Local Anesthetic anti-bacterial activity
(Ropivacaine has a
Poor antibacterial effect in
comparison with Bupivacaine)
Joseph
Eldor, MD
http://www.csen.com/anesthesia
Naropin (ropivacaine)
is a long-acting local anaesthetic and analgesic,
used for surgical anaesthesia and acute pain management (post-operative pain management and labour pain). First launched in 1996, Naropin
is the world's first enantiomerically pure local anaesthetic (an S-form enantiomer),
and is now available in over 30 countries, including the
Naropin® solution for
injection is a sterile, isotonic, aqueous solution. The pH of the solution is
adjusted with sodium hydroxide or hydrochloric acid and the solution is free
from preservatives.
At the AstraZeneca Prescribing Information under “Undesirable effects” is written:
“4.8
Undesirable effects
The adverse event profile of Naropin®
is similar to that of other long-acting local anesthetics of the amide-type.
Adverse reactions to local anesthetics are very rare in the absence of overdose
or inadvertent intravascular injection. They should be distinguished from the
physiological effects of the nerve block itself, e.g. a decrease in blood
pressure and bradycardia during epidural anaesthesia. The effects of systemic overdose and
inadvertent intravascular injections can be serious (see "Overdosage").”
However, it seems that
the statement “The adverse event profile of Naropin®
is similar to that of other long-acting local anesthetics of the amide-type.”
has to be rewritten related to the anti-bacterial activity of Ropivacaine Vs. Bupivacaine.
Based on the following
survey it is concluded that : Ropivacaine has a Poor
antibacterial effect in comparison with Bupivacaine.
Since Ropivacaine is now frequently used for epidural anesthesia
and analgesia as well as for wound analgesia infiltration and peripheral nerve
blocks this “unrecognized” poor antibacterial effect has a very important
implication on its use.
Rosenberg PH and Renkonen OV (1)
examined the antimicrobial activity of bupivacaine
and morphine against 10 microbial strains with an agar dilution method. The
strains tested were Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus
(ATCC 25923), and one of each of the clinical isolates of Staphylococcus epidermidis (a multiresistant
strain), Staphylococcus epidermidis (a sensitive
strain), Streptococcus pneumoniae, Streptococcus pyogenes (A), Streptococcus faecalis,
Bacillus cereus, and Candida albicans. The
antimicrobial effect of bupivacaine was tested at
concentrations of 0.5, 1.25, 2.5, and 5 mg/ml (0.05% 0.125%, 0.25%, and 0.5%). Bupivacaine at a concentration of 2.5 mg/ml inhibited the
growth of the sensitive S. epidermidis strain, S. pyogenes, and S. pneumoniae, and
all of the others except P. aeruginosa at a
concentration of 5 mg/ml. Morphine 0.2 and 2 mg/ml (0.02 and 0.2%) did not
inhibit any of the strains.
James FM et al. (2) studied the incidence of contamination of
catheters and syringes used during epidural analgesia for parturients
and the effectiveness of bacterial filters. The effect of bupivacaine
on bacterial viability and growth was also studied. Syringes in 5/101 cases
were contaminated, while catheter tips located in the epidural space were
sterile. Organisms isolated were skin commensals and
probably originated on the hands of anesthetic personnel. Bupivacaine
(0.25%) was bacteriocidal to S epidermidis
and Corynebacterium spp at
37C but not at room temperature. These findings illustrate the efficacy of
using bacterial filters during continuous epidural analgesia. New syringes
should be used for each epidural injection as insurance against seeding of
bacteria in the presence of a defective filter.
Noda H et al. (3) studied the
antibacterial activity of local anesthetics quantitatively, by procuring their
minimum inhibitory concentration (MIC), killing curves and postantibiotic
effect (PAE), using the standard colony of Staphylococcus aureus
ATCC 25923, Staphylococcus epidermidis ATCC 14990 and
Pseudomonas aeruginosa NCTC 10490. Both bupivacaine and lidocaine had
bactericidal activity at a clinical concentration. MIC of the former was lower
than that of the latter, and it means that bupivacaine
has a greater antibacterial activity than lidocaine.
