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British Journal of Anaesthesia 1998; 81: 444–448
Antibacterial activity of lidocaine in mixtures with Diprivan
R. J. GAJRAJ, M. J. HODSON, J. A. GILLESPIE, G. N. C. KENNY AND N. B. SCOTT of a range of organisms to lidocaine; the concentra- tions of lidocaine required for bactericidal and bacte- We have studied the antibacterial activity of dif- riostatic effects; and the antibacterial effects of ferent concentrations of 0.005–2% lidocaine (lig- clinically used concentrations of lidocaine. nocaine) in mixtures with Diprivan (propofol), against micro-organisms commonly implicated in sepsis as a result of extrinsically contaminated Diprivan. Bacterial colony counts were reduced Test mixtures of lidocaine and Diprivan were inocu- progressively with increasing concentrations of lated with suspensions of organisms, and colonies lidocaine. Bacteriostatic and bactericidal concen- were counted from samples of the inoculated suspen- trations of lidocaine were 0.2–2%. Lidocaine 2% sions after a period of incubation. The organisms was not bactericidal for one of the seven organ- used were clinical (hospital) isolates (CI) or standard- isms tested. By inhibiting bacterial replication, ized typed organisms from the National Collection of lidocaine, when added to Diprivan to reduce pain Typed Cultures (NCTC) as follows: Staphylococcus on injection, may possibly reduce the harmful (S.) aureus (NCTC 6571), S. epidermidis (coagulase- consequences if extrinsic contamination occurs. negative staphylococcus—NCTC 7944), Bacillus (B.) (Br. J. Anaesth. 1998; 81: 444–448).
subtilis (NCTC 10452), Escherichia (E.) coli (NCTC 10418), Moraxella (M.) osloensis (NCTC 10465), Keywords: anaesthetics local, lidocaine; anaesthetics i.v., Serratia (S.) marcescens (CI) and Burkholderia (B.) propofol; infection, bacterial; formulations, propofol; formu- lations, concentration The lidocaine–Diprivan test mixtures (5.25 ml) were prepared under aseptic conditions. The quan- The lipid-based i.v. drugs Diprivan (propofol)1 2 and tity of lidocaine in the mixtures ranged from 0.25 ml Diazemuls (diazepam)3 have been shown to support of 0.1% to 5.25 ml of 2%, producing a range of lido- growth of micro-organisms at room temperature. caine concentrations of 0.005–2%. Diprivan was the Most other i.v. anaesthetics are not lipid-based, and diluent used when preparing the lower concentra- studies have confirmed that they do not support tions of lidocaine. A sample of 1% Diprivan 5.25 ml As a result, there is concern that infusion of Suspensions of the bacteria diluted to a Bacto Diprivan may contribute to an increased incidence of McFarland Barium Sulfate Standard Number 1 postoperative infections. Investigators for the (measured by a Vitek colorimeter), equivalent to Centers for Disease Control (CDC) in the USA found that in some cases of postoperative sepsis, the millilitre, were prepared. Standardized suspensions organism isolated from infected patients was the containing approximately 105 cfu ml91 were made by same as that cultured from the throat or hands of the serial dil ution with 0.9% sal ine. The test mixtures anaesthetic personnel involved, or from syringes of were inoculated with 50-␮l samples of the standard Diprivan that had been used in these patients.6 7 suspensions of organisms to produce a final concen- Organisms implicated in postoperative sepsis caused tration of approximately 103 cfu ml91. These inocu- by administration of contaminated Diprivan include lated test mixtures were incubated at 37ЊC for 24 h. Staphylococcus (S.) aureus, Klebsiella pneumoniae, After this initial incubation, 100-␮l sampl es were Moraxella (M.) osloensis, Enterobacter agglomerans, obtained from each culture and from serial dilutions Serratia (S.) marcescens and Candida albicans.6–8 of each culture, and added to blood agar plates for It is wel l known that Diprivan is associated with another 24 h of incubation at 37ЊC. After this second pain on injection.9 10 Of the many drugs and tech- period of incubation, the resulting colony counts niques used to reduce the incidence of pain, only aspirin11 and local anaesthetics11–13 have demonstrable antimicrobial activity. The exact mechanism of the R. J. GAJRAJ, DM, FRCA, Department of Anaesthesia, The General Infirmary at Leeds, Leeds. M. J. HODSON, FRCA, Department of antimicrobial action of local anaesthetics is not Anaesthesia, Southern General Hospital, Glasgow. J. A. GILLESPIE, known, but may be caused by an effect on microbial FRCA, Department of Anaesthesia, Victoria Infirmary, Glasgow. cell membrane structure or function,11 14 15 or pH G. N. C. KENNY, BSC (HONS), MD, FRCA, University Department of Anaesthesia, Royal Infirmary, Glasgow. N. B. SCOTT, FRCS, FRCA, Department of Anaesthesia, HCI International Medical Centre, The aims of this study were to investigate