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MAJOR ARTICLE
Treatment Outcomes for Serious Infections Caused
by Methicillin-Resistant Staphylococcus aureus
with Reduced Vancomycin Susceptibility
Benjamin P. Howden,1 Peter B. Ward,1 Patrick G. P. Charles,1 Tony M. Korman,2 Andrew Fuller,3 Philipp du Cros,3
Elizabeth A. Grabsch,1 Sally A. Roberts,9 Jenny Robson,8 Kerry Read,10 Narin Bak,4 James Hurley,7
Paul D. R. Johnson,1,5 Arthur J. Morris,9 Barrie C. Mayall,1 and M. Lindsay Grayson1,5,6
1
Departments of Infectious Diseases and Microbiology, Austin Health, 2Department of Infectious Diseases, Southern Health, 3Department
of Infectious Diseases, The Alfred Hospital, 4Western Health, 5Department of Medicine, University of Melbourne, 6Department of Epidemiology
and Preventive Medicine, Monash University, Melbourne, and 7Ballarat Health Services, Ballarat, and 8Sullivan Nicolaides Pathology, Brisbane,
Australia; and 9Auckland District Health Board and 10North Shore Hospital, Auckland, New Zealand
Although infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility (SA-RVS) have been reported from a number of countries, including Australia, the optimal therapy is
unknown. We reviewed the clinical features, therapy, and outcome of 25 patients with serious infections due
to SA-RVS in Australia and New Zealand. Eight patients had endocarditis, 9 had bacteremia associated with
deep-seated infection, 6 had osteomyelitis or septic arthritis, and 2 had empyema. All patients had received
vancomycin before the isolation of SA-RVS, and glycopeptide treatment had failed for 19 patients (76%).
Twenty-one patients subsequently received active treatment, which was effective for 16 patients (76%). Eighteen
patients received linezolid, which was effective in 14 (78%), including 4 patients with endocarditis. Twelve
patients received a combination of rifampicin and fusidic acid. Surgical intervention was required for 15
patients (60%). Antibiotic therapy, especially linezolid with or without rifampicin and fusidic acid, in conjunction with surgical debulking is effective therapy for the majority of patients with serious infections
(including endocarditis) caused by SA-RVS.
Nosocomial infections due to methicillin-resistant
Staphylococcus aureus (MRSA) are an increasing problem in many parts of the world, including in Australia
[1]. The therapeutic options available to treat serious
infections due to MRSA are limited. The emergence of
MRSA strains with reduced vancomycin susceptibility
(SA-RVS) further reduces treatment options. Initially,
the clinical significance of heterogeneous vancomycin–
Received 7 August 2003; accepted 11 October 2003; electronically published
29 January 2004.
Presented in part: 43rd Interscience Conference on Antimicrobial Agents and
Chemotherapy, Chicago, Illinois, 14–17 September 2003 (abstract K-1750).
Reprints and correspondence: Dr. Benjamin Howden, Department of
Microbiology, Austin Hospital, Locked Bag 25, Heidelberg, Victoria, Australia, 3084
([email protected]).
Clinical Infectious Diseases 2004; 38:521–8
2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3804-0009$15.00
intermediate S. aureus (hVISA) strains was debated, but
they have now been clearly associated with glycopeptide
treatment failure [2–7], as well as with higher in-hospital patient mortality rates than MRSA [8]. Serious
clinical infections with SA-RVS—both vancomycinintermediate S. aureus (VISA) and hVISA—have now
been reported in many countries, yet treatment efficacy
has not been systematically assessed [9–11].
The laboratory confirmation of SA-RVS remains
problematic and time-consuming, with the population
analysis profile (PAP) being considered the current reference standard test [12]. After our initial report [11],
we developed a protocol incorporating PAP testing for
the investigation of possible SA-RVS isolates. Many isolates from across Australasia have since been referred
to our department for testing. To assess the clinical
features and treatment outcomes of patients with serious infections due to SA-RVS, we systematically reTreatment of SA-RVS • CID 2004:38 (15 February) • 521
viewed data for all patients whose referred sterile site isolates
were confirmed to be SA-RVS in our laboratory.
PATIENTS, MATERIALS, AND METHODS
Ascertainment and review of patients. All patients with a
sterile site isolate confirmed as SA-RVS (see laboratory methods
and susceptibility definitions below) whose isolate was referred
to our laboratory during the period of 1 May 2001 through 31
January 2003 were eligible for inclusion in this study. A questionnaire was sent to the referring clinician to obtain the patient’s demographic characteristics and data on comorbidities,
risk factors for infection, infection, treatment, and outcome.
