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Antimicrobial Agents and Chemotherapy, June 1998, p. 1355-1360, Vol. 42, No. 6
Department of Internal
Medicine1 and
Microbiology/Immunology,3 Medical
College of Virginia Campus of Virginia Commonwealth University,
Richmond, Virginia, and
AMBI, Inc., Tarrytown, New
York2
Received 2 January 1998/Returned for modification 5 March
1998/Accepted 25 March 1998
The emergence of clinical isolates of methicillin-resistant
Staphylococcus aureus with reduced susceptibility to
vancomycin has prompted a search for new and novel therapeutic agents
active against S. aureus. Lysostaphin, a peptidase produced
by Staphylococcus simulans, specifically cleaves the
glycine-glycine bonds unique to the interpeptide cross-bridge of the
S. aureus cell wall. The effectiveness of various regimens
of dosing with intravenous lysostaphin was compared to that of
vancomycin in the rabbit model of aortic valve endocarditis caused by a
clinical methicillin-resistant S. aureus isolate. All
animals were treated for a total of 3 days. The most active regimen,
lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial
counts of 8.5 log10 CFU/g compared to the counts in the
untreated controls. In contrast, vancomycin given twice daily
sterilized no vegetations and reduced vegetation bacterial counts by
only 4.8 log10 CFU/g. Lysostaphin given once daily was less
effective, reducing mean vegetation bacterial counts by only 3.6 log10 CFU/g, but the combination of lysostaphin once daily
and vancomycin twice daily reduced the mean vegetation bacterial
density by 7.5 log10 CFU/g, a result that was significantly
better than that for either regimen alone (P < 0.05).
Lysostaphin was well tolerated by the rabbits, with no evidence of
immunological reactions following up to 9 weeks of intravenous
administration. We conclude that lysostaphin given alone or in
combination with vancomycin is more effective in the treatment of
experimental methicillin-resistant S. aureus aortic valve
endocarditis than vancomycin alone.
Vancomycin is the treatment of
choice for serious methicillin-resistant Staphylococcus
aureus (MRSA) infections. However, despite the susceptibility in
vitro of most clinical isolates of MRSA to vancomycin, failure of
vancomycin therapy has been reported in 14 to 35% of patients with
endocarditis caused by this organism (29, 42). The high
vancomycin failure rate and the lack of alternative therapeutic agents
has prompted a search for newer antimicrobial agents with activity
against MRSA. The emergence of vancomycin-resistant strains of
enterococci (12) and the recent discovery of strains of MRSA
with decreased susceptibility to vancomycin (2, 4, 25, 38,
43) emphasize this need.
Lysostaphin is a 27-kDa peptidase produced by Staphylococcus
simulans and was isolated in 1960 by Schindler and Schuhardt, as
described previously (39, 41, 45). Lysostaphin specifically cleaves the pentaglycine cross-links unique to the cell wall of S. aureus and lyses cells in all metabolic states (growing,
resting, or heat killed). Because staphylococci are highly resistant to lysis with such standard agents as lysozyme or detergents, lysostaphin has been widely used in research laboratories as a staphylolytic agent.
Lysostaphin was studied in the 1960s and 1970s as a potential therapeutic agent in numerous animal models and in a single human patient (3, 15, 21, 23, 24, 33, 40, 44, 45). However,
although its antimicrobial properties appeared promising, development
of lysostaphin as a therapeutic agent was abandoned. Some of the
reasons for failure to pursue the clinical use of lysostaphin included
the availability of antistaphylococcal antibiotics, fears concerning
the potential immunogenicity of a parenterally administered protein,
and the impurity of lysostaphin preparations. The availability of
recombinant lysostaphin that is >90% pure and that can be produced in
quantity from Bacillus sphaericus (37) has
provided an opportunity to assess the efficacy of lysostaphin in an
animal model of S. aureus endocarditis and to compare it to
the efficacy of standard therapy with vancomycin. We assessed the
susceptibility of MRSA to lysostaphin in vitro, determined its
therapeutic efficacy in the rabbit model of aortic valve MRSA endocarditis, and evaluated its toxicity and immunogenicity after long-term administration.
Bacterial strains.
S. aureus 27619, a homotypically
methicillin-resistant isolate, was used to challenge rabbits.