further Beardmore Street, Clydebank G81 4HX. Accepted for publication: the antibacterial activity of lidocaine (lignocaine) in mixtures with Diprivan to determine: the susceptibility Antibacterial activity of lidocaine in Diprivan Figure 2 Colony counts for gram-positive bacteria (B. subtilis, S. aureus and S. epidermidis) after 24 h of incubation in Diprivan (D), 2% lidocaine (L) and Diprivan–lidocaine mixtures. †Colony counts higher (Mood Median test, P:0.05) than colony counts in Diprivan; *colony counts not significantly lower (Mood Median Figure 1 Inoculum sizes (colony counts at 0 h) and colony counts test, P:0.05) than colony counts in Diprivan. after 24 h of incubation in Diprivan for gram-positive and gram- negative bacteria. organisms had significantly lower colony counts in For a more precise measurement of the inoculum lidocaine concentrations of 0.05% or higher, com- size and to verify growth and viability of the organ- pared with counts in propofol alone (fig. 2). All gram- isms, 0.9% saline 5.25 ml was also inoculated with negative organisms had significantly lower colony 50 ␮l of the standard suspensions of each bacterium counts in lidocaine concentrations of 0.2% or higher, to produce the same final concentration (103 cfu ml91) compared with counts in propofol alone (fig. 3). as the test mixtures. Samples of 100 ␮l from this The recommended dose of lidocaine 10 mg in growth control were then added to Columbia blood Diprivan 20 ml (producing a concentration of almost agar plates and colony counts recorded after incuba- 0.05%) produced significantly lower colony counts tion for 24 h at 37ЊC. To verify sterility, samples from compared with colony counts in propofol alone, for the sources of Diprivan, lidocaine and 0.9% saline all except two organisms (table 1; figs 1, 2). were also incubated for 24 h at 37ЊC, and added to Lidocaine 0.1% (20 mg in Diprivan 20 ml) produced blood agar plates for colony counts after another 24 h significantly lower colony counts for all except one For each organism a bactericidal effect was defined Figure 4 demonstrates the bacteriostatic and bac- as the killing (or 99.9% elimination) of the initial tericidal concentrations of l idocaine for the organ- inoculum, and a bacteriostatic effect as the preven- isms tested. Lidocaine 0.2% was bacteriostatic for all tion of growth, that is no significant change in viable of gram-positive organisms. Bacteriostatic concen- count from the initial inoculum.17 Three replicates trations of lidocaine were 0.6–2% for the gram-nega- were performed with each organism to complete the tive organisms. Bactericidal concentrations were 0.2–2% for gram-positive organisms and 0.95–2% for gram-negative organisms. Bactericidal concentra- Windows) was used to compare the colony counts of tion was not determined for B. cepacia, as growth of each organism in each mixture of l idocaine and this organism persisted at the highest concentration Diprivan, with P:0.05 considered significant. The final concentrations of the organisms after inoculation in Diprivan–lidocaine mixtures were 160–1350 cfu ml91. Figure 1 demonstrates the differ- ent rates of growth of the various organisms in Diprivan, most notable with S. aureus, which was the largest inoculum used yet had the lowest colony counts after 24 h of incubation in Diprivan. Figures 2 and 3 illustrate the colony counts of the gram- positive and gram-negative organisms after 24 h of incubation in the Diprivan–lidocaine mixtures. With few exceptions, there was a progressive reduction in colony counts of all organisms with increasing concentration of lidocaine (figs 2, 3). Comparing colony counts in the lowest concentra- Figure 3 Colony counts of gram-negative bacteria (B. cepacia, tion of lidocaine (0.005%) with colony counts in S. marcescens, E. coli and M. osloensis) after 24 h of incubation in propofol alone, only one organism had significantly Diprivan (D), 2% lidocaine (L) and Diprivan–lidocaine mixtures. †Colony counts higher (Mood Median test, P:0.05) than colony lower counts (E. coli) while three organisms had counts in Diprivan; *colony counts not significantly lower (Mood significantly higher colony counts. All gram-positive Median test, P:0.05) than colony counts in Diprivan. Table 1 Colony counts of gram-positive and gram-negative bacteria after 24 h of incubation in Diprivan and in mixtures of lidocaine (L) and Diprivan. The Mood Median test (P:0.05) was used to compare colony counts. Lidocaine–Diprivan mixtures with colony counts that were not significantly lower (ns) than the corresponding colony counts in Diprivan alone are indicated Discussion