Clinical definitions. “Glycopeptide failure” was defined as
a blood culture positive for S. aureus after ⭓7 days of glycopeptide therapy or as a sterile site isolate positive for S. aureus
after ⭓21 days of glycopeptide therapy. The type of infection
was accepted as that reported by the treating clinician. However,
a diagnosis of osteomyelitis required consistent nuclear or radiographic image (e.g., technetium bone scan or MRI) findings
and/or histological confirmation, and a diagnosis of endocarditis was required to meet recognized criteria [13].
“Cure” was defined as no clinical or laboratory evidence of
infection after the completion of antimicrobial therapy; furthermore, the patient had to be alive at follow-up. “Effective
suppression” was defined as no clinical or laboratory evidence
of active infection while receiving suppressive oral antimicrobial
therapy. “Effective therapy” was defined as cure or effective
suppression; patients who were apparently cured but who died
of another cause during the follow-up period were also considered to have received effective therapy. “Relapse” was defined
as additional sterile site isolate(s) that tested positive for SARVS or MRSA either after cessation of the antimicrobial therapy
that had initially lead to clearance of infection or during receipt
of appropriate therapy. Because patient outcomes were assessed
in May 2003, the duration of follow-up varied on the basis of
the date of initial diagnosis of SA-RVS infection.
Laboratory methods and susceptibility definitions. The
identification of all isolates as S. aureus was confirmed using
standard methods [14]. The MIC of vancomycin was determined using the broth microdilution method for all isolates,
in accordance with NCCLS recommendations [15], using cation-adjusted Mueller-Hinton broth. Susceptibility tests for linezolid, quinupristin-dalfopristin, and oxacillin were performed using the Etest (AB Biodisk), in accordance with the
manufacturer’s instructions. Testing of all other antimicrobial
susceptibility was performed using agar dilution, in accordance
with NCCLS criteria [15].
Population analysis profile testing and calculation of the area
under the curve (AUC) of test strains and an Mu3 control
(ATCC 700698) were performed as described elsewhere [12].
522 • CID 2004:38 (15 February) • Howden et al.
The ratio of the AUC of the test isolate to that of the Mu3
control (PAP/AUC ratio) was calculated. SA-RVS was defined
as an isolate of S. aureus with a PAP/AUC ratio of ⭓0.9 [12].
PFGE and riboprinting. Riboprint patterns were obtained
using the RiboPrinter Microbial Characterisation System
(Qualicon) with EcoR1 digestion. The riboprint pattern was
determined using a combination of visual and computerassisted analysis. PFGE was performed on all isolates using
methods described elsewhere, with some modifications [16].
For PFGE, strains were considered to be indistinguishable if
there was no difference in bands, and they were considered to
be related (i.e., subtypes of the same PFGE subtype) if they
varied by 1–3 bands. A PFGE dendogram was constructed using
GelCompar II (Applied Maths) to calculate similarity coefficients and to perform unweighted pair group analysis using
arithmetic mean clustering. Dice coefficient with 0.5% optimization and 1.0% position tolerance was used. Three isolates
from each of the 2 major PFGE groups found were referred to
another laboratory for comparison, by PFGE analysis, with reference epidemic MRSA strains currently circulating in Australia
and New Zealand.
RESULTS
Clinical treatment questionnaires were completed for 25 (89%)
of the 28 patients who had a referred sterile site isolate confirmed to be SA-RVS at our laboratory during the study period.
Patient demographics and risk factors for infection are presented in table 1. Twenty-three patients had a previously documented MRSA infection, but all 25 patients had received glycopeptide therapy at some time before the diagnosis of SA-RVS.
The source of the SA-RVS infection was determined in 18 cases
(surgical wound infection, 12 [67%] of 18; central intravenous
line infection, 2 [11%]; diabetic foot infection, 2 [11%]; biliary
stent infection, 1 [6%]; catheter related urinary tract infection,
1 [6%]). Data on 5 patients (patients 1, 2, 6, 9, 14; table 2)
had been briefly reported in a previous publication by our
group [17], but because this report did not include the patients’
treatment and outcome data, they were further described in
this study.
