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ABSTRACT
Background: Since the introduction of cocaine in 1884, local anesthetics have been used as a
mainstay of pain management. However, numerous studies over the past several decades have
elucidated the supplemental role of local anesthetics as antimicrobial agents. In addition to
their anesthetic properties, medications such as bupivacaine and lidocaine have been shown
to exhibit bacteriostatic, bactericidal, fungistatic, and fungicidal properties against a wide
spectrum of microorganisms.
Methods: A comprehensive literature search was conducted using MEDLINE 1950—present
for in vitro and in vivo studies pertaining to the antimicrobial activity of various local anes-
thetics on a broad range of bacterial and fungal pathogens. Studies testing the effect on mi-
crobial growth inhibition of local anesthetics alone and in combination with other agents,
such as preservatives and other medications, as well as the effect of conditions such as con-
centration and temperature, were included for review. Outcome measures included colony
counts, area-under-the-curve and time-kill curve calculations, minimum inhibitory concen-
trations, and post-antibiotic effect.
Results: Evidence suggests that local anesthetics as a class possess inherent antimicrobial
properties against a wide spectrum of human pathogens. Multiple local anesthetics at con-
centrations typically used in the clinical setting (e.g., bupivacaine 0.125%–0.75%; lidocaine
1%–3%) inhibit the growth of numerous bacteria and fungi under various conditions. Dif-
ferent local anesthetics showed various degrees of antimicrobial capacity; bupivacaine and li-
docaine, for example, inhibit growth to a significantly greater extent than does ropivacaine.
Greater concentrations, longer exposure, and higher temperature each correlate with a pro-
portional increase in microbial growth inhibition. Addition of other agents to the anesthetic
solutions, such as preservatives, opioids, or intravenous anesthetics such as propofol, mod-
ify the antimicrobial activity via either synergistic or antagonistic action. Limited studies at-
tribute the mechanism of action of antimicrobial activity of local anesthetics to a disruption
of microbial cell membrane permeability, leading to leakage of cellular components and sub-
sequent cell lysis.
Conclusions: Local anesthetics not only serve as agents for pain control, but possess an-
timicrobial activity as well. In such a capacity, local anesthetics can be considered as an ad-
junct to traditional antimicrobial use in the clinical or laboratory setting. Additionally, cau-
tion should be exercised when administering local anesthetics prior to diagnostic procedures
in which culture specimens are to be obtained, as the antimicrobial activity of the local anes-
thetic could lead to false-negative results or suboptimal culture yields.
205
206 JOHNSON ET AL.
C. E. E. H. P. S. S. S.
albicans coli faecalis influenzae MRSA aeruginosa aureus epidermidis pneumoniae Other pathogens Reference
and fungal infections; only Pseudomonas aerug- greater the growth inhibition, corresponding to
inosa showed no inhibition of growth at bupi- lower colony counts. Bupivacaine (0.5%)
vacaine concentrations as high as 5 mg/mL showed the greatest antimicrobial activity,
(0.5%). Morphine 0.2 and 2 mg/mL failed to in- likely bactericidal, inhibiting growth by more
hibit the growth of any of the ten strains. than 99% at 24 h, 70% at 6 h, and 60% at 3 h.
Hodson et al. [10] compared the antibacter- Colony counts were highest using 0.125% bupi-
ial activity of the isomers bupivacaine and vacaine and 2.0% mepivacaine.
levobupivacaine against S. epidermidis, S. au- In a follow-up study, Sakuragi et al. [14] ex-
reus, and E. faecalis, and found the minimum amined the bactericidal activity of preserva-
bactericidal concentration of bupivacaine to be tive-free bupivacaine (0.125%, 0.25%, 0.5%, and
lower than that of levobupivacaine (0.25% vs. 0.75%) for two strains of MRSA, two strains of
0.5%, respectively). Racemic bupivacaine there- methicillin-susceptible S. aureus (MSSA), S. epi-
fore appears to have more potent antimicrobial dermidis, and E. coli. The pathogens were ex-
activity than its isomer levobupivacaine. posed to the bupivacaine for 1, 3, 6, 12, and 24
Noda et al. [11] performed quantitative h at 37°C and room temperature. The results
analysis of the antibacterial activity of local showed both temperature- and concentration-
anesthetics by calculating their minimum in- dependent bactericidal activity. Increasing con-
hibitory concentration (MIC), killing curves, centrations of bupivacaine correlated with
and post-antibiotic effect (PAE). Colonies of S. lower colony counts. Likewise, increasing tem-
aureus, S. epidermidis, and P. aeruginosa were peratures from room temperature to 37°C in-
used in the study. At standard clinical concen- creased the growth inhibition of the S. aureus
trations, both bupivacaine and lidocaine had strains from 81% to 96% at 24 h with 0.5% bupi-
bactericidal activity against the aforemen- vacaine, and 22% to 34% at 1 h. No E. coli or S.
