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Canadian Journal of Anesthesia 51:911-914 (2004)
© Canadian Anesthesiologists' Society, 2004
Regional Anesthesia and Pain

Sufentanil modifies the antibacterial activity of bupivacaine and ropivacaine

[Le sufentanil modifie l’activité antibactérienne de la bupivacaïne et de la ropivacaïne]

Zohreh Tamanai-Shacoori, PhD*,{dagger},{ddagger}, Valliollah Shacoori, PhD{dagger}, Jean-Marie Vo Van, MD{dagger}, Jean-Claude Robert, PhD*,{dagger},{ddagger} and Martine Bonnaure-Mallet, PhD*,{dagger},{ddagger}

* From the Laboratoire de Microbiologie Pharmaceutique,
{dagger} Université de Rennes I, Département d’Anesthesiologie,
{ddagger} CHR (Hôtel Dieu), Equipe de Biologie Buccale, Université de Rennes I, Rennes, France.

Address correspondence to:: Dr. Zohreh Tamanai-Shacoori, Équipe de microbiologie, 1254 Faculté de Pharmacie 2 Av. du Pr Léon Bernard, 35043 Rennes Cedex, France. Phone: 33 2 23 23 43 91; Fax: 33 2 23 23 43 06; E-mail: zohreh.shacoori{at}univ-rennes1.fr


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: The purpose of our study was to investigate the effect on the growth of Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Enterococcus faecalis (E. faecalis) of bupivacaine at a final concentration of 0.77 mg·mL–1, ropivacaine at 1.2 mg·mL–1, and sufentanil at 0.38 and 0.5 µg·mL–1 (alone or in combination with bupivacaine and ropivacaine).

Methods: The strains were diluted to approximately 3 x 104 cfu·mL–1 in Mueller-Hinton broth. The anesthetics (0.5 mL) were incubated with the bacterial suspensions (0.5 mL) for 24 hr at 37°C.

Results: Bupivacaine inhibited the growth of E. coli (59 ± 0.8%; P < 0.05) and S. aureus (22 ± 3.6%; P < 0.05). Ropivacaine also inhibited the growth of E. coli (41 ± 1.2%; P < 0.05) and S. aureus (25.5 ± 4.1%; P < 0.05). Both anesthetics were ineffective against E. faecalis. Sufentanil only inhibited S. aureus (13.8 ± 3.1%; P < 0.05) at a concentration of 0.5 µg·mL–1. Sufentanil modified the antibacterial activity of bupivacaine and ropivacaine. It increased the inhibitory effect of bupivacaine on E. faecalis and S. aureus by 10 ± 2.1% (P < 0.05) and on E. coli by 7% (P < 0.05). Sufentanil did not increase the inhibitory effect of ropivacaine on the growth of S. aureus. On the other hand, sufentanil reduced the inhibitory effect of ropivacaine on E. coli by 11% (P < 0.05).

Conclusion: Both bupivacaine and ropivacaine alone or combined with sufentanil inhibited the growth of E. coli and S. aureus. E. faecalis was partially sensitive to a bupivacaine + sufentanil mixture. Sufentanil had a partial synergistic effect on bupivacaine and a partial antagonistic effect on ropivacaine’s antibacterial activity.


   Introduction
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 Abstract
 Introduction
Methods
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THE incidence of epidural abscesses has been reported to be one to two cases for every 10,000 hospital admissions. Epidural space infections caused by epidural anesthesia are rare. The antibacterial properties of local anesthetics may contribute to this low incidence.1,2 Various reports have demonstrated that bupivacaine, ropivacaine, lidocaine, and levobupivacaine inhibit the growth of bacterial strains in vitro.3–6

Conflicting results on the antibacterial properties of opioids have been reported. Some studies report that analgesic drugs alone or in combination with local anesthetics have no effect on the growth of bacteria,4,5 while others report that these drugs reduce bacterial growth in vitro.4,7 The antibacterial activity of opioids may have important implications for epidural space infections related to catheters and needles, especially given the current trend to use low concentrations of local anesthetics. Since we use bupivacaine, ropivacaine, and sufentanil in our obstetric department for labour pain, we thought it important to determine: i) whether sufentanil has a antibacterial effect on bacteria commonly found on the skin; and ii) whether sufentanil modifies the antibacterial properties of low concentrations of bupivacaine and ropivacaine.