At the same concentration, the commercial solutions, such as Xylocaine and Marcain, which
contain preservatives, showed a greater antibacterial activity than the pure
anesthetic solutions which contain no preservatives. However, the preservatives
had no bactericidal activity, but weak bacteriostatic
activity.
Grimmond TR and Brownridge P (4) studied the
antimicrobial activity of bupivacaine and pethidine in concentrations commonly used in epidural practice
by an agar dilution method against ten common micro-organisms. Both drugs
showed increasing microbe inhibition with increasing drug concentrations. Bupivacaine at common epidural concentrations inhibited
eight of the ten organisms and pethidine inhibited
six. These findings confirm previous reports of microbe inhibition by bupivacaine, and in addition demonstrate a similar but
slightly lesser activity by pethidine.
Feldman JM et al. (5) found that local
anesthetics inhibit bacteria growth in culture although this effect diminishes
as the concentration of the drug is reduced. Potential bacteria pathogens were
cultured in agar media containing: agar alone, 2%, 1.5%, and 1% lidocaine, 0.5%, 0.25%, and 0.125% bupivacaine,
0.125% bupivacaine + fentanyl
2 mcgs/mL, 0.125% bupivacaine
+ sufentanil 0.3 mcgs/mL,
and fentanyl 5 mcgs/mL, fentanyl 2 mcgs/mL or sufentanil 0.3 mcgs/mL. Organisms
were deemed sensitive to the study agent if no growth was apparent after
incubation for 24 hours. Both lidocaine and bupivacaine significantly reduced bacteria growth at all
concentrations studied compared to the growth observed in agar alone (P <
.0001). This growth inhibition diminished as the concentration of local
anesthetic was reduced especially for certain bacteria species for example. Staphylococcus aureus (P < .0001).
Neither fentanyl nor sufentanil
inhibited any bacterial growth in culture.
Fariss BL et al. (6)
studied the
toxicity and anesthetic properties of two anesthetic agents, bupivacaine and lidocaine. These
anesthetic agents did not damage tissue defenses or invite infection in
experimental animals. In addition, the pain of subdermal
injection, the onset of anesthesia, and the frequency of satisfactory
anesthesia in human volunteers were remarkably similar.
Sakuragi T et al. (7) investigated the rate and potency of the
antimicrobial activity of 0.125%, 0.25%, and 0.5% bupivacaine,
2.0% mepivacaine and 2.0% lidocaine
with preservatives, and 2.0% lidocaine without
preservatives on two strains of methicillin-resistant
Staphylococcus aureus. The pathogen was exposed to
each local anesthetic for 1, 3, 6, 12, and 24 hours at room temperature. The inocula from these suspensions were diluted to 1:1,000 with
physiological saline to inactivate the antimicrobial activity of the local
anesthetics and then were cultured for 24 hours at 37 degrees C on agar plates.
Lower colony counts were observed with a 3-hour or longer exposure to 0.5% bupivacaine in both strains of S. aureus
(P < .05). The 3-hour exposure reduced the count by approximately 60%, the
6-hour exposure by 70%, and the 24-hour exposure by
more than 99%. The bactericidal activity was lowest with 0.125% bupivacaine and 2.0% mepivacaine.
Antimicrobial activity was observed shortly after exposure of S. aureus to local anesthetics and appeared to be bactericidal
rather than bacteriostatic.
Pina-Vaz C et al. (8) evaluated the activity of benzydamine,
lidocaine, and bupivacaine,
three drugs with local anesthetic activity, against Candida albicans
and non-albicans strains The minimal inhibitory
concentration (MIC) was determined for 20 Candida strains (18 clinical isolates
and two American Type Culture Collection strains). The fungistatic
activity was studied with the fluorescent probe FUN-1 and observation under epifluorescence microscopy and flow cytometry.
The fungicidal activity of the three drugs was assayed by viability counts.
