solution is prepared with tobramycin sulfate in preserved distilled water using orange syrup for flavoring

Table 10. Formula for preserved distilled water [39]

Nipasept 0.12% 24 g

Absolute alcohol 200 ml

Glacial acetic acid to pH 4–6

Distilled water to 20 l

Shelf life: 1 year

The same dose using an extemporaneously prepared 100 mg/ml colistin oral solution would equate to a volume of 1 ml, i.e., 4 ml/day. Amphotericin sus- pension is another example of a problem encountered with a commercial prod- uct. Although the strength of the licensed product, Fungilin (Squibb) at 100 mg/ml is equivalent to the extemporaneously prepared product, Fungilin is only available in 12-ml bottles and therefore is very inconvenient for a 5 ml four times a day dose that would be required for a patient over 12 years. Another disadvantage with Fungilin is that once opened the manufacturers advise that the suspension should be discarded after 4 days.

Costs of Decontaminating Agents

Formal cost-benefit analyses of SDD in ICU patients have not been performed.

In theory successful prevention of infection may make the ICU more cost-effec- tive, in that reduced infection rates secondary to SDD may lead to a shorter patient stay on ICU, lower ICU costs, parenteral antibiotic usage, and microbi- ology laboratory costs [30]. It has not been firmly established whether these potential savings offset the additional costs that the SDD regimen incurs through the use of non-absorbable antimicrobials, systemic antimicrobials, and additional microbiological cultures [47]. Hence, despite 54 randomized con- trolled trials and nine meta-analyses including two recent analyses suggesting that using the full concept of SDD leads to a 22% reduction in mortality [15, 16], the routine use of SDD in ICUs remains controversial [47, 48].

The average costs for the drugs used in the PTA regimen using products pre- pared by a specialist hospital manufacturing unit are listed in Table 11 and the costs of commercially available preparations in Table 12. The cost of treating a patient over 12 years of age using the available commercial products and prod- ucts manufactured in the hospital manufacturing unit are also compared.

Tables 11 and 12 show that the cost of SDD can be substantially reduced if preparations for SDD are manufactured in the hospital pharmacy [50]. Due to the commercial unavailability of a tobramycin oral solution and an SDD gel, it would not be possible to follow the PTA regimen without the provision of hos- pital-made products. Although the daily cost of the licensed amphotericin sus- pension is actually less than the hospital-prepared product, the small pack size of only 12 ml makes this product impractical for routine use on a busy ICU.

One factor that may make it difficult for a hospital pharmacy to begin man-

ufacturing preparations for SDD regimes is sourcing the “raw ingredients” nec-

essary to make the products. Table 13 therefore provides useful information to

overcome this problem.

Table 11. Costs of hospital preparations (March 2004)

Drug Supplier Pack size Cost (£) Total daily Cost/day (£) dose >12 years

Amphotericin Western 100 ml 21.85 2,000 mg 4.37

100 mg/ml Infirmary, suspension Glasgow

Colistin Alder Hey 100 ml 41.50 400 mg 1.66

solution Hospital, 100 mg/ml Liverpool

Tobramycin Alder Hey 100 ml 97.0 320 mg 3.88

solution Hospital, 80 mg/ml Liverpool

SDD gel Western 5 g 7.50 A pea-sized 1.5

Infirmary, application

Glasgow four times a day

SDD paste Western 5 g 10.0 A pea-sized 2.0

Infirmary, application

Glasgow four times a day

SDD pastilles Western 28 14.0 1 pastille 2.0

Infirmary, four times a day

Glasgow

Table 12. Costs of commercially available preparations (March 2004) [49]

Drug Supplier Pack size Cost (£) Total daily Cost/day (£) dose >12 years

Colomycin Syrup Forest 80 ml 3.71 400 mg 11.13

(colistin sulfate (
12,000,000 units)

250,000 units/5 ml)

Colomycin tablets Forest 50 62.18 400 mg 9.95

(colistin sulfate (
12,000,000 units

1.5 million unit tablets)

Fungilin suspension Squibb 12 ml 2.31 2,000 mg 3.84

(amphotericin 100 mg/ml)

Fungilin tablets Squibb 56 8.32 2,000 mg 2.97

(amphotericin 100 mg tablets)

Fungilin lozenges Squibb 60 3.95 1 lozenge four 0.26

(amphotericin times a day

10-mg lozenges)

Table 13. Possible sources of ingredients

Ingredient Supplier

Sodium carboxymethylcellulose (Blanose), E. Merck and Lipha, Hunter Boulevard,

Sodium benzoate Magna Park, Lutterworth,

Leics, LE17 4XN, UK Tel.: 0800 22 33 44

Amphotericin B powder Fahrhaus Pharma

Tobramycin sulfate powder USP Hamburg, Germany Colistin sulfate powder Ph.Eur. Tel: 00 49 40 61 17 18 19

Fax 00 49 40 61 17 18 18 Glycerol BP, citric acid Thornton and Ross Ltd.

monohydrate, liquid paraffin Linthwaite Laboratories, Huddersfield HD7 5QH, UK Tel.: 01484 842 217

Methylhydroxybenzoate BP J.M. Loveridge plc. Southampton, UK Tel.: 02380 228411

Fax: 02380 639836

Conclusion

Although the application of the SDD concept to intensive care medicine has been proven to reduce ICU-related morbidity and mortality and in spite of a recent publication validating SDD as an evidence-based medicine maneuver [51], the SDD approach is still not widely used on ICUs. Reasons for this may include:

1. SDD is contrary to the traditional concept that prophylaxis creates resist- ance.

2. A primacy of opinion over evidence.

3. Opinion leaders control the medical media.

4. SDD formulations are not marketed by the pharmaceutical industry.

5. There is little physician-pharmaceutical industry interaction to stimulate industry interest in manufacturing SDD products.

In the current climate, with a lack of commercial products, the necessary

extemporaneous production of SDD formulations must be undertaken by a

pharmacy department that is able to commit to the additional workload that

this entails. This means that at present the formulation and supply role of the

hospital pharmacist is vital in order to facilitate the application of the SDD

concept to clinical practice.

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