Bactericidal activity of oxacillin and glycopeptides against Staphylococcus aureus in patients with endocarditis: Looking for a relationship between tolerance and outcome
Annals of Clinical Microbiology and Antimicrobials
Bactericidal activity of oxacillin and glycopeptides against Staphylococcus aureus in patients with endocarditis: Looking for a relationship between tolerance and outcome
Maria Bruna Pasticci 0
Amedeo Moretti 0
Giuliano Stagni 0
Veronica Ravasio 2
Laura Soavi 2
Annibale Raglio 1
Francesca Vailati 1
Angela Cardaccia 0
Antonella Santucci 0
Rita Papili 0
Alessio Sgrelli 0
Carlo Pallotto 0
Franco Baldelli 0
0 Section of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, University of Perugia , Perugia , Italy
1 Unit of Microbiology and Virology, Ospedali Riuniti di Bergamo , Bergamo , Italy
2 Infectious Disease Department, Ospedali Riuniti di Bergamo , Bergamo , Italy
Background: There is no clear relationship between in vitro bactericidal activity tests and clinical outcome. We studied bactericidal activity of oxacillin, vancomycin and teicoplanin against Staphylococcus aureus isolates in patients with endocarditis and then we sought to determine if there was a relationship between in vitro bactericidal activity and clinical outcome. Methods: Minimal bacteriostatic and minimal bactericidal concentrations were determined for Staphylococcus aureus strains isolated from patients with endocarditis following standardized methods. Medical records were reviewed retrospectively to collect data on antimicrobial susceptibility at admission, antimicrobial therapy, need for surgery, embolic events and outcome. Results and Discussion: Sixty-two Staphylococcus aureus strains were studied in 62 patients with endocarditis. Overall, 91.9% definite, 21% methicillin resistant and 72.6% cured. Surgery was performed in 32.3% and embolic events were documented in 64.5%. Tolerance to oxacillin and teicoplanin was more common than vancomycin tolerance among methicillin susceptible Staphylococcus aureus. Among methicillin resistant Staphylococcus aureus teicoplanin was shown to have a higher rate of tolerance than vancomycin. No statistically significant differences on clinical outcome between oxacillin tolerant and oxacillin non tolerant Staphylococcus aureus infections were observed. Tolerance to oxacillin did not adversely affect clinical outcomes of patients with methicillin susceptible Staphylococcus aureus endocarditis treated with a combination of antimicrobials including oxacillin. The cure rate was significantly lower among patients with methicillin resistant Staphylococcus aureus endocarditis. Conclusions: In vitro bactericidal test results were not valid predictors of clinical outcome. Physicians need to use additional parameters when treating patients with staphylococcal endocarditis.
In recently published surveys Staphylococcus aureus (S.
aureus) is reported to overstep viridans Streptococci as a
cause of endocarditis (IE) and associated morbidities and
mortality [1,2]. S.aureus is an extraordinarily adaptable
bacterium, developing increasing patterns of resistance
which contribute to clinical failures. Penicillin resistance
was soon followed by methicillin resistance, which always
includes resistance to all beta-lactam antimicrobials and
often to several other classes of antibiotics . The
efficacy of vancomycin against methicillin resistant S.aureus
(MRSA) has been reported to be inferior to that of
betalactams against methicillin susceptible S.aureus (MSSA)
due to its slower in vitro bactericidal activity with a lower
clinical response [4-6]. Recently other reasons for the
clinical failure of vancomycin have been indicated and
include: the progressive increase of vancomycin
minimum inhibitory concentrations (MICs) over time, but
with values still in the susceptibility range, and the
emergence of S.aureus showing either glycopeptide
heteroresistance, an intermediate level of resistance (GISA) or
full resistance (GRSA) [7-10].
Tolerance is another form of antimicrobial resistance
of S.aureus hypothesised to be a cause of clinical failure.
Tolerance has been described for anti-staphylococcal
beta-lactams but involves also glycopeptide antimicrobial
agents. There have been studies reporting infections
caused by tolerant strains more difficult to eradicate and
antimicrobial regimens with bactericidal activity superior
to that of bacteriostatic regimens in the treatment of
serious S.aureus infections. Tolerant strains are
susceptible as judged by MICs but show an increasing resistance
to the killing with high minimal bactericidal
concentrations (MBCs) and an MIC/MBC ratio32. Bactericidal
activity can also be evaluated with time killing curves
but, independently from the method used, there are
theoretical and technical difficulties in performing these
tests. Thus, highly standardised methods should be
followed. To date, bactericidal activity has been regarded
as a desirable characteristic in antimicrobial agents
when treating patients with endocarditis, while, routine
MBC testing is not recommended because of the
technical difficulties associated with these tests [11-15].
The aims of this study were:
a) To determine the in vitro bactericidal activity of
oxacillin, vancomycin and teicoplanin against S.aureus
isolated in patients with S.aureus endocarditis
b) To look for a relationship between in vitro
bactericidal activity and clinical outcome using data
available from patients that had been previously enrolled
in observational studies on endocarditis.
Isolates of S.aureus were collected from patients with IE
admitted to the Infectious Disease Departments (IDD) of
Perugia and Bergamo from 1988-2009. A total of 30
strains were from Perugia and 32 from Bergamo. The
initial blood isolates on the day of admission were stored
at -70C until the time of in vitro testing. MICs and MBCs
were determined at the IDD of Perugia under blinded
conditions according to CLSI guidelines [16-18].
1) Oxacillin: Cefoxitin disk diffusion using Muller-Hin
ton agar plates (bioMerieux) and 30 g cefoxitin disk
(bio-Merieux) and interpreted according to CLSI break
points (16), macro-method MIC using Muller Hinton
Broth (MHB), inoculum 1-5 105 CFU/ml, stationary
phase of growth) (17) and E-test MIC according to the
E-test manufacturer (AB Biodisk).
2) Vancomycin: macro-method MIC (MHB, inoculum
1-5 105 CFU/ml, stationary phase of growth) (17) and
3) Teicoplanin: macro-method MIC (MHB, inoculum
1-5 105 CFU/ml, stationary phase of growth) (17),
MBC was determined by sub-culturing 50 l from each
vial without a visible growth onto plates of Muller
Hinton agar (MHA), after 24h of incubation at 35C. The
geometric mean of duplicate colony counts were used to
determine the MBC defined as the antibiotic
concentration with killing of 99.9% of the initial inoculum (18). In
the presence of Eagle phenomenon, MBC was the
antibiotic concentration yielding persistent killing of 99.9% of
the initial inoculum.
MIC50 and MIC90 were determined by interpolation
from graphs of cumulated percent strains inhibited
versus MIC .
MSSA ATCC 29213 was used as a control strain in all
Medical records of each patient were reviewed
retrospectively to collect data on: demographic data, year of
diagnosis, valve localization, hospital or community
acquired infection, antimicrobial susceptibility results at
the time of patient admission and antimicrobial
treatment, surgery, embolic events and outcomes.
There was no research related effect for patients.
Patients gave informed consent to be included in the
observational protocol on endocarditis cases. The
protocol was approved by the institutional ethical committee
of Perugia and Bergamo. All activity was conducted in
accordance with the Declaration of Helsinki, and
national and institutional review board.
Associations among qualitative variables were analysed
using the contingency table. The statistical significance
was assessed with the Fisher exact test.
Sixty-two isolates of S.aureus were collected from
patients with endocarditis, 58% male, 91.9% definite
(DE) and 8.1% possible (PE) according to Duke criteria,
47 (75.8%) native valve endocarditis (NVE) and 15
(24.2%) prosthetic valve endocarditis (PVE), three
pacemaker wire (PM) infections and 37% hospital acquired.
Overall, 13/62 (21%) were caused by MRSA and 76.9 of
these were hospital acquired. All the isolates were
reported vancomycin and teicoplanin susceptible.
Overall, 45 patients (72.6%) were cured and 17 (27.4%) died
of endocarditis. Surgery was performed on 20 (32.3%)
and embolic events were documented in 40 cases
(64.5%) (Table 1).
Oxacillin, vancomycin and teicoplanin susceptibility of
62 S.aureus isolates are reported in Table 2. Oxacillin
and teicoplanin results in this study were in agreement
Table 1 Epidemiology of S.aureus endocarditis
Macromethod MICs N.susceptible/N.tested (%)
E-test MICs N.susceptible/N.tested (%)
DE (definite endocarditis, NVE (native valve endocarditis), PVE (prosthetic valve endocarditis), PM (pace maker), HA (hospital acquired), SUR (surgery), EMB
with the laboratory results obtained at admission.
Vancomycin susceptibility was not fully confirmed for two
isolates tested. One of these was cultured from a patient
in Bergamo and one from Perugia; both had
macromethod MICs of 4 mg/l while their MICs with the
E-test were 2.5 mg/l and 2.0 mg/l respectively.
Methicillin resistance was confirmed in 13 out of 62
MSSA susceptibility tests: oxacillin geometric mean
MIC 0.52 mg/l (range 0.25-1), MIC50 0.35 mg/l, MIC90
0.48 mg/l, tolerance rate 63.2%; vancomycin mean MIC
1.69 mg/l (range 1-2), MIC50 1.1 mg/l, MIC90 1.7 mg/l,
tolerance rate 18.4%; teicoplanin mean MIC 1.39 mg/l
(range 1-2), MIC50 0.9 mg/l, MIC90 1.7 mg/l, tolerance
MRSA susceptibility tests: vancomycin mean MIC
2.3 mg/l (range 2-4), MIC50 1.5 mg/l, MIC90 2.5 mg/l,
tolerance rate 30.8%; teicoplanin mean MIC 2.1 mg/l
(range 1-4), MIC50 1.3 mg/l, MIC90 2.5 mg/l, tolerance
rate 76.9% (Table 3).
Among the 31 oxacillin tolerant strains, 8 (26%) were
also vancomycin tolerant and 18 (58%) were teicoplanin
tolerant. Only one of the oxacillin non tolerant isolates
was vancomycin tolerant while 12 (66%) were tolerant
Table 2 Bacteriostatic activity of oxacillin and glycopeptides
Oxacillin (MIC: S2 mg/l) (DISK:S22 mm)
*/**Vancomycin (S2 mg/l)
*Teicoplanin (S8 mg/l)
**Teicoplanin (S2 mg/l)
CLSI and EUCAST susceptibility break point, cefoxitin disk diffusion same results as oxacillin
*CLSI susceptibility break point
**EUCAST susceptibility break point
Antimicrobial susceptibility tests had been performed
at local laboratories at the time of diagnosis, as well,
treatment had been decided by the curing physicians
on the basis of available susceptibility results and the
clinical conditions of patients. MSSA IE antimicrobial
therapy consisted of: oxacillin 37, cefazolin 5,
vancomycin 4, teicoplanin 1 and not known 2. MRSA IE (13
cases) were treated with vancomycin 10, teicoplanin 1
and in 2 therapy was not known. Beta-lactam or
glycopeptide antimicrobials were administered in
combination with rifampin or an aminoglycoside, or a
quinolone or a combination of two or more of these
antimicrobials for MSSA and MRSA in most of the
cases. Need for surgery had been individualised
following international indications. Overall, the cure rate was
79.6% for MSSA: 31 oxacillin, 4 cefazolin, 3
vancomycin and 1 teicoplanin while the cure rate for MRSA
was 46.2%: 5 vancomycin and 1 unreported treatment
(p < 0.032). There was no evidence of any differences
with regard to need for surgery or embolic events
between MSSA and MRSA IE (Table 4). There were
only four patients with MRSA IE vancomycin tolerant
and all of these had been treated with antimicrobial
combinations including vancomycin and had a cure
rate of 25% (Table 4).
Table 4 Rates of cure, surgery, and embolism in endocarditis caused by MSSA and MRSA
Table 5 Rates of cure, surgery, and embolism in MSSA endocarditis caused by oxacillin tolerant and oxacillin
Cured N. (%)
MSSA N. 49 (79%)
MRSA N. 13 (21%)
Vancomycin tolerant N. 4/13 (30.8%)
Vancomycin non tolerant N. 9/13 (69.2%)
*p < 0.032, **p = 1, ***p = 0.51, p = 0.55.
A negative effect of oxacillin tolerance was not
observed either in the entire subgroup of IE cases
caused by MSSA or in the subgroup of patients with
MSSA IE being treated with an antibiotic regimen
containing oxacillin (Table 5).
This study was designed to assess the rate of tolerance
to oxacillin, vancomycin and teicoplanin among S.aureus
isolates in patients with IE. Thereafter, we sought to
determine a relationship between in vitro bactericidal
tests and clinical outcome.
The bactericidal test results of this study, defined by
MBCs, showed that vancomycin bactericidal activity was
not inferior to that of oxacillin and teicoplanin against
MSSA. Glycopeptide tolerance was more common
among MSSA oxacillin tolerant strains but a few non
tolerant MSSA oxacillin with high MBC for
glycopeptides were also observed.
Among MRSA isolates, vancomycin tolerance rate was
inferior to that of teicoplanin and all the 4 vancomycin
tolerant isolates were also teicoplanin tolerant.
Previous papers have reported that vancomycin has in
vitro bactericidal activity slower than that of nafcillin
with more frequent clinical failures in animal models
and also patients being treated with vancomycin [4-6].
Technical variables such as inoculum size, growth
conditions and killing curves, instead of MBCs, may be
responsible for some of the differences in the results of
this study. May et al.  found MBCs and the killing
rates comparable with some discrepancies. Lack of
killing in vitro has also been hypothesised to be a reversible
phenotypic response due to growth conditions of the
test with some types of constitutional changes noted in
MSSA 49/62 (79%)
Oxacillin tolerant N. 31 (63.2%)
Oxacillin non tolerant N. 18 (36.8%)
MSSA oxacillin tolerant treated with oxacillin/total MSSA oxacillin tolerant N.
MSSA oxacillin non tolerant treated with oxacillin/total MSSA oxacillin
nontolerant N. 13/18 (72.2%)
*p = 0.46, **p = 1, p = 0.64
Surgery N. (%)
16/49 ** (32.7%)
4/13 ** (30.8%)
Embolic events N. (%)
33/49 *** (67.3%)
7/13 *** (53.8%)
tolerant strains [21,22]. It has been reported that most
beta-lactam tolerant strains of S.aureus show cross
tolerance to vancomycin and teicoplanin .
Regarding clinical outcome, 79% of IE cases in this
study were caused by MSSA. In these patients, oxacillin
was the most common antibiotic prescribed and it was
usually given in combination with other antibiotics in
both oxacillin tolerant and oxacillin non-tolerant MSSA
infections. Analysis was unable to demonstrate either
increased mortality or morbidity in oxacillin tolerant
MSSA IE patients. Strikingly, a non-statistically
significant higher cure rate was observed in patients with IE
caused by oxacillin tolerant MSSA in both the entire
MSSA IE group and in the MSSA subgroup treated with
Despite its greater in vitro bactericidal activity, a
higher rate of clinical failures was observed among
patients with MRSA IE. Among MRSA IE patients,
higher rates of clinical failure were observed among
patients with endocarditis caused by vancomycin
tolerant MRSA strains, but there were only four patients in
this group of patients to comment on.
With regard to bacteriostatic activity, methicillin
resistance was confirmed in 21% of the isolates. Methicillin
resistance occurred more commonly among hospital
acquired infections with the exception of three cases.
One of these should be classified as health care
associated even though the isolate had a mecA cassette type
V, which is a marker for methicillin-resistant
community acquired infection  and was susceptible to all
other classes of antibiotics except penicillin. This patient
reported a traumatic tibia fracture, was treated with
external devices and discharged from hospital.
Subsequently, the patient developed osteomyelitis and
Cured N. (%)
26/31 * (83.9%)
13/18 * (72.2%)
Surgery N. (%)
10/31 ** (32.3%)
6/18 ** (33.3%)
Embolic events N. (%)
21/31 ** (67.7%)
12/18 ** (66.7%)
endocarditis with multiple septic lung emboli and
myocardial abscess. The other two cases were community
acquired MRSA IE from the Bergamo cohort.
Concordant susceptibility test results were obtained
also with teicoplanin.
With regard to vancomycin, there was no full agreement
on the grade of susceptibility obtained at admission. Two
isolates had vancomycin macro-method MICs of 4 mg/l,
which are intermediate susceptible values. The obtained
values were still in the susceptible range when performing
the E-test, being 2 mg/l for the Perugia isolate and 2.5 mg/l
for the Bergamo isolate. The former was methicillin
resistant, hospital acquired, non tolerant to vancomycin but
teicoplanin tolerant, cultured in early prosthetic infection
with valve abscess. The patient treatment included
teicoplanin, followed by daptomycin and rifampin then
tigecycline. The patient died. The latter isolate was methicillin
resistant, hospital acquired and vancomycin tolerant,
cultured from a case of pace-maker infection. The patient
underwent both the surgical removal of the device and
vancomycin plus fosfomicin and co-trimoxazole treatment
In this study, all 62 isolates had slightly higher
macromethod vancomycin MICs than with the E-test.
Previously in literature, higher vancomycin MICs have been
observed with the E-test compared to the micro-dilution
method. Nonetheless, the micro-dilution method and
Etest both have been reported to perform differently than
disk diffusion and some automated systems [25,26].
Given this, while these in vitro vancomycin susceptibility
testing parameters are being standardised, it may be
advisable to assess vancomycin MICs with more than
one method and to carry out a close clinical and
microbiological follow up while the patients are being treated
A progressive increase in vancomycin MICs over time
was not observed in this study [7,25,26] however, there
were very few strains included before the year 2004 and
all of these, though methicillin susceptible, already had
vancomycin MIC of 1-2 mg/l.
This study reports that oxacillin and teicoplanin
tolerance was common among S.aureus and more common
than vancomycin. This study was unable to show a
statistically significant correlation between bactericidal
activity in vitro and clinical outcome. However, one
must consider that these results were from a
retrospective analysis and treatment was not standardized.
Additional, prospective standardized studies are
needed to evaluate if in vitro bactericidal tests are
valid predictors of clinical outcome in staphylococcal
We would like kindly thank Professor Stefania Stefani, Department of
Microbiology, University of Catania, Catania, Italy for having examined the
staphylococcal mecA cassette in the isolate from Perugia.
PMB designed the study, supervised laboratory experiments, performed
clinical examinations, recruited patients, analysed the data and drafted the
manuscript. AM and AC collected bacterial isolates, performed on admission
susceptibility tests and laboratory experiments. VR, LS, AS and CP carried out
clinical examinations and the recruitment of patients. AR and AG collected
strains and performed on admission susceptibility tests. AS and RP analysed
the data. GS and FB revised the manuscript. All authors read and approved
the final manuscript.
The authors declare that they have no competing interests.
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