Diagnostic Microbiology and Infectious Disease 57 (2007) 413 – 418

www.elsevier.com/locate/diagmicrobio
Antimicrobial susceptibility studies
In vitro activity of lysostaphin, mupirocin, and tea tree oil against clinical
methicillin-resistant Staphylococcus aureus
Kerry L. LaPlante4
Department of Pharmacy Practice, University of Rhode Island, Veterans Affairs Medical Center, Providence, RI 02908, USA
Received 26 July 2006; accepted 20 September 2006

Abstract

Colonization of methicillin-resistant Staphylococcus aureus (MRSA) commonly leads to infection by the same strain. We examined the
activity of lysostaphin, mupirocin, and tea tree oil against clinical MRSA (n = 98) isolates. MIC50 (range) were as follows: lysostaphin,
0.125 mg/L (0.125–0.25); mupirocin, 0.5 mg/L (0.19–1024); tea tree oil, 1024 mg/L (512–2048). High- and low-level mupirocin resistance
was noted in 9.2% of our MRSA isolates. Time kill results indicate MRSA activity at 24 h was lysostaphin = gentamicin = vancomycin
( P V .001) N mupirocin N tea tree oil ( P z .05). Checkerboard testing indicated a synergistic relationship between lysostaphin and
mupirocin in combination with gentamicin. Antagonism was observed with the combination of vancomycin and tea tree oil; time kill studies
confirmed this result. Decolonization options are limited and resistance to mupirocin exists. Lysostaphin and tea tree oil may offer additional
therapeutic options for the decolonization of MRSA where current treatment alternatives are limited.
D 2007 Elsevier Inc. All rights reserved.
Keywords: Lysostaphin; Mupirocin; Tea tree oil; Gentamicin; Vancomycin methicillin-resistant Staphylococcus aureus; Colonize; Decolonize