Additional MRSA strains were taken from a collection of clinical
strains maintained at the Medical College of Virginia as described
previously (13). Two S. aureus isolates with
reduced susceptibility to vancomycin were kindly provided by Fred
Tenover, Centers for Disease Control and Prevention (4, 38,
43). A final S. aureus strain with reduced susceptibility to vancomycin was an isogenic derivative of S. aureus 27619, designated 27619VR, which was produced through
stepwise passage in the presence of increasing concentrations of
glycopeptides. MICs were determined by a broth microdilution method in
cation-adjusted Mueller-Hinton broth (Becton Dickinson, Cockeysville,
Md.) according to standards of the National Committee for Clinical
Laboratory Standards with a final inoculum of 105 CFU/ml
(31). The MICs of lysostaphin were determined following the
addition of 0.1% bovine serum albumin (Sigma). Bovine serum albumin
prevents the absorption of lysostaphin to polystyrene microtiter wells.
The lowest concentration of antibiotic yielding no visible growth after
incubation at 37°C for 24 h was taken as the MIC.
Experimental infection.
The rabbit model of aortic valve
endocarditis, as described previously (35), was used to
evaluate antibiotic treatment regimens. Seventy-two hours after
transcarotid placement of a polyethylene catheter across the aortic
valve, rabbits were injected intravenously through the marginal ear
vein with 1 ml of an overnight culture containing 107 CFU
of MRSA strain 27619 per ml. Blood samples for culture were obtained
24 h later, and the rabbits were randomly assigned to one of the
following treatment groups: lysostaphin at 5 mg/kg of body weight given
intravenously (i.v.) every 8 h (t.i.d.), lysostaphin at 5 mg/kg
given i.v. once a day (q.d.), vancomycin at 30 mg/kg given i.v. every
12 h (b.i.d.), lysostaphin at 5 mg/kg given i.v. q.d. plus
vancomycin at 30 mg/kg given i.v. b.i.d., or no treatment (control
group). The surviving animals were killed by i.v. administration of
pentobarbital after a total of 3 days of antibiotic treatment. Rabbits
with negative blood cultures at 24 h after infection were excluded
from subsequent analysis. To reduce the possibility of antibiotic
carryover, rabbits were killed at least 18 h after administration
of the last dose. The heart and kidneys were aseptically removed from
each rabbit. Aortic valve vegetations were removed from each rabbit's
heart and weighed, and serial dilutions of vegetation homogenates were
made. Kidneys were examined, and areas of abscess or infarct were
removed, weighed, homogenized in saline, and serially diluted.
Dilutions were plated on Mueller-Hinton agar, and colonies were counted
after 48 h of incubation at 37°C. Titers of bacteria were
expressed as log10 CFU per gram of vegetation or kidney
tissue. Sterile vegetation cultures contained Antibiotics.
Lysostaphin (Ambicin L) was supplied by AMBI,
Inc., Tarrytown, N.Y. Lysostaphin powder was stored at 4°C, and fresh
solutions were prepared daily in 0.05 M Tris HCl-0.145 M NaCl.
Vancomycin was obtained from Abbott Laboratories, Chicago, Ill.
Inclusion criteria.
For the final analysis, animals that
fulfilled the following criteria were included: (i) cultured blood
samples were positive for MRSA 27619, the test organism, at 24 h;
(ii) the rabbits survived at least 24 h of antibiotic treatment;
(iii) the catheter was properly placed across the aortic valve at
necropsy, with macroscopic evidence of aortic valve endocarditis
(visible vegetations); and (iv) the aortic valve vegetation and kidney
tissue either were sterile or yielded pure cultures of MRSA 27619.
Bacteremia clearance.
Six rabbits with experimentally
induced aortic valve endocarditis as described above were used. Blood
samples for culture were obtained 24 h following infection with
S. aureus 27619 (time zero). The rabbits then received a
single i.v. dose of either lysostaphin at 15 mg/kg or vancomycin at 60 mg/kg. Blood samples for culture were obtained serially from all
rabbits at 2, 4, 6, 8, 10, 12, 24, 30, and 48 h after
administration of the single dose of antibiotics. Blood collected from
the rabbits was serially diluted and plated onto Mueller-Hinton agar
for quantitative bacterial count determinations. Sterile blood cultures
contained <10 CFU/ml of blood (the limit of detection).