Membrane alterations induced in the yeast cells were evaluated by staining with
propidium iodide, by quantitation
of intracellular K+ leakage and by transmission electron microscopy of intact
yeast cells and prepared spheroplasts. The MIC ranged
from 12.5-50.0 microg/mL, 5.0-40.0 mg/mL, and 2.5-10.0 mg/mL for benzydamine, lidocaine, and bupivacaine, respectively. The inhibitory activity of these
concentrations could be detected with the fluorescent probe FUN-1 after
incubation for 60 minutes. A very fast fungicidal activity was shown by 0.2,
50, and 30 mg/mL of benzydamine,
lidocaine, and bupivacaine,
respectively. At lower concentrations, the tested drugs had a fungistatic activity, due to yeast metabolic impairment,
while at higher concentrations they were fungicidal, due to direct damage to
the cytoplasmic membrane.
Sakuragi T
et al (9) studied the bactericidal activity of preservative-free bupivacaine on two strains of methicillin-resistant
Staphylococcus aureus (MRSA), two strains of methicillin-susceptible S. aureus
(MSSA), and each of Staphylococcus epidermidis and
Escherichia coli. The pathogen was exposed to 0.5% bupivacaine
for 1, 3, 6, 12, and 24 h at 37 degrees C and room temperature. In addition,
each strain of MRSA, MSSA, and S. epidermidis was
exposed to distilled water, and 0.125%, 0.25%, 0.5%, and 0.75% bupivacaine at 37 degrees C. The inocula
from the suspensions were cultured for 48 h at 37 degrees C. The 1- through 24-h exposures of 4 strains of
S. aureus to 0.5% bupivacaine
at room temperature reduced the colony count by 21.7%, 34.7%, 51.1%, 65.6%, and
81.1%, respectively, and the exposure at 37 degrees C reduced the count by
34.1%, 50.8%, 66.3%, 94.5%, and 96.0%, respectively. The differences were
significant at all exposure times (P < 0.001, respectively). No organisms
grew in the strain of E. coli after 24-h exposure and in the strain of S. epidermidis after 12- and 24-h exposures at 37 degrees C.
The percent change from controls in the strains of E. coli and S. epidermidis was significantly higher than that in the
strains of S. aureus at all exposure times at room
temperature and 37 degrees C (P < 0.0001, respectively). Higher
concentrations of bupivacaine were associated with
lower colony count. The preservative-free bupivacaine
possessed a temperature- and concentration-dependent bactericidal activity, and
S. aureus was more resistant to the bactericidal
activity of bupivacaine than were S. epidermidis and E. coli.
Hodson M et al. (10)
compared
the antibacterial activity of bupivacaine with levobupivacaine against a range of bacteria implicated in
epidural infection to determine whether any differences existed between the two
drugs. Concentrations of 0.125%, 0.25% and 0.5% bupivacaine
and levobupivacaine were inoculated with suspensions
of either Staphylococcus epidermidis, Staphylococcus aureus or Enterococcus faecalis. After incubation, the mixtures were plated onto
blood agar and colony counts were recorded after a further period of
incubation. The minimum bactericidal concentration of local anaesthetic
against the three bacteria studied was found to be 0.25% for bupivacaine and 0.5% for levobupivacaine
showing racemic bupivacaine
to have a more potent antibacterial action than levobupivacaine.
This finding suggests that the dextrobupivacaine
isomer of racemic bupivacaine
has a more potent antibacterial action than the levobupivacaine
isomer.