1. Introduction (Davis et al., 2004). It is therefore suggested that this

bacteria be cleared from the nares of patients before surgery
Methicillin-resistant Staphylococcus aureus (MRSA) is
or hospitalization (Dombros et al., 2005; Shrestha et al.,
now a public health threat, and little is know regarding
2006; von Eiff et al., 2001; Wertheim et al., 2004). In
effective decolonization therapies and emergence of resis-
addition, several outbreaks of community-associated MRSA
tance. Today, infections due to MRSA exist at alarming
(CA-MRSA), which are rapid and aggressive colonizers,
rates in our hospitals and in our communities, and
may further require investigations into additional decoloni-
delineation between community- and hospital-associated
zation options (Ellis et al., 2004; Rybak, 2005).
MRSA is becoming difficult (Rybak and LaPlante, 2005).
Several agents have been individually evaluated
Patients who develop these infections have risk factors that
for effectiveness in staphylococcus nasal decolonization.
include harboring MRSA bacteria in mucosal and epithelial
They include:
surfaces (Davis et al., 2004; Ellis et al., 2004). When MRSA
bacteria are identified in patient’s nares, there is a 10-fold ! Lysostaphin (cream), a natural enzyme derived from
likelihood that these patients will develop an infection Staphylococcus simulans, which breaks down the
from the exact same bacteria strain identified in their nares S. aureus cell wall (Climo et al., 2001);
! Mupirocin, an antibiotic produced from the bacteria
Pseudomonas fluorescens (Cookson, 1998);
! Tea tree oil (terpinen-4-ol, active agent), a product
A portion of this work was presented at the 45rd Interscience derived from a native Australian plant Melaleuca
Conference on Antimicrobial Agents and Chemotherapy, Washington,
DC, December 2005).
alternifolia (Carson and Riley, 1995);
4 Tel.: +1-401-273-7100x2339; fax: +1-401-457-3305. ! Gentamicin and vancomycin are commonly used anti-
E-mail address: kerrytedesco@uri.edu. biotics that demonstrate activity against staphylococci.
0732-8893/$ – see front matter D 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.diagmicrobio.2006.09.007
414 K.L. LaPlante / Diagnostic Microbiology and Infectious Disease 57 (2007) 413 – 418
Most of these compounds have been applied topically to
the interior nares of patients or used in oral formulations to
decolonize patients who are colonized with drug-resistant
S. aureus bacteria (Caelli et al., 2000; Doebbeling et al.,
1994; Kokai-Kun et al., 2003; Maraha et al., 2002).
To date, there has been no side-by-side comparison in
killing activity (defined as, 99.9% kill) of these compounds
against MRSA. It is therefore unknown which agent
demonstrates the best in vitro activity. In addition, rates of
resistance to these compounds against S. aureus are currently
unknown. The assessment of killing activity, resistance
development, and combination therapy (synergistic versus
antagonistic activity) is important when evaluating potential
decolonizing options for patients. It is therefore the intent of
this study to identify which compound(s) demonstrate good
in vitro activity against MRSA bacteria.
2. Materials and methods
2.1. Bacterial isolates
Clinical MRSA (n = 98) bacteria were obtained from
patients at the Veterans Affairs Medical Center (VAMC) in
Providence, RI (June 2004 through December 2005). The
bacterial cultures were obtained from blood, nares, sputum,
tissue, and urine samples and were provided by Janet Ovalles,
Clinical Microbiologist, at the VAMC. Before use, all
bacteria were stored in 20% glycerol and frozen at 80 8C.
2.2. Antimicrobial agents
Lysostaphin, gentamicin, and vancomycin analytical
powder was commercially purchased from Sigma-Aldrich
(St. Louis, MO). Lysostaphin powder was stored at 4 8C,
and fresh solutions were prepared daily in 0.05 mol/L Tris-
HCl–0.145 mol/L NaCl. Mupirocin analytical powder was
obtained from SmithKline Beecham Pharmaceuticals
(Epsom, United Kingdom) and tea tree oil (terpinen-4-ol)
was obtained from Plant Life (San Clemente, CA). Mueller–
Hinton broth (Difco Laboratories, Sparks, MD) supple-
mented with 25 mg/L calcium and 12.5 mg/L magnesium
were used. Colony counts were determined using tryptic soy
agar (TSA, Difco, Becton Dickinson) plates.
2.3. Susceptibility testing
MICs and resistance testing were determined in duplicate
using serial dilution methodologies described in documents
published by the Clinical and Laboratory Standards Institute
(CLSI), formerly the National Committee for Clinical
Laboratory Standards (2003, 2004). Initial inoculum was
5  105 CFU/mL and subculture volume was 0.01 mL to
ensure the accurate determination of the killing end point
(Pearson et al., 1980; Taylor et al., 1983). Mupirocin
resistance was determined using previously published
recommendations defined as susceptible (b 4 mg/L), low-
level resistance (8–256 mg/L), and high-level resistance
( N512 mg/L) (Kresken et al., 2004).
2.4. Time kill study
Time kill experiments with randomly selected MRSA
(n = 4) isolates were evaluated. Each time kill experiment
was preformed in triplicate. All antimicrobial agents were
tested at 4 and 8 times their respective MIC with a starting
inoculum of 5  105 CFU/mL using methodologies
previously described (LaPlante and Rybak, 2004). Sample
aliquots (0.1 mL) were removed from cultures at 0, 4, and
24 h. Antimicrobial carryover was accounted for by serial
dilution (10- to 10 000-fold) of plated samples with normal
saline. This methodology has a lower limit of detection of
2.0 log10 CFU/mL (Rybak et al., 2005). Growth control
wells for each organism were prepared without antibiotic
and run in parallel to the antibiotic test wells.
For antimicrobial agents not evaluated in combination,
bactericidal activity (99.9% kill) was defined as a z 3 log10
CFU/mL reduction in colony count from the initial
inoculum at 24 h. Bacteriostatic activity was defined as a
b 3 log10 CFU/mL reduction in colony count from the initial
inoculum at 24 h, whereas inactive was defined as no
observed reductions in the initial inocula. Time to 99.9% kill
was determined by linear regression of the sample points if
r 2 N .95 or by visual inspection.
2.5. Checkerboard screening test
Next, we used the mean fractional inhibitory concentra-
tion (FIC) index (AFIC) to screen for potential relationships
between the different antimicrobial agents (den Hollander
et al., 1998). We randomly selected 2 MRSA isolates to test
in combination. For each agent in combination, the AFIC
was calculated for each antimicrobial combination as the
sum of the individual FICs (Bonapace et al., 2002). The
nature of interaction between 2 antibiotics (synergy,
indifference, or antagonism) was determined based on FIC
index: V 0.5 was considered synergistic, N 0.5 to V 4 was
considered indifferent, and N4 was considered antagonistic.
Combinations that demonstrated an FIC index of V 0.5
(synergistic) or N4 (antagonistic) were further evaluated in a
time kill study as previously described (Rybak et al., 2005).
Each organism was tested against each antimicrobial agent
alone and in combination. All antimicrobial agents that
demonstrated synergy or antagonism using the AFIC method
were tested at 2 times their respective MIC. Synergy was
defined as an increase in kill of z 2 log10 CFU/mL by
combination of antimicrobials versus the most active single
agent of that combination at 24 h. Indifference was defined as
a 1–2 log10 CFU/mL increase in kill in comparison to the
most active single agent. Combinations that resulted in z 1
log10 bacterial growth in comparison to the least active single
agent were considered to represent antagonism. The lower
limit of detection for this methodology is 2.0 log10 CFU/mL
(Rybak et al., 2005).
2.6. Resistance
Development of resistance was evaluated at the 24-h
time point (time kill) for each of the randomly selected
 K.L. LaPlante / Diagnostic Microbiology and Infectious Disease 57 (2007) 413 – 418 415

post hoc test for multiple comparisons. A P value of b.05

indicates statistical significance.