Long-term effects of lysostaphin administration.
Two female
New Zealand White rabbits (weight, 2 to 3 kg) received a weekly i.v.
injection of lysostaphin at 15 mg/kg for 9 weeks. Animals were closely
observed for the development of any signs of allergic or anaphylactic
reactions. Urine was tested for proteinuria with urinalysis reagent
strips (Multistix; Bayer Inc., Etobicoke, Ontario, Canada), and at the
end of 9 weeks rabbits underwent autopsy, with removal of the kidneys
for pathological study. Serum collected at 9 weeks was examined for
evidence of neutralizing antibodies, and serum bactericidal titers were
determined. A decreased lytic activity of lysostaphin was used as
evidence for the presence of neutralizing antibodies against
lysostaphin. A modification of the broth microdilution method was used
to determine the effect of serum on lysostaphin activity. Lysostaphin
was serially diluted in microtiter wells in a volume of 50 µl, and
then 25 µl of serum from immunized rabbits was added. Finally, 25 µl of the test organism, S. aureus 27619, was added at a
concentration that resulted in a final inoculum of 105
CFU/ml. Pooled commercial rabbit serum served as a negative control. The MIC was that concentration of lysostaphin yielding no visible growth after 24 h of incubation at 37°C.
Statistical analysis.
The mean numbers of bacteria per gram
of vegetation and kidney tissue in all treatment groups were compared
by analysis of variance. Sterile cultures were entered as 2 log10 CFU/g, the limit of detection. The
Student-Newman-Keuls test was used to adjust for multiple comparisons.
For analysis of the rate of sterilization of valve vegetations, we used
Fischer's exact test (two-tailed) with the permutation-style
adjustment to adjust for multiple comparisons. A P value of
<0.05 was considered statistically significant for all tests.
In vitro studies.
The MICs of antibacterial agents for
S. aureus 27619, the isolate used in the rabbit endocarditis
model, were as follows: oxacillin, >100 µg/ml; vancomycin, 1 µg/ml; and lysostaphin, 0.03 µg/ml. For 16 additional MRSA strains,
the MICs of lysostaphin ranged from 0.007 to 0.125 µg/ml. Lysostaphin
demonstrated similar activity (MICs, 0.015 to 0.030 µg/ml) against
three MRSA isolates with reduced susceptibility (MIC, 8 µg/ml) to
vancomycin.
Serum bactericidal activity and long-term tolerability.
Lysostaphin exhibited excellent serum bactericidal activity in rabbits.
To assess the long-term tolerability and activity of lysostaphin,
uninfected rabbits received weekly i.v. injections of lysostaphin (15 mg/kg) for a total of 9 weeks. At 9 weeks, rabbits demonstrated serum
bactericidal levels of 1:128 4 h following i.v. dosing. In
addition, measurable bactericidal activity was still present 12 h
postdosing.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Lysostaphin Treatment of Experimental
Methicillin-Resistant Staphylococcus aureus Aortic
Valve Endocarditis
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
2 log10
CFU/g (the limit of detection).
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Bacterial clearance in the rabbit model of endocarditis. The results of the bacterial clearance studies are presented in Fig. 1. In the treatment of endocarditis, both lysostaphin and vancomycin had similar effects on bacterial clearance. Following the administration of a single dose of vancomycin (60 mg/kg) or lysostaphin (15 mg/kg) to rabbits with experimental endocarditis, there were similar rates of bacterial clearance for both agents. Twelve hours after the administration of a single dose, blood from all three rabbits treated with vancomycin and two of three rabbits treated with lysostaphin were sterile on culture. All rabbits had a return to positive blood cultures by 30 h postdosing.
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) and vancomycin (
). For the three
rabbits in each group, means and ranges of bacterial counts in blood
are given.
Endocarditis. The results obtained from the 3-day antibiotic treatment regimen used to treat experimental endocarditis caused by MRSA 27619 are presented in Table 1. A total of 56 rabbits infected with MRSA 27619 were assigned to the various treatment regimens. Control rabbits had a mean aortic valve vegetation bacterial count of 10.79 ± 1.58 (standard deviation [SD]) log10 CFU/g, which is comparable to those reported previously from trials of MRSA endocarditis (1, 5, 6, 9, 10, 13, 14, 34).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The treatment of serious infections caused by MRSA requires
prolonged i.v. administration of bactericidal antibiotics. Since these
strains are resistant to all 
-lactams, glycopeptides such as
vancomycin or teicoplanin are considered the treatments of choice.