   Methods
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 Methods
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Solutions of bupivacaine, ropivacaine hydrochloride and sufentanil were prepared in a physiological saline solution, individually and in combination.

Fresh mid-log phase bacterial cultures of Escherichia coli (E. coli; CIP 7624), Staphylococcus aureus (S. aureus; ATCC 9144), and Enterococcus faecalis (E. faecalis; CIP 3818). were diluted in Mueller-Hinton broth to obtain standard inocula ({approx} 3 x 104 cfu·mL–1).

The tested solutions (0.5 mL; 2 x concentration) and controls (0.5 mL; physiological saline) were added to 0.5 mL of standard bacterial preparations. The final concentrations of the anesthetics were: bupivacaine [0.77 mg·mL–1 (0.08%)], ropivacaine [1.2 mg·mL–1 (0.12%)], and sufentanil (0.38 µg·mL–1 with bupivacaine, 0.5 µg·mL–1 with ropivacaine). These concentrated mixtures of local anesthetic + opioid are most commonly used in our department.

The cultures were incubated for 24 hr at 37°C (T24), vortexed, and aliquots (200 µL) were pipetted into microplate wells to measure the optical density at 540 nm (Dynatech MR 5000, Embrach-Embraport, Switzerland). Each experiment was repeated by three parallel assays, and each assay was performed in duplicata.

One-way analyses of variance followed by the multiple range Student-Newman-Keuls test were used. Results are expressed as means ± SDs.


   Results
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Discussion
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Bupivacaine and ropivacaine had no effect on the growth of E. faecalis (Figures 1Go and 2Go). Bupivacaine inhibited the growth of E. coli and S. aureus by 59 ± 0.8% (P < 0.05) and 22 ± 3.6% (P < 0.05) respectively (Figure 1Go). Ropivacaine inhibited the growth of E. coli and S. aureus by 41 ± 1.2% (P < 0.05) and 25.5 ± 4.1% (P < 0.05) respectively (Figure 2Go). The difference between the effect of bupivacaine and ropivacaine was significant for E. coli (18%; P < 0.05) but not S. aureus (Figures 1Go and 2Go).



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  		FIGURE 1 Effect of bupivacaine (0.77 mg·mL–1) and sufentanil (0.38 µg·mL–1, alone or combined) on Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Enterococcus faecalis (E. faecalis). A lower optical density at 540 nm (mean ± SD) indicates greater growth inhibition. *Significantly different from control (P < 0.05); a = significantly different from bupivacaine alone (P < 0.05). C = control; bupi = bupivacaine; suf.1 = sufentanil 0.38 µg·mL–1.

 


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  		FIGURE 2 Effect of ropivacaine (1.2 mg·mL–1) and sufentanil (0.5 µg·mL–1, alone or combined) on Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Enterococcus faecalis (E. faecalis). A lower optical density at 540 nm (mean ± SD) indicates greater growth inhibition. *Significantly different from control (P < 0.05); b = significantly different from ropivacaine alone (P < 0.05). C = control; ropi = ropivacaine; suf.2 = sufentanil 0.5 µg·mL–1.

 
Sufentanil alone only affected the growth of S. aureus, which was inhibited by 13.8 ± 3.1% (P < 0.05) at a concentration of 0.5 µg·mL–1 (Figure 2Go). Sufentanil modified the antibacterial activity of bupivacaine and ropivacaine. It increased the inhibitory effect of bupivacaine on the growth of E. faecalis (from 0% to 10 ± 2.1%; P < 0.05), S. aureus (from 22 ± 3.6% to 32.3 ± 4.1%; P < 0.05), and E. coli (from 59 ± 0.8% to 66 ± 1%; P < 0.05) (Figure 1Go). Sufentanil did not increase the inhibitory effect of ropivacaine on the growth of S. aureus. In contrast, it reduced the inhibitory effect of ropivacaine on the growth of E. coli by 11% (from 41 ± 1.2% to 30 ± 0.5%; P < 0.05) (Figure 2Go).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our investigation focused on bacteria commonly present on human skin, which are, in part, responsible for nosocomial infections, and which are often used for studies on the antibacterial effects of local anesthetics.2,5 Low concentrations of bupivacaine and ropivacaine had an antibacterial effect on E. coli and S. aureus, unlike other reports indicating that higher concentrations are required.6,8 Some studies have shown that ropivacaine has no effect on the growth of these bacterial species.3,5 The different results may be attributable to the experimental conditions: bacterial strains used, methods of evaluating bacterial growth, and/or drug dilutions. E. faecalis growth was not inhibited by any of the drugs, which confirms the results reported by Hodson et al.8 with bupivacaine and levobupivacaine.