3. Results
Of the 98 clinical MRSA isolates evaluated, 13.3% were
derived from blood, 21.4% from nares, 26.5% from tissue,
25.5% from sputum, 8.2% from urine, and 5.1% were from
other sites (i.e., ear swab, catheter site, etc.). Three isolates
from nasal cultures and 2 isolates from tissue demonstrated
high-level mupirocin MIC of N 1024 mg/L. Two isolates from
urine specimens and 2 isolates from tissue demonstrated low-
level MIC of 8–32 mg/L. The remaining isolates demon-
strated MIC ranging between 0.094 and 2 mg/L. High-level
(5.1%) and low-level (4.1%) mupirocin resistance was noted
in 9.2% of our MRSA isolates. The MIC50 of all isolates
tested against mupirocin was 0.25 mg/L. For other com-
pounds the MIC50 and MIC range were as follows:
gentamicin, 0.5 mg/L (0.125–1); lysostaphin, 0.125 mg/L
(0.125–0.25); tea tree oil, 1024 mg/L (512–2048); and
vancomycin, 1 mg/L (0.25–1).
In a time kill study conducted over 24 h we evaluated
4 MRSA isolates in triplicate at 4 and 8 times the respective
MIC. MIC for the isolates tested are as follows: gentamicin,
Fig. 1. Methicillin-resistant S. aureus (n = 4, average) at (A) 4 MIC and b0.5 mg/L; lysostaphin, b0.25 mg/L; mupirocin, b2 mg/L;
(B) the respective 8 MIC. tea tree oil, b1024 mg/L; and vancomycin, b1 mg/L.
Mupirocin, gentamicin, and vancomycin demonstrated
isolates. One hundred microliters of samples from the significant in vitro activity at 24 h with the time kill study
24-h time points were plated on TSA containing 4-fold results at 4 the respective MIC (Fig. 1A). The inoculum
the MIC of the respective antibiotic to assess the decrease for mupirocin was 1.95 F 0.014 log10 CFU/mL,
development of resistance or an increase in MIC. Plates gentamicin 3.345 F 0.072, and vancomycin 3.06 F 0.295.
were examined for growth after 24 and 48 h of incubation Lysostaphin demonstrated significant bactericidal activity at
at 35 8C. When isolates grew on antibiotic containing TSA 4 h but regrew by 24 h with a 2- to 4-fold MIC increase.
containing, MIC testing was conducted using CLSI guide- Initial kill of MRSA was seen with tea tree oil; however,
lines as previously stated. regrowth was observed at 24 h. The MIC for the isolates at
the 24-h time point had a 2-fold increase in MIC.
2.7. Statistical analysis
At 8 the respective MIC (Fig. 1B), lysostaphin,
All statistical analyses were performed using SPSS mupirocin, gentamicin, tea tree oil, and vancomycin demon-
statistical software (release 14; SPSS, Chicago, IL). After strated significant in vitro activity at 24 h for the time
24 h of exposure to each compound, the bacteria were kill study results. At 24 h, lysostaphin (decrease, 3.08 F
counted and time to 99.9% kill was compared between 0.18 log10 CFU/mL), gentamicin (3.26 F 0.09), and
groups using 1-way analysis of variance followed by Tukey vancomycin (3.01 F 0.29) demonstrated bactericidal activity
Table 1
The AFIC calculated for each antimicrobial combination
MRSA Drug Drug combination Result MRSA Drug Drug combination Result
L218 lyso tto Indifference L53 lyso tto Indifference
lyso vanco Indifference lyso vanco Indifference
lyso gent Synergy lyso gent Synergy
lyso mup Indifference lyso mup Indifference
mup tto Indifference mup tto Indifference
mup vanco Indifference mup vanco Indifference
mup gent Synergy mup gent Synergy
vanco tto Antagonism vanco tto Indifference
vanco gent Indifference vanco gent Indifference
gent tto Indifference gent tto Indifference
lyso = lysostaphin; tto = tea tree oil; vanco = vancomycin; gent = gentamicin; mup = mupirocin.
416 K.L. LaPlante / Diagnostic Microbiology and Infectious Disease 57 (2007) 413 – 418
Fig. 2. Time kill study of each agent alone and in combination against MRSA (n = 2 averaged).
(99.9% kill). Mupirocin (2.05 F 0.12 log10 CFU/mL) and tea
tree oil (0.52 F 0.23) demonstrated bacteriostatic activity.
The AFIC was calculated for each antimicrobial combi-
nation. Table 1 demonstrates the FIC index results. Results
from the FIC index testing were used as a screening tool for
further investigations into antimicrobial relationships. Using
this screening test, synergy was noted for lysostaphin and
gentamicin combinations and mupirocin and gentamicin
combinations. Antagonism was noted for vancomycin and
tea tree oil. Each of these combination regimens were then
tested together in a time kill at 2 times the respective isolate