Sakuragi T
et al. (11) studied the bactericidal activity of 0.5% bupivacaine
with 0.08% methyl para-oxybenzoate and 0.02% propyl para-aminobenzoate as
preservatives and of the preservatives alone at 37 degrees C and at room
temperature on two strains of methicillin-resistant
Staphylococcus aureus, two strains of methicillin-susceptible S. aureus,
and one strain each of Staphylococcus epidermidis and
Escherichia coli. The pathogen was exposed to 0.5% bupivacaine
with preservatives or to the preservatives alone for 1, 3, 6, 12, and 24 hours
at 37 degrees C and at room temperature. The inocula
from these suspensions were cultured for 48 hours at 37 degrees C after the
antimicrobial activity of bupivacaine was inactivated
by 1:1,000 dilution with physiological saline. The 1-
through 12-hour exposures of four strains of S. aureus
to 0.5% bupivacaine with preservatives at room
temperature reduced the mean colony count by 24.2%, 49.2%, 71.3%, and 89.6%,
respectively, and the exposure at 37 degrees C reduced the count by 74.1%,
95.2%, 99.9%, and 99.8%, respectively. The differences for 1- through 12-hour
exposures were significant (P < .001). The percentage kill in the strains of
E. coli and S. epidermidis was significantly higher
than that in the strains of S. aureus at all exposure
times at room temperature (E. coli, P < .001; S. epidermidis,
P < .0001) and at 1- and 3-hour exposures at 37 degrees C (E. coli, P <
.001; S. epidermidis, P < .0001). The bactericidal
activity of the preservatives was markedly lower that that of 0.5% bupivacaine with preservatives (P < .0001). It was
concluded that the bactericidal activity of 0.5% bupivacaine
with preservatives is stronger at body temperature than at room temperature;
the bactericidal activity may be due, to a large extent, to bupivacaine
rather than to the preservatives; and S. aureus is
more resistant to the bactericidal activity of bupivacaine
than are S. epidermidis and E. coli.
Welters ID et al. (12) studied the influence of racemic bupivacaine and its enantiomers on neutrophil phagocytic activity, oxidative burst as well as surface
expression of complement and Fcgamma receptors.
Venous blood was pre-incubated with different concentrations of either racemic bupivacaine, R-(+) or
S-(-) bupivacaine. Fluoresceine
isothiocyanate (FITC)-labeled antibodies against Fcgamma receptor III (CD16), complement receptor 1 (CD35)
and complement receptor 3 (CD11b) were used to determine surface receptor
expression. Phagocytic activity was measured by
ingestion of FITC-labeled vital Staphylococcus aureus.
Oxidative burst was determined by conversion of nonfluorescent
dihydrorhodamine 123 into fluorescent rhodamine 123. Fluorescent intensity of each sample was
determined by flow cytometry. Racemic bupivacaine inhibited surface receptor expression, phagocytosis, and oxidative burst in a time- and
concentration-dependent manner. Although the S-(-) enantiomer
exerted significantly less inhibitory action on neutrophil
function compared to R-(+) and racemic bupivacaine, these effects were small compared to the overall
changes. These findings suggest that bupivacaine
impairs surface receptor expression and may thereby contribute to reduced phagocytic activity and oxidative burst. Enantiomer-specific effects of bupivacaine
may play a minor role in the inhibition of these leukocyte functions.
Batai I et al. (14) found that Ropivacaine 10 mg/mL killed Staphylococcus aureus and Escherichia coli; however, ropivacaine 2 mg/mL supported the growth of E. coli.
Pere P et al. (15)
found Poor antibacterial effect of ropivacaine in comparison with bupivacaine.
Rodrigues AA et al (16)
found that the novel drug ropivacaine was less
potent than the former two drugs (lidocaine and bupivacaine) related to the formation of germ tubes by
Candida albicans that has been assumed as a
putative virulence factor.
The study suggested that the inhibitory effect of Local Anesthetics (LAs) on germ tube formation by C. albicans is due to blockade of ionic channels, particularly calcium channels. Therefore, LAs can affect morphology and probably also the pathogenesis of C. albicans.
Morris W et al. (17) aseptically collected 201 antibacterial filters that had been
used for top-ups with ropivacaine +/- sufentanil for epidural analgesia during labour. They flushed them first with 2 mL
of saline and then with 2 mL of a solution containing
1.5 x 10(6) Staphylococcus epidermidis/mL. The
filtrates were incubated at 37 degrees C for 72 h. Number of top-ups and
duration of epidural analgesia were expressed as
median (extremes). 3 (1-10) top-ups were performed for labour
analgesia over a period of 6.5 h (1.8-18). After filtering, all the solutions
were found to be sterile. Especially, when using Staphylococcus epidermidis solutions, bacteria were not found beyond any
filter. These results suggested the integrity of the filter membrane after
several boluses. No infection related to epidural analgesia was reported. They
concluded that antibacterial filters provide a good protection against a
potentially contaminated procedure during epidural top-ups.
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