All patients had serious infections caused by SA-RVS (table
2), including 17 patients with bacteremia (endocarditis, 8 patients; osteomyelitis and/or septic arthritis, 4; intra-abdominal
or biliary sepsis, 2; pacemaker abscess, 1; other, 2). Six patients
had osteomyelitis and/or septic arthritis (including 3 patients
with prosthetic joint infection) without bacteremia, and 2 patients had postsurgical empyema. Prolonged bacteremia while
receiving vancomycin therapy was common among patients
with endocarditis (median duration of bacteremia, 13 days;
range, 7–32 days) and among those with osteomyelitis and/or
septic arthritis (median duration of bacteremia, 9.5 days; range,
Table 1. Demographic characteristics of and risk factors for 25 patients
infected with Staphylococcus aureus with reduced vancomycin susceptibility (SA-RVS).
Characteristic
Value
Ratio of men to women
16:9
Age, median years (range)
65 (45–83)
MRSA infection before SA-RVS
23
Median time from initial diagnosis of MRSA infection to
SA-RVS detection (range)
22 days (3 days–
31 months)
Duration of glycopeptide therapy during the 6 months
before SA-RVS detection, median days (range)
15 (0–91)
Predose vancomycin serum level of !10 mg/mL in the
first week of therapy
16
a
Risk factor
Diabetes
8
Immunosuppression
7
Malignancy
6
End-stage renal failure
3
Surgery !8 weeks before SA-RVS detection
18
Hospital location at time of diagnosis of SA-RVS infection
ICU
9
Medical ward
7
Surgical ward
8
Outpatient
1
NOTE.
Data are no. of patients, unless otherwise indicated. ICU, intensive care unit.
a
Data are for only 20 patients with SA-RVS infection who had vancomycin levels assessed during the first week of glycopeptide therapy.
5–33 days). Glycopeptide therapy failed for 19 (76%) of 25
patients, 15 of whom had detectable S. aureus bacteremia after
7 days of glycopeptide therapy, and 4 of whom had S. aureus
isolated from a sterile site after 21 days of glycopeptide therapy.
The PAP/AUC ratio range was 0.9–1.87, and the MIC of
vancomycin (determined using the broth microdilution method) was 2–4 mg/L for all isolates (table 2). Although all
isolates were susceptible to linezolid and quinupristin-dalfopristin, resistance and intermediate susceptibility were common
for multiple other antibiotics, as follows: 100% of the isolates
were resistant to oxacillin and to trimethoprim-sulfamethoxazole, 96% were resistant and 4% had intermediate susceptibility to tetracycline, 88% were resistant and 8% had intermediate susceptibility to erythromycin, 88% were resistant to
gentamicin, 88% were resistant to ciprofloxacin, 36% were resistant to rifampicin, 8% were resistant to fusidic acid, and 4%
were resistant to chloramphenicol. Notably, resistance to rifampicin developed during initial therapy for bacteremia in 3 cases
(2 cases were being treated with vancomycin and rifampin, and
1 case was being treated with vancomycin, rifampicin, and fusidic acid).
PFGE demonstrated 7 groups, with the majority of isolates
being in 2 main groups (figure 1). There were 3 riboprint
patterns, with most isolates in 2 groups. There was only limited
correlation between the riboprint pattern and PFGE group.
Although a number of isolates were found to be identical by
PFGE, they had generally been isolated from different hospitals
or at different times, indicating that cross-transmission was
unlikely to be responsible for the similarities. Isolates from
PFGE groups E and G were found, by comparison with reference strains, to be AUS2 and AUS3 epidemic MRSA, the
most common multidrug-resistant strain of MRSA found in
Australian hospitals, especially those in eastern Australia [18].
Twenty-one of the 25 patients received active antibiotic therapy to treat their SA-RVS infection, and 4 patients (patients
15, 16, 17, and 22; table 2) received either no therapy or minimal therapy directed at their SA-RVS infection. Three patients
(patients 15–17) died before or soon after the SA-RVS infection
was recognized. A fourth patient (patient 22) with a past history
of multiple antibiotic-related adverse reactions and complications who had infected bilateral total hip prostheses was considered to have no treatment options except complete surgical
removal of the infected prostheses, but this was refused by the
patient.
A number of antibiotic combinations were used by the 21
actively treated patients, but treatment with linezolid was most
common (n p 18), either alone (n p 9) or sequentially with
other agents, especially rifampicin and fusidic acid (n p 8). For
Treatment of SA-RVS • CID 2004:38 (15 February) • 523
Table 2. Details of disease and treatment in patients infected with Staphylococcus aureus with reduced vancomycin susceptibility
(SA-RVS).