MIC (Fig. 2). Each time kill experiment was performed in
triplicate. At 4 h, combination of lysostaphin plus gentami-
cin demonstrated synergy (difference of 2.898 F 0.13 log10
CFU/mL) against the MRSA isolate, but no difference at
24 h because kill was at the limit of detection. In this same
time kill, gentamicin significantly ( P = .04) enhanced
mupirocin activity, but, overall, the combination was
indifferent. Antagonism was noted with vancomycin and
tea tree oil combination with a 1.74 F 0.39 log10 CFU/mL
increase in bacterial growth when compared to vancomycin
alone. Overall, when agents were evaluated at 2 MIC in
combination, no resistance or increase in MIC was noted.
4. Discussion
Of the entire human population, S. aureus transiently or
persistently colonizes 18–38% of human nares (Claassen
et al., 2005; Ellis et al., 2004; Jernigan, 2004). Persons who
harbor this bacteria within their anterior nares are at great
risk for the development of infection (Davis et al., 2004).
These bacteria residing in the nares serve as a reservoir for
future infection. This had been demonstrated in surgical
candidates, patients undergoing continuous peritoneal dial-
ysis and hemodialysis, and other groups who are at risk for
repeated puncture of the skin (Bloom et al., 1996;
Doebbeling et al., 1994; Luzar et al., 1990; Mody et al.,
2003; Perl et al., 2002). Studies have demonstrated that
these patients are typically infected with the same S. aureus
previously found in their nares (Cespedes et al., 2005). Most
noteworthy is that MRSA colonization is 10 times more
likely to cause an infection than the methicillin-susceptible
S. aureus (Davis et al., 2004). Therefore, it is suggested that
these patients have MRSA cleared from the nares (Davis
et al., 2004; Dombros et al., 2005; Shrestha et al., 2006; von
Eiff et al., 2001; Wertheim et al., 2004).
Several techniques have been developed and evaluated to
assist in the removal of MRSA from colonized individuals.
These include use of oral antibiotics, antiseptic body washes,
and antibiotics topically placed in the nares. For several
reasons, including efficacy, resistance development, and
minimization of administering oral antibiotic use, topical
intranasal therapies have become the preferred method.
Nasal decolonization of methicillin-resistant MRSA is
recommended in surgical and dialysis patients. It may also
be necessary to evaluate this efficacy in persons colonized
with CA-MRSA (Laupland and Conly, 2003; Mody et al.,
2003). Mupirocin calcium ointment is the topical antibiotic
 K.L. LaPlante / Diagnostic Microbiology and Infectious Disease 57 (2007) 413 – 418
of choice in decolonizing patients from MRSA. High- and
low-level mupirocin resistance was noted in 9.2% of our
MRSA isolates. We also examined the inhibitory activity of
mupirocin against several clinical strains of MRSA and
found that lysostaphin, mupirocin, and tea tree oil demon-
strate good activity at concentrations exceeding 8 times the
respective MIC. In clinical settings, concentrations of
lysostaphin 0.5% (150 Ag) in a petrolatum-based cream
(Kokai-Kun et al., 2003), mupirocin 2%, and tea tree oil 4%
(Caelli et al., 2000) have been evaluated. These concen-
trations exceed concentrations used in this study and
therefore exceed the concentrations necessary to inhibit
resistance development in this study.
In evaluating the activity of potential decolonizing agents
against MRSA in an in vitro assay, the order of activity is
lysostaphin = gentamicin = vancomycin ( P V .001) N
mupirocin N tea tree oil ( P z .05), whereas gentamicin in
combination with mupirocin or lysostaphin may offer
additional advantages or prevent resistance. These data
suggest that resistance to mupirocin exists, and lysostaphin
and tea tree oil may offer additional therapeutic options for
the decolonization of MRSA where current treatment
alternatives are limited. Further in vitro as well as clinical
investigations are warranted.
Acknowledgments
We thank Kia Lor and Deirdre M. Fuller for technical
assistance on this project, and Janet Lane and Janet Ovalles,
Clinical Microbiologist, Veterans Affairs Medical Center
(Providence, RI), for providing the isolates. This research
was supported by a Research Proposal Development Grant
from the University of Rhode Island’s Council for Research.
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