Sufentanil (0.5 µg·mL–1) inhibited the growth of S. aureus. A similar effect was observed with meperidine (2%) and morphine (0.6%) on S. aureus, E. coli, and Pseudomonas aeruginosa.7 In contrast, Feldman et al.4 reported that fentanyl and sufentanil have no antibacterial effect. The non-specific antibacterial effect of opioids may depend on their molecular weight, thermodynamic activity, and pH.

Our results indicate that sufentanil had a weak but significant synergistic effect on the antibacterial activity of bupivacaine (7–10% increase) against the three bacterial species tested. At this concentration sufentanil alone had no effect. A similar but non-significant effect (7%) on S. aureus was also observed with sufentanil + ropivacaine. These results are in agreement with those of Cook et al.,9 who studied the antimicrobial effects of diamorphine + bupivacaine mixtures. Cook et al.9 reported that diamorphine increases the antibacterial activity of bupivacaine, but since they did not test the activities of each drug alone it is impossible to know how diamorphine affects the antibacterial activity of bupivacaine (synergistic or additive). Surprisingly, our results showed that sufentanil decreased the inhibitory effect of ropivacaine on E. coli. The synergistic and/or antagonist effect of sufentanil on the antibacterial activities of bupivacaine and ropivacaine may be due to an interaction between sufentanil and the cytoplasmic membrane, which disturbs the antibacterial activities of local anesthetics. It is known that local anesthetics interact with the cytoplasmic membrane and alter membrane functions in both eukaryotic and prokaryotic cells.10 Further studies are necessary to determine: i) whether the effect of sufentanil on these drugs is dose dependent; and ii) whether they have the same effect on other microorganisms.


   Acknowledgments
 
The authors would like to thank E. Le Ray for the statistical analyses, C. Allaire for editorial assistance, and G. Bourgeau for reading and revising this article.


   Footnotes
 
Manuscript assessed September 16, 2003. Revised November 4, 2003. 1st revision accepted February 26, 2004. Final revision accepted May 18, 2004.


   References
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 
1 Hlavin ML, Kaminski HJ, Ross JS, Ganz E. Spinal epidural abscess: a ten-year perspective. Neurosurgery 1990; 27: 177–84.[Medline]

2 Sakuragi T, Ishino H, Dan K. Bactericidal activity of preservative-free bupivacaine on microorganisms in the human skin flora. Acta Anaesthesiol Scand 1998; 42: 1096–9.[Medline]

3 Batai I, Kerenyi M, Falvai J, Szabo G. Bacterial growth in ropivacaine hydrochloride. Anesth Analg 2002; 94: 729–31.[Abstract/Free Full Text]

4 Feldman JM, Chapin-Robertson K, Turner J. Do agents used for epidural analgesia have antimicrobial properties? Reg Anesth 1994; 19: 43–7.[Medline]

5 Aydin ON, Eyigor M, Aydin N. Antimicrobial activity of ropivacaine and other local anaesthetics. Eur J Anaesthesiol 2001; 18: 687–94.[Medline]

6 Pere P, Lindgren L, Vaara M. Poor antibacterial effect of ropivacaine. Comparison with bupivacaine. Anesthesiology 1999; 91: 884–6.[Medline]

7 Rota S, Kaya K, Timliothlu O, Karaca O, Yzdep S, Öcal E. Do the opioids have an antibacterial effect? Can J Anaesth 1997; 44: 679–80.[Medline]

8 Hodson M, Gajraj R, Scott NB. A comparison of the antibacterial activity of levobupivacaine vs. bupivacaine: an in vitro study with bacteria implicated in epidural infection. Anaesthesia 1999; 54: 699–702.[Medline]

9 Cook TM, James PA, Stannard CF. Diamorphine and bupivacaine mixtures: an in vitro study of microbiological safety. Pain 1998; 76: 259–63.[Medline]

10 Lazdunski C, Baty D, Pages JM. Procaine, a local anesthetic interacting with the cell membrane, inhibits the processing of precursor forms of periplasmic proteins in Escherichia coli. Eur J Biochem 1979; 96: 49–57.[Medline]




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