Patient
Age in
years/sex
Type (site) of infection
Underlying disease or risk factor
Duration of positive
blood culture results
during glycopeptide
therapy, days
MIC of
a
vancomycin,
mg/L
1
80/M
Endocarditis (TV)
Diabetes mellitus, Wegner granulomatosis, ESRF,
immunosuppression, IVC filter
29
4
2
66/F
Endocarditis (TV), PPM, IVC filter
Diabetes mellitus, IHD, PPM, recent IVC filter
19
2
3
73/M
Endocarditis (MV)
Retroperitoneal fibrosis, steroid therapy, recent
laparotomy
8
2
4
73/F
Endocarditis (TV), vertebral OM, epidural, psoas, splenic abscesses
Bowel carcinoma, steroid therapy
8
4
5
66/F
Endocarditis (MV)
Diabetes mellitus, cervical carcinoma, steroid
therapy, aortic stenosis
13
4
6
72/M
Endocarditis (prosthetic AV)
Inflammatory arthritis, steroid therapy, AVR,
MVR, PPM, recent open cholecystectomy
7
2
7
77/F
Endocarditis (AV), splenic, renal abscess
Diabetes mellitus, AS, MR, recent small bowel
resection for polyps
20
2
8
67/M
Endocarditis (prosthetic AV),
mediastinitis
Diabetes mellitus, recent AVR
32
2
9
45/M
Bacteremia, spinal OM, spinal wound
infection
Automobile accident, paraplegic, recent thoracic
fusion
12
4
10
46/F
Bacteremia, extensive OM (foot),
stump infection
Diabetes mellitus, ESRF, PVD
5
2
11
63/M
Bacteremia, SA (knee), vertebral OM,
epidural abscess
Diabetes mellitus, recent knee reconstruction
and posttrauma ORIF
33
4
12
80/M
Bacteremia, SA (shoulder, THR, TKR)
RA, steroid therapy, THR, TKR
7
2
13
50/F
Bacteremia, intraabdominal collections
PVD, recent AAA graft and small bowel
resection
1
2
14
55/F
Bacteremia, biliary stent, liver abscess
Cholangiocarcinoma, chemotherapy, recent
biliary stent
15
2
15
83/M
Bacteremia, PPM abscess
PPM, AVR, colonic cancer, recent
hemicolectomy
8
4
16
56/F
Bacteremia
Diverticular disease, recent hemicolectomy
1
4
17
64/F
Bacteremia, pneumonia, meningitis
Removal of pituitary adenoma, CSF leak
1
2
18
60/M
OM (1st metatarsal), abscess (foot)
Diabetes mellitus, PVD
…
2
19
69/M
SA (prosthetic knee joint)
TKR
…
2
20
70/M
SA, OM (shoulder)
Fall, recent arthroscopy of shoulder
…
2
21
52/F
OM, SA (tibia/knee)
ORIF of tibial fracture
…
4
22
66/M
Bilateral SA, OM (THR)
Bilateral THR
…
2
23
63/M
OM, SA (first MTPJ)
ESRF, renal transplantation
…
2
24
62/M
Empyema
Dermoid tumor in chest wall, recent
thoracotomy
…
4
25
59/M
Empyema, pneumonia
Lung cancer, recent lobectomy
…
4
NOTE. AAA, abdominal aortic aneurysm; AUC, area under the curve; AV, aortic valve; AVR, aortic valve replacement; CCF, congestive cardiac failure; ESRF,
end-stage renal failure; IVC, inferior vena cava; MTPJ, metatarsophalyngeal joint; MV, mitral valve; OM, osteomyelitis; ORIF, open reduction internal fixation; PAP,
population analysis profile; PPM, permanent pacemaker; PVD, peripheral vascular disease; SA, septic arthritis; THR, total hip replacement; TKR, total knee
replacement; TV, tricuspid valve.
a
Determined using the broth microdilution method.
cases in which linezolid was used in combination with other
antibiotics, linezolid monotherapy was usually given until the
infection was clinically controlled (range, 17–78 days), followed
by an alternative regimen (usually rifampicin with fusidic acid)
either to complete a defined treatment course or for long-term
524 • CID 2004:38 (15 February) • Howden et al.
