Hospital
Pharmacist Vol 7 No 8 p228-236
September 2000 Articles
Microbial survival in infusion fluids - the relevance to the management of aseptic facilities
By S. A. Langford, PhD, MRPharmS
This article presents an overview of studies of microbial growth in intravenous fluids carried out within the past 28 years, and discusses the significance of the data for hospital pharmacists involved in aseptic preparation
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| Pharmacists working in aseptic preparation should be aware of microbial growth which can occur in intravenous fluids |
Aseptic compounding in National Health Service hospitals continues to
be the focus of much attention. In view of the risks arising from microbial
contamination, the hospital pharmacist involved in the management of aseptic
facilities needs to know which micro-organisms are most likely to cause
problems, where they come from, how they can be detected and eliminated,
and, not least, whether current standards and procedures are correctly
focused.
The clinical incidents resulting from microbial contamination have been
reviewed previously.1 This article examines data from microbial growth
studies in intravenous fluids and discusses their relevance to the management
of aseptic processes.
| Click on the pictures below to view table 1 |
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A review of microbial growth studies presents several difficulties, ranging from establishing the clear identity of the microorganism studied, differences between strains, varying nutritional requirements, different study methodologies and contradictory study outcomes. The data presented in this article represent a heavily edited “overview”; a complete citation of references is also provided for further study if required. An attempt has been made to use current nomenclature for the species cited.
Methods
Data were collected from published papers and the references cited therein
were followed up. In addition, computer searches covering the past 10
years were carried out on Pharmline and Medline.
Data relating to intravenous fluids no longer in use, particularly parenteral
nutrition solutions, were excluded. Only papers giving clear species identification
are quoted. In addition, study methods had to include washed cultures
and provide quantitative growth data. This resulted in the exclusion of
several papers cited in other reviews.
Where possible, simplified quantitative data are reported and represent
the growth of the most prolific strain for that species. Most studies
relate to clinical isolates for the species cited, ie, those species isolated
from patients.
Table 1 shows the survival data in general intravenous fluids, individual
parenteral nutrition ingredients and simple amino acid/carbohydrate mixtures.
Table 2 gives details of more complex parenteral nutrition formulae. Although
based on a recent review by Didier et al,10 it differs from that review
in the selection of papers and attempts a more quantitative presentation
of the data.
Discussion
Examination of Table 1 confirms contradictions in the data cited, which
clearly require careful interpretation. Baggerman identified some of the
limitations of these studies, including microbial innocula ranging from
1cfu/ml to 106cfu/ml, different times and temperature
of incubation, different sampling frequencies, and whether the micro-organisms
had been metabolically depleted or not.28 Also, the
species selected for study have mostly been those associated with septic
patients, rather than those found in the manufacturing or ward environment.
An informative general review of microbial hazards in pharmaceuticals
and cosmetics has been published by Parker.37 A good
recent review by Hyde covers changes in nomenclature, particularly in
the Corynebacterium group, and gives some guidance on monitoring.38
The following general conclusions may be drawn:
- Gram-negative organisms, particularly Tribe Klebsiella (TK, comprising Enterobacter, Klebsiella and Serratia) and pseudo- monads, clearly represent a hazard, owing to their ability to grow in a wide variety of fluids
- Lipid formulations are a high-risk area,
so that consideration should be given to handling these formulations in aseptic facilities, especially if delays in use are expected. A maximum infusion time of 12 hours for lipid-containing infusions has been recommended39 - Refrigeration on storage and transport
is essential. Most micro-organisms do not proliferate at low temperatures; an exception is Pseudomonas fluorescens.29 However, most species do remain viable at low temperatures, even if frozen.40,41
Recent American guidelines on intravascular device-related infections
have drawn attention to the preponderance of coagulase-negative staphylococci
(CoNS, Staphylococcus epidermidis), S aureus, Candida species (C albicans)
and enterococci in nosocomial bloodstream infections since the mid 1980s.42,43
An interesting observation is the enhancement of CoNS growth in heparin
solutions used to maintain line patency.
Akers,44 and Holmes and Allwood45
have reviewed general sources of contamination. Gram-negative organisms
have been isolated from hand cultures in 55 per cent of ward staff,46
of which 87.5 per cent were TK organisms, with half of these isolates
being antibiotic-resistant. A similar survey of patients found 51 per
cent of hand cultures with Gram-negative organisms.47
Among pharmacy staff, a hand contamination rate of 79 per cent has been
reported,48 of which 52 per cent were TK organisms.
A survey of hospital sinks recovered a wide range of Gram-negative organisms,
of which 86 per cent were antibiotic resistant.49
Parenteral nutrition has a long association with increased risk of sepsis,
and two reviews cover infection control for this therapy.50,51
However, many studies suffer from methodological flaws, and these have
been well reviewed by Didier et al.10 The hazard
presented to total parenteral nutrition solutions (TPN) by Candida species
is confirmed by the data in Table 2.
Escherichia coli and Kl pneumoniae also appear to present particular risks.
It is notable, however, that Enterobacter cloacae does not appear to grow
in TPN solutions, despite being associated with serious episodes of sepsis.
Could this be due to gross failure in asepsis, allowing a high bacterial
concentration to develop in TPN solutions before causing disease?
A detailed discussion of environmental controls is beyond the scope of
this article and is the subject of ongoing debate.52,53
However, environmental monitoring for fungi should be carried out in departments
preparing TPN solutions. The data in Tables 1 and 2 reinforce the need
to adhere to current aseptic guidelines,54 ie, control
of hand-washing facilities and sinks, and good hygiene and cleaning practices,
with robust staff training and monitoring.
An area for further work is the elaboration of environmental monitoring
programmes, particularly with regard to the interpretation of results
and actions to be taken in the event of out-of-limit results. The latter
are particularly relevant, given the unreliability of product testing.
In many hospital pharmacies, product sterility testing is retrospective,
subject to well-known sampling inadequacies and, for cytotoxic products,
not widely available, owing to the handling precautions required. In addition,
staphylococci do not survive well in intravenous fluids and will have
died out before testing.55
A final point on testing is that only total filtration methods are reliable,
as many fluids remain clear even when containing very high levels of contamination
— up to 106cfu/ml;4,5,23,30
similarly, no physical changes may be apparent in lipid emulsions.20 The
recommendations can be summarised as follows:
l Gram-negative organisms, particularly TK, represent a significant risk
to intravenous solutions and require a rapid and vigorous response on
detection
l Monitoring for fungi should be carried out where TPN solutions and lipid
formulations are handled. Lipid formulations, eg, propofol, should preferably
be handled in aseptic facilities
l All intravenous products should be stored and transported under refrigeration,
unless specific stability considerations are to the contrary
l Product testing for microbial contamination should be based on total
filtration methods
Acknowlegments: With thanks to Dr Peter Lambert, department of
pharmacy, Aston university, for microbiological advice.