Despite the universal susceptibility of S. aureus to
vancomycin, clinical failures in patients with severe MRSA infections
are not uncommon (29, 42). Relapse rates of up to 15% have
been reported following the treatment of endocarditis due to S. aureus with vancomycin (42). Many investigators have
also suggested that the duration of S. aureus bacteremia is
prolonged with vancomycin treatment compared to that with -lactam
treatment (29). Although the effectiveness of vancomycin in
animal models of endocarditis can be improved with the addition of
aminoglycosides and rifampin (1, 34), studies demonstrating
effective alternative therapeutic agents in the treatment of MRSA
endocarditis have been lacking.
In the studies reported above, we investigated the efficacy of lysostaphin compared to that of vancomycin in the treatment of experimental endocarditis due to MRSA. Lysostaphin given t.i.d. was significantly more effective than vancomycin at reducing the mean vegetation bacterial counts, producing sterile vegetations in 91% of rabbits, while vancomycin sterilized the vegetations in none of the rabbits. Our experiments did not examine rabbits for evidence of relapse, although the high rate of sterilization would argue against a risk for relapse among rabbits treated with lysostaphin t.i.d. However, in rabbits treated with vancomycin or lower doses of lysostaphin, in which vegetation bacterial counts were higher, there may be a significantly higher risk of relapse. Lysostaphin was also an effective adjunctive treatment when it was given in combination with vancomycin. The addition of lysostaphin q.d. to vancomycin reduced the mean aortic valve vegetation counts by 2.5 log10 CFU/g compared to those after treatment with vancomycin alone (3.23 versus 5.91 log10 CFU/g).
The reductions in aortic valve vegetation counts and rates of sterilization seen with lysostaphin in our study are the highest reported for single agents in the rabbit model of MRSA endocarditis (Table 2). The most effective single-agent regimens used to treat experimental MRSA endocarditis in the rabbit have been glycopeptides, either teicoplanin or vancomycin, with aortic valve sterilization rates of 27 to 80% reported for teicoplanin and sterilization rates of 0 to 87% reported for vancomycin. Although vancomycin is considered the best agent in this model, it is relatively ineffective at sterilizing aortic valve vegetations, results that mirror the lack of efficacy reported for vancomycin therapy of human S. aureus endocarditis. Of 15 studies of experimental MRSA aortic valve endocarditis with vancomycin doses and treatment durations similar to those used in our study, 6 reported no sterilization of aortic valve vegetations (5, 7, 13, 16, 18, 19), while 4 described sterilization of fewer than half of the vegetations (1, 6, 10, 32). Five remaining studies (11, 14, 26-28) reported aortic valve sterilization rates of 55 to 87%, although three of those studies used an MRSA strain that appears to have been more easily eradicated by a variety of antimicrobial agents in this model (26-28). Overall, 67% of studies with vancomycin for the treatment of experimental endocarditis due to MRSA have reported sterilization of aortic valve vegetations for fewer than half of treated animals.
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Lysostaphin was first tested in animal models of staphylococcal infection in the 1960s (15, 21, 23, 24, 40, 41). Most of that work was with mice, and acute intraperitoneal infection or renal abscess models and standard penicillin-susceptible S. aureus strains were used. Lysostaphin was clearly efficacious in those models. Although the doses were as high as 100 mg/kg, the purity or potency of the lysostaphin preparations used was not always reported, so the true doses of the active ingredient may have been significantly lower in some cases. In one study (24), a very rapid reduction in kidney bacterial loads was demonstrated with single lysostaphin doses as low as 1.5 or 3 mg/kg; among the other agents tested, only penicillin G benzathine (Bicillin; at 25 or 100 mg/kg) gave results comparable to those achieved with lysostaphin. There is also a report of therapy of endocarditis in dogs caused by a penicillinase-producing S. aureus strain (21). That study was of an exploratory nature, and only one or a few dogs with documented endocarditis were treated with any given regimens of lysostaphin. Some evidence of efficacy was seen with dosages of 50 mg/kg/treatment or greater.