tioned species. A comparison of MIC values epidermidis growth occurred at all after 24 h at
indicated that bupivacaine has greater antibac- 37°C; in fact, E. coli growth was inhibited at 12
terial activity than lidocaine. At equal concen- h. Thus, S. epidermidis and E. coli proved more
trations, even greater antibacterial activity was sensitive than S. aureus to the bactericidal ac-
found when preservatives were added to the tivity of bupivacaine.
anesthetics, as is common in commercial solu- In an earlier complementary study in 1997,
tions. The preservatives alone, however, were Sakuragi et al. [15] used the same parameters,
only weakly bacteriostatic and not bactericidal, yet examined the antimicrobial effect of preser-
merely enhancing the bactericidal activity of vatives (methyl para-oxybenzoate and propyl
the pure anesthetic solutions. Similarly, Grim- para-aminobenzoate) alone and when added to
mond and Brownridge [12] showed increasing 0.5% bupivacaine. Preservatives alone showed
microbial inhibition with increasing concentra- significantly lower bactericidal activity than
tions of bupivacaine and pethidine (meperi- when combined with bupivacaine. As in the
dine) using an agar dilution method. At clini- previous study, increasing the temperature
cal concentrations, bupivacaine inhibited eight from room temperature to body temperature
of ten pathogens tested, and pethidine inhib- increased the growth inhibition of S. aureus
ited six, confirming the antimicrobial potential from 89.6% to 99.8% at 12 h and from 24% to
of local anesthetics. 74% at 1 h using 0.5% bupivacaine with preser-
In addition to examining the antimicrobial vatives. Again, S. aureus was found to be more
capacity of particular local anesthetics, resistant to the bactericidal activity of bupiva-
Sakuragi et al. [13] analyzed the rate of onset caine than S. epidermidis and E. coli.
of bacterial growth inhibition. Bupivacaine Aydin et al. [16] examined the antimicrobial
(0.125%, 0.25%, and 0.5%), mepivacaine (2.0%), activity of the local anesthetics ropivacaine,
lidocaine (2.0%), and lidocaine (2.0%) with bupivacaine, lidocaine, and prilocaine on vari-
preservatives were each tested with two strains ous pathogens, namely E. coli, S. aureus, P.
of methicillin-resistant S. aureus (MRSA) for 1, aeruginosa, and C. albicans. Of the four drugs
3, 6, 12, and 24 h at room temperature and tested, lidocaine and prilocaine had the most
cultured subsequently on agar. The authors potent antimicrobial activity, both inhibiting all
found that the greater the exposure time, the growth of all pathogens tested at anesthetic
ANTIMICROBIAL LOCAL ANESTHETICS 209
aforementioned pathogens and concluded that significantly, whereas the opioids failed to in-
clinically relevant concentrations of lidocaine hibit growth. The degree of growth inhibition
did not exhibit antimicrobial properties when was directly proportional to the concentration
added to contaminated propofol. In a letter to of local anesthetic; decreasing concentrations of
the editor, Driver [25] described such a claim the local anesthetic yielded a significant re-
as misleading. Driver argued that the condi- duction in bacterial growth inhibition, particu-
tions maintained in Wachowski’s study, such larly for certain species such as S. aureus.
as temperature, pH, and drug concentration, In 2003, Kampe et al. [29] studied the effect
were either suboptimal or unspecified. In their of ropivacaine (0.1%) when mixed with sufen-
own study, Driver et al. [26] did in fact achieve tanil (1 mcg/mL) on the growth of the
results that supported bacterial growth inhibi- pathogens S. aureus and P. aeruginosa at room
tion using a mixture of propofol/lidocaine. temperature. The combination of the local anes-
Aliquots of S. aureus diluted to a 1:108 ratio thetic and the opioid inhibited growth of P.