suppression. One patient (patient 12; table 2) was treated with
fusidic acid and chloramphenicol after initial control of the
infection with linezolid, because the infection was resistant to
rifampicin and all other available agents. Of note, 1 patient
with osteomyelitis and septic arthritis of the first metatarso-
PAP/AUC
ratio
Antibiotic therapy (duration)
Treatment
outcome
Other interventions
Overall
outcome
Comments
1.43
Linezolid (40 days)
None
Effective therapy
Cured
Follow-up duration of 10 months
1.14
Rifampin plus fusidic acid (11
days), then linezolid (38 days)
TV vegetectomy, removal of
PPM and IVC filter
Effective therapy
Cured
Follow-up duration of 10 weeks
1.01
Linezolid (49 days)
None
Effective therapy
Cured
Follow-up duration of 3 months
1.77
Linezolid (42 days), then rifampin plus fusidic acid (8 days)
None
Effective therapy
Died
Died of comorbidities; culture results
were negative after linezolid therapy
1.40
Linezolid plus rifampin and
fusidic acid (12 days)
MV repair
Not effective
Died
Died of cardiac failure; culture results
were negative after linezolid therapy
0.91
Rifampin plus fusidic acid
(12 days)
None
Not effective
Died
Active therapy ceased after cerebral
embolus
1.14
Rifampin (9 days), then linezolid
(7 days)
None
Not effective
Died
Died of severe sepsis, CCF;
culture results were positive
after linezolid therapy
0.90
Linezolid (42 days)
Redo AVR with homograft 10
days after linezolid therapy
was stopped
Not effective
Died
Died of postoperative bleeding; further
positive blood culture results after
linezolid therapy was ceased
1.36
Linezolid (32 days), then rifampin plus fusidic acid to
suppression
Laminectomy, wound
debridement
Effective suppression
Clinically
healthy
Follow-up duration of 10 months
0.95
Linezolid (60 days)
Above-knee amputation
Effective therapy
Cured
Follow-up duration of 1 month
1.34
Rifampin plus fusidic acid (10
months) to suppression
Multiple washouts, cervical
and tho-racic laminectomies
Effective suppression
Clinically
healthy
Follow-up duration of 7 months
0.93
Linezolid (31 days), then fusidic
acid and chloramphenicol
long term
None
Relapse
Clinically
healthy
Relapse of SA-RVS bacteremia while
receiving fusidic acid and chloramphenicol; resolved
1.12
Linezolid (17 days), then rifampin plus fusidic acid (14 days)
None
Effective therapy
Died
Died of bacteremia due to gram-negative organisms; no further SA-RVS
detected
1.17
Linezolid (34 days), then rifampin plus fusidic acid (14 days)
Multiple drainages
Effective therapy
Died
Died of cancer; no further SA-RVS
detected
1.38
Rifampin plus fusidic acid (1 day)
PPM explanted
N/A
Died
Died of overwhelming sepsis
1.87
None
None
N/A
Died
Died of overwhelming sepsis
0.93
None
None
N/A
Died
Died of overwhelming sepsis
0.95
Linezolid (42 days)
Abscess drainage
Effective therapy
Cured
Follow-up duration of 4 months
1.22
Linezolid (78 days), then rifampin plus fusidic acid
Removal of prosthetic knee
Effective suppression
Clinically
healthy
Received suppressive therapy; followup duration of 10 months
1.15
Linezolid (63 days)
Shoulder washout
Effective therapy
Cured
Follow-up duration of 5 months
1.10
Linezolid (28 days)
Removal of plates and screws
Effective therapy
Cured
Follow-up duration of 69 days
1.14
None
Removal of THR
N/A
Chronic
infected
Chronic low-grade infection of left THR
0.91
Vancomycin (77 days)
None
Effective therapy
Cured
Follow-up duration of 6 months
1.28
Linezolid (56 days)
Drainage of empyema
Effective therapy
Cured
Follow-up duration of 2 weeks
1.07
Linezolid (42 days)
Decortication
Effective therapy
Cured
Follow-up duration of 4 months
phalangeal joint (patient 23; table 2) was treated (and cured)
with 11 weeks of vancomycin therapy because the managing
clinicians were unaware that the infection was due to SA-RVS.
Although this isolate fulfilled the definition of SA-RVS (PAP/
AUC ratio, 0.91), the clinical course was such that no additional
isolates were recovered for testing.