In humans, a lysostaphin spray was shown to eradicate S. aureus from the nares of 80% of carriers (30). One human patient has been treated with a single 500-mg i.v. dose of lysostaphin (44). The patient was suffering from acute myelocytic leukemia with profound pancytopenia and severe daunorubicin-induced cardiomyopathy. During his period of pancytopenia, he developed MRSA pneumonia and abscesses of the buttocks, thighs, and arms. He failed to respond to 3 weeks of treatment with antistaphylococcal antibiotics including nafcillin, methicillin, vancomycin, and cephalothin. Prior to the i.v. dosing, the patient demonstrated a 5-mm erythematous reaction to the intracutaneous administration of lysostaphin. A brief episode of flushing, hypotension, and tachycardia was noted following i.v. dosing, but the episode resolved with diphenhydramine and epinephrine. Unfortunately, the patient died of progressive heart failure 3 days after the lysostaphin infusion. Prior to death and at autopsy there was no evidence of staphylococcal infection, with negative cultures of samples of blood, lungs, and abscess sites. There was no examination for the presence of antibody directed against lysostaphin. The investigators concluded that further trials of lysostaphin treatment as adjunctive treatment for severe staphylococcal infections were warranted.
Since those studies were reported, rabbit and rat models of MRSA endocarditis have been established and are widely used to assess new therapeutic regimens. Our studies with the rabbit indicate that lysostaphin may be an effective therapeutic agent for the treatment of serious staphylococcal infections, despite concerns about potential immunogenicity. Lysostaphin was well tolerated by the rabbits, even with prolonged treatment for up to 9 weeks. In particular, there was no evidence of serum sickness, as assessed by the absence of fever, weight loss, proteinuria, joint swelling, or histologic renal lesions, following prolonged dosing. Rabbits demonstrated evidence of the presence of neutralizing antibodies following extended dosing, as indicated by an eightfold reduction of the lytic action of lysostaphin in the presence of immune serum. Despite the presence of neutralizing antibodies, high levels of serum bactericidal activity persisted. This is in concordance with earlier studies with the rabbit, in which Schaeffner et al. (40) demonstrated the presence of neutralizing and precipitating antibodies in the rabbit following repeated i.v. dosing. However, as in our own study, no adverse reactions were seen by those investigators following the administration of multiple doses.
Data on the immunogenicity of lysostaphin in human subjects is largely limited to studies evaluating its topical use. Among patients treated with topical lysostaphin in attempts to eradicate nasal staphylococcal carriage, there has been little evidence of sensitization or induced antibody formation (22, 36). Protein products such as thrombolytic enzymes (streptokinase) have been used with success for some time to treat humans with a low rate of medically manageable hypersensitivity reactions. These observations, in conjunction with previous data from studies with animals, would indicate that short-term or adjunctive therapy with lysostaphin may be possible in humans.
These studies also highlight the potential for the use of peptides as antimicrobial agents. Although lysostaphin is a large protein of approximately 27 kDa, its effectiveness in the endocarditis model indicates that the level of permeation into vegetations is adequate and that large protein products can exert potent antimicrobial activity in vivo.
In summary, lysostaphin may be an effective antimicrobial agent for the treatment of severe MRSA infections. Lysostaphin also demonstrates potent in vitro activity against S. aureus strains with reduced susceptibility to vancomycin. Additional studies with rabbits evaluating the activity of lysostaphin in the treatment of experimental endocarditis due to S. aureus with intermediate susceptibility to vancomycin are planned. These studies may have a significant impact as the search for alternative therapeutic agents in the treatment of serious MRSA infections continues.
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ACKNOWLEDGMENTS |
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We thank Geri Hale-Cooper for technical assistance. We also thank Richard Novick for advice and encouragement in completing these experiments.
This work was supported in part by a grant from AMBI, Inc., and Public Health Service grant R37 AI35705.
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FOOTNOTES |
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* Corresponding author. Mailing address: McGuire Veterans Affairs Medical Center, 1201 Broad Rock Blvd., Section 111-C, Richmond, VA 23249. Phone: (804) 675-5018. Fax: (804) 675-5437. E-mail: CLIMO.MICHAEL{at}RICHMOND.VA.GOV or MCLIMO{at}GEMS.VCU.EDU.
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Abstract
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Materials & Methods
Results
Discussion
References
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