were incubated at 37°C and transferred to so- aeruginosa significantly; multiplication of S. au-
lutions containing either lidocaine, propofol, or reus was slowed as well.
a mixture of the two. Colony counts were low- Tamanai-Shacoori et al. [30] extended pre-
est in the mixture and highest in the propofol vious study to the local anesthetics ropiva-
solution alone. Such results suggest a syner- caine and bupivacaine in 2004. The effect of
gistic antimicrobial action achieved with the ropivacaine (1.2 mg/mL), bupivacaine (0.77
combination of lidocaine and propofol that ex- mg/mL), sufentanil (0.38 and 0.5 mcg/mL),
ceeds that of either of the two agents alone. Dri- and combinations of sufentanil and the two lo-
ver proposed activation of the lidocaine driven cal anesthetics on the growth of E. coli, S. au-
by the higher pH when the two agents are com- reus, and E. faecalis at 37°C was investigated.
bined. Both bupivacaine and ropivacaine alone were
Another local anesthetic, lignocaine, was found to inhibit growth of E. coli and S. aureus,
tested by Ozer et al. [27] to assess its effect on yet both were ineffective against E. faecalis. The
bacterial growth in contaminated propofol addition of sufentanil to each of the two local
emulsions. Cultures of E. coli, S. aureus, S. epi- anesthetics had opposing effects, modifying
dermidis, and P. aeruginosa were incubated at the antimicrobial activity of each drug. When
37°C and added to either propofol alone or a combined with bupivacaine, sufentanil exhib-
propofol/lignocaine mixture (0.1%–2.0%). A ited a synergistic effect, increasing the
significant decrease in colony-forming units inhibitory effect on the growth of all three
(CFU) numbers was seen with E. coli in mix- pathogens. When added to ropivacaine, how-
tures of 1% and 2% lignocaine. With the three ever, the antibacterial activity of the mixture
other pathogens, only 2% lignocaine signifi- was lower than that of ropivacaine alone,
cantly suppressed colony counts. As the rec- thereby exerting an antagonistic effect.
ommended clinical doses of lignocaine are
reported to be 0.05%–0.1%, the authors con-
cluded that this particular local anesthetic ex- EFFECTS OF LOCAL ANESTHETICS ON
hibits inadequate antimicrobial activity to pre- THE YIELD OF BACTERIAL CULTURES
vent infection in a clinical setting.
The addition of other agents, namely opioids, Because of this antimicrobial activity, several
to local anesthetic solutions was tested by in- studies have focused on the potential of local
vestigators including Feldman et al. [28]. Vari- anesthetics to interfere with clinical diagnostic
ous bacteria were cultured in agar media cultures and lead to false-negative results. With
preparations containing clinical concentrations the sensitivity of bronchoalveolar fluid (BAL)
of lidocaine, bupivacaine, fentanyl, or sufen- cultures as low as 50%–60% for the diagnosis
tanil and in mixtures of bupivacaine with each of pneumonia, Anding et al. [31] investigated
of the two opioids. Reinforcing the findings of the antimicrobial activity of local anesthetics
Rosenberg et al. [9], both lidocaine and bupi- used in the procedure as a possible explanation
vacaine were found to inhibit bacterial growth for the low sensitivity found with bronchos-
ANTIMICROBIAL LOCAL ANESTHETICS 211
copy. The bactericidal potential of various con- using a low concentration of anesthetic to de-
centrations (0.01%–1%) of the local anesthetic crease the possibility of obtaining false-nega-
oxybuprocaine was tested against 104/mL tive cultures.
inocula of S. pneumoniae, Haemophilus influen- Topical anesthetics are used routinely prior
zae, P. aeruginosa, and E. coli. Time–kill curves to obtaining bacterial cultures for ophthalmic
revealed significant bactericidal activity diagnoses such as bacterial keratitis as well.