In the actively treated group (n p 21 ), 16 patients (76%)
had an effective response to therapy. Ten patients (48%; patients
1–3, 10, 18, 20, 21, and 23–25) were cured at follow-up (table
2), 3 (14%; patients 9, 11, and 19) received effective suppressive
therapy (table 2), and an additional 3 (14%; patients 4, 13, and
14), although they were apparently cured of infection, had died
Treatment of SA-RVS • CID 2004:38 (15 February) • 525
Figure 1. PFGE analysis of 25 Staphylococcus aureus isolates with reduced vancomycin susceptibility. A, Alfred Hospital (Australia); B, Ballarat
Health Services (Australia); M, Monash Medical Centre (Australia); N, Auckland District Health Board (New Zealand); O, North Shore Hospital (New
Zealand); Q, Sullivan Nicolaides Pathology (Australia); R, Royal Melbourne Hospital (Australia); U, Austin Health (Australia); W, Western Hospital
(Australia).
of their underlying diseases at the time of follow-up (table 2).
The length of follow-up for these effectively treated patients is
described in table 2. SA-RVS infection clearly contributed to
the death of an additional 4 patients. Thus, 7 patients (33%)
had died at follow-up. The sole patient who experienced relapse
(patient 12; table 2) had a good response to linezolid for multifocal prosthetic joint septic arthritis, but his clinical condition
deteriorated, with a single additional blood culture positive for
MRSA 4 months after treatment was changed to long-term
suppressive therapy with fusidic acid and chloramphenicol. Despite the fact that the patient remained on fusidic acid and
chloramphenicol, the results of 4 additional sets of blood cultures were negative, and the patient eventually stabilized. He
was clinically healthy 2 months later while receiving suppressive
therapy.
Among the 18 patients who received linezolid therapy, the
duration of linezolid treatment varied (range, 7–78 days) but
was generally prolonged (median, 41 days). Side effects while
receiving linezolid occurred in 8 patients and included thrombocytopenia (n p 5), abnormal liver function test values
(n p 1), nausea (n p 1), and taste disturbance (n p 1 ). In 3
patients, the platelet count decreased to !50 ⫻ 10 9 platelets/L,
with 1 patient requiring a platelet transfusion. All 3 patients
had endocarditis and developed thrombocytopenia after ⭓35
days of therapy. Two patients (patients 2 and 4; table 2) com-
526 • CID 2004:38 (15 February) • Howden et al.
pleted their course of linezolid therapy despite having platelet
counts of 40 ⫻ 10 9 and 46 ⫻ 10 9 platelets/L, respectively, with
no further decrease in the platelet count. One patient (patient
1; table 2), whose platelet count decreased to 7 ⫻ 10 9 platelets/
L, stopped taking linezolid therapy 2 days early, and no alternate
therapy was used. The other 2 patients who developed mild
thrombocytopenia continued to receive linezolid therapy.
Surgery was an important component of therapy for 13 patients in the actively treated group, including 69% of patients
for whom therapy was effective. Of the 13 actively treated patients who underwent surgery, 11 (85%) received effective therapy, whereas, of those who did not undergo surgery, 5 (63%)
of 8 received effective therapy. The surgery usually involved
significant debulking of infection (e.g., vegetectomy, debridement and removal of infected prosthetic devices, and drainage
of multiple liver abscesses), and, in some cases, repeated surgery
was required.
DISCUSSION
We found that serious infections due to SA-RVS in Australasia
were generally identified in patients in whom glycopeptide
treatment had failed. This correlates with previous reports of
treatment failure in patients infected with these SA-RVS strains
[4, 7, 8]. Nevertheless, the vast majority of these patients were
effectively treated with antibiotics, either alone (31%) or in
combination with surgical debulking of the infected site (69%).
Linezolid was the most commonly used antibiotic, particularly
for initial therapy, followed, in some patients (n p 5), by a
switch to combination therapy with rifampicin and fusidic acid.
Overall, adverse reactions were uncommon, except for thrombocytopenia in patients receiving prolonged courses of linezolid. These results are encouraging, given the serious nature
of the infections we observed and the high rate of complex
comorbidities in these patients. In particular, our relative success in treating endocarditis due to SA-RVS (therapy was effective for 4 of 8 patients) is notable, given that there is only
a single previous reported case of successful treatment of SARVS endocarditis [19]. However, the fact that the remaining 4
patients with endocarditis died of complications (2 had ongoing
bacteremia, despite receiving linezolid therapy) highlights the
difficulties associated with this disease. Overall, in our study,
linezolid appeared to be a relatively safe and effective agent, as
long as therapy was not prolonged.