greater than 0.1 mg kg91.30 This dose of lidocaine (0.1 mg kg91) would be achieved with the manufac- Postoperative immunosuppression is well recog- turer’s recommended dose of 10 mg. However, other nized18–20 and there is also concern that administration studies have reported that larger doses of lidocaine of contaminated infusions of Diprivan may contribute are more effective.31–33 In several hundred anaesthet- to an increased incidence of postoperative infections. ics at our institution, one of the authors (N. B. S.) has Unfortunately, poor aseptic technique is common- used lidocaine in doses of at least 20 mg in Diprivan place among health care workers in the hospital envi- 20 ml, and we are unaware of any clinical problems ronment,21 22 and there is poor compliance with data related to this practice. Further, Lilley and colleagues sheet recommendations for the use of Diprivan.7 This suggested that clinically significant emulsion instability problem is so great that it led the authors of the CDC does not occur when l idocaine 20 mg is added to report7 and the accompanying editorial23 to suggest restriction of the use of Diprivan to personnel prop- In our study, the manufacturer’s recommended erly educated in the aseptic techniques of handling dose of 0.05% lidocaine was not bacteriostatic or the drug. As there is a delay of 8 h or more before bactericidal for any of the organisms tested, although organisms begin to multiply rapidly when inoculated there were significantly reduced colony counts for into Diprivan, Langevin and colleagues24 disputed al l gram-positive organisms and two of the gram- the conclusions of the CDC report6 that simple bac- negative organisms. Colony counts were reduced terial replication in contaminated Diprivan results in further with 0.1% lidocaine (equivalent to lidocaine postoperative infections. Others have suggested that 20 mg in Diprivan 20 ml), but 0.2% was the lowest by careful aseptic handl ing, it is possibl e to use the concentration of lidocaine with bacteriostatic effects. drug in multiple patients or long after opening the The bacteriostatic concentration of lidocaine ampoule, without significant risk of contamina- against S. aureus was found to be lower in this study than that reported in some studies34 35 but higher than The manufacturers recommend the addition of in others.36 The potency of l idocaine against E. coli lidocaine 10 mg to Diprivan 20 ml (approximately reported in some studies34 35 was similar to the find- 0.05% lidocaine) for the relief of pain on injection,28 ings of our study, but greater than in others.15 37 The as there may be problems of chemical incompatibility potency of lidocaine against S. marcescens and with larger doses.29 Gehan and colleagues suggested M. osloensis in one study35 was greater than that in our that there was no additional improvement in reduc- study. Fazly Bazaz and Salt concluded that the ing the pain of injection with lidocaine in doses antibacterial activity of lidocaine was greater against gram-positive than against gram-negative organisms.15 This is consistent with the findings of our study but contrary to those of Schmidt and Rosenkranz35 who investigated more than 1200 strains of bacteria and fungi and showed greater antibacterial activity against gram-negative organisms. These inconsisten- cies may be a result of differences in methodology34 or pH,16 presence of preservatives in the local anaes- thetic preparations,34 37 different serotypes of organ- isms tested,35 type of growth medium used38 and size of the initial inoculum.17 The size of the initial inoculum is an important factor that influences determination of antimicrobial potency.17 This should ideally be between 4 106 bacteria per sample.39 40 The use of larger inoc- ula may result in erroneously low antibacterial activ- ity because of the inclusion of spontaneously resistant bacteria,41 while measurement of Ն99.9% Figure 4 Bacteriostatic and bactericidal concentrations of killing for determination of bactericidal concentra- lidocaine for various gram-positive and gram-negative bacteria. tions may not be possible with insufficient colonies The bactericidal concentration for Burkholderia (B.) cepacia was not determined. from small inocula.39 The inoculum size used in our Antibacterial activity of lidocaine in Diprivan study was large enough to determine Ն99.9% killing 11. Ohsuka S, Ohta M, Masuda K, Arakawa Y, Kaneda T, Kato N. for only two of the organisms tested. Therefore, for Lidocaine hydrochloride and acetylsalicylate kill bacteria by disrupting the bacterial membrane potential in different ways. the other five organisms, we considered a bactericidal Microbiology and Immunology 1994; 38: 429–434.
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that the degree of killing of the initial inoculum con- 13. Erlich H. Bacteriologic studies and effects of anesthetic solu- sidered representative of bactericidal activity has tions on bronchial secretions during bronchoscopy. American
Review of Respiratory Diseases
1961; 84: 414–421.
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