against S. pneumoniae and H. influenzae with Mullin and Rubinsfeld [35] examined the bac-
even the lowest concentration of oxybupro- teriostatic and bactericidal effects of three pre-
caine (0.01%). Oxybuprocaine 1% inhibited the served anesthetic agents, proparacaine, tetra-
growth of E. coli and P. aeruginosa. If local anes- caine, and cocaine, on P. aeruginosa and S.
thetics such as oxybuprocaine are used prior to aureus. Proparacaine exhibited the strongest an-
obtaining material for culture, false-negative timicrobial activity, inhibiting the growth of S.
results may ensue. aureus at even the lowest concentration of
Olsen et al. [32] investigated the effect of 0.125%, whereas P. aeruginosa was inhibited at
adding lidocaine to suspensions of BAL fluid 0.25% and 0.5%. Tetracaine inhibited growth of
contaminated with clinical respiratory isolates. S. aureus at 0.5% and P. aeruginosa at 0.25% and
There was significant inhibition of the growth 0.5% concentrations. Cocaine exhibited only
of two of the four S. pneumoniae isolates in the mild inhibition of growth of P. aeruginosa at a
presence of lidocaine compared with saline 4% concentration. Because culture yields are re-
controls, suggesting that S. pneumoniae may be portedly suboptimal in diagnosing clinical ul-
underestimated as a pathogen with the use of cerative keratitis, the authors proposed that this
the local anesthetic lidocaine. growth inhibition by local anesthetics is a likely
A recent study in 2005 by Chandan et al. [33] reason, and recommended that clinicians use a
examined whether lignocaine (1% and 2%), an- low concentration of the minimally inhibitory
other anesthetic agent commonly used prior to cocaine in place of the standard commercial
bronchoscopy and BAL procedures, inhibited anesthetics in order to optimize culture yields.
growth of respiratory tract flora, particularly S.
pneumoniae, Moraxella catarrhalis, H. influenzae,
P. aeruginosa, and C. albicans. With a microbroth ANTIBACTERIAL MECHANISM
dilution method, lignocaine 2% exhibited bac- OF ACTION OF LOCAL ANESTHETICS
tericidal activity against S. pneumoniae, M. ca-
tarrhalis, and H. influenzae; however, no inhibi- An early study by Leung and Rawal in 1977
tion of growth of P. aeruginosa or C. albicans was [36] reported on a mechanism of action by
observed. Lignocaine 1% partially inhibited the which tetracaine exerts its bactericidal action
growth of S. pneumoniae. Because of such an- on the bacterial cell. The authors found that
timicrobial activity, the authors advise using tetracaine damaged the cell membrane of P.
the lowest concentration possible of local anes- aeruginosa through lysis, leakage of intracellu-
thetic prior to bronchoscopy and BAL proce- lar components, dehydrogenase activity, and
dures in order to maximize recovery of increased cell wall permeability.
pathogens on culture.
Aldous et al. [34] also investigated the po-
tential for false-negative results with culture LOCAL ANESTHETICS
specimens when using local anesthetics. The AND PROPHYLAXIS
antimicrobial activity of 4% lidocaine with OF SURGICAL SITE INFECTION
phenylephrine and 4% cocaine in nasal pro-
cedures was examined. Both agents exhibited Parr et al. [37] analyzed the antibacterial ac-
antimicrobial activity against the following tivity of clinical doses of lidocaine with and
pathogens: S. aureus, S. pneumoniae, K. pneumo- without epinephrine on isolates of a spectrum
niae, H. influenzae, M. catarrhalis, and Enterobac- of bacterial pathogens common in surgical site
ter spp., with cocaine exhibiting greater inhibi- infections, namely E. faecalis, E. coli, P. aerugi-
tion than lidocaine. The authors recommended nosa, S. aureus, MRSA, and vancomycin-resis-
212 JOHNSON ET AL.
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24. Wachowski I, Jolly DT, Nrazdil J, et al. The growth Address reprint requests to:
of microorganisms in propofol and mixtures of Alan P. Dine
propofol and lidocaine. Anesth Analg 1999;88:
209–212.
20202 Windrow
25. Driver RP. Conclusions regarding propofol/lidocaine Lake Forest, CA 92630
admixture may be misleading. Anesth Analg 1999;89:
1331–1332. E-mail: alandine@iflo.com