All patients in this study had a clinical course that was consistent with infection with a staphylococcal strain that had reduced susceptibility to vancomycin. Nevertheless, these isolates
highlighted the difficulty in readily detecting such vancomycin
resistance in vitro, given that all strains initially demonstrated
an MIC of vancomycin in the susceptible range (⭐4 mg/L),
with a number of strains (n p 15) having an MIC of vancomycin of only 2 mg/L. Thus, studies that use the criteria of an
MIC of vancomycin of ⭓4 mg/L or growth on media containing vancomycin, 4 mg/L, as diagnostic for SA-RVS [8, 20]
may overlook such strains as ours and not proceed to PAP
testing. However, as 1 patient (patient 23) in our study demonstrated, even PAP findings do not always correlate with clinical outcome. The SA-RVS strain isolated from patient 23 had
a PAP/AUC ratio of 0.91 (i.e., just above the cutoff for SARVS) and an MIC of vancomycin of 2 mg/L (as determined
using the broth microdilution method), yet the infection was
apparently eradicated and the patient cured after receiving an
11-week treatment course of vancomycin. There are a number
of potential explanations for the outcome in this case. First,
given that the patient had end-stage renal failure and reduced
vancomycin clearance, serum and bone vancomycin concentrations may have been substantially higher than in patients
with more normal renal function. Second, the proportion of
this patient’s S. aureus population with reduced susceptibility
to vancomycin may have been sufficiently low that the combination of high vancomycin levels and the patient’s routine
immune function may have been sufficient to eradicate resistant
subpopulations.
The mechanisms of vancomycin resistance in S. aureus are
not known, although a thickened cell wall is a common feature,
and this appears to be inducible by vancomycin [10, 21]. Consistent with this observation, most of our patients not only had
previous MRSA infection and glycopeptide exposure, but 80%
of those with recorded vancomycin levels had a low (!10 mg/
L) trough concentration during the first week of vancomycin
therapy. Low vancomycin levels, particularly in the early stages
of therapy, could result in induction of preexisting low-level
vancomycin resistance or could select for new vancomycinresistant strains [10]. This clearly has implications in terms of
the emphasis placed on surgical drainage and debulking of
high–bacterial load infections in such patients (e.g., MRSAassociated abscesses and infected prostheses) and possibly has
implications on vancomycin dosing. Whenever possible,
MRSA-associated abscesses should be drained and a high priority given to removal of infected prosthetic devices.
Molecular assessment of our SA-RVS isolates indicated a
number of PFGE groups, with no substantive evidence of clonal
dissemination. Isolates that appeared to be clonal were generally
not epidemiologically linked—either by institution or time.
Nevertheless, the fact that PFGE analysis suggested that some
strains were closely related to the AUS2 and AUS3 MRSA strains
that are the most common multidrug-resistant MRSA strains
found in Australia [18] is concerning and highlights the potential for MRSA strains with reduced susceptibility to vancomycin to become widespread in Australia.
Our study has some limitations. First, it is not possible, given
the methodology of our case detection, to identify the correct
clinical sequence in our patients—namely, whether our patients’ infections were ineffectively treated with glycopeptides
with reduced susceptibility to vancomycin, thereby being induced and resulting in greater glycopeptide failure; or whether
SA-RVS strains were primarily responsible for the infection all
along, and glycopeptide failure was an inevitable consequence.
Second, given the size and descriptive nature of our study, we
cannot be certain about the efficacy of agents such as linezolid
and rifampicin plus fusidic acid. However, our results are encouraging, especially if a combined medical and surgical approach is taken.
Our study suggests that SA-RVS is not just a laboratory
phenomenon, but that such strains are associated with serious
infections that respond to carefully targeted nonglycopeptide
therapy. With the increasing recognition of SA-RVS, future controlled studies comparing the efficacy of therapeutic agents
should be performed.
Acknowledgment
We thank Geoff Coombs (Royal Perth Hospital; Perth, Australia), for performing PFGE typing of selected isolates, and the
Treatment of SA-RVS • CID 2004:38 (15 February) • 527
microbiology and clinical staff from each of the hospitals that
contributed cases.
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