is possible that treatment failures with cefazolin may be caused by a combination of
the recalcitrant nature of the infection and the instability of cefazolin against a
particular subtype of penicillinase produced by the staphylococcal strain, which is
not readily detectable via routine MIC testing. For patients with endocarditis caused
by S. aureus who have immediate-type hypersensitivity to penicillin, vancomycin or
daptomycin may be used. Other treatment options include linezolid and
62 Selection of agent depends on organism susceptibility,
potential of drug–drug interactions, and host predisposition for development of
An enhanced response to combination therapy in the experimental animal model of
MSSA endocarditis has prompted clinical trials to evaluate whether the addition of
gentamicin to nafcillin confers any additional benefit. The combination of nafcillin
and gentamicin resulted in more rapid clearing of organisms from the blood, but the
response rates were similar to patients treated with nafcillin alone.
the group receiving gentamicin had a higher incidence of nephrotoxicity. Thus, for the
routine management of endocarditis caused by MSSA, the addition of a second drug
does not appear to offer additional benefit when a penicillinase-resistant penicillin is
used and is discouraged due to the lack of clearly established efficacy and
aminoglycoside toxicity. (see Case 66-3, Question 2, previous discussion). For
patients who remain bacteremic or who fail to improve clinically (usually
nonaddicts), imaging studies are often performed to identify metastatic sites of
infection (i.e., occult abscess) with possible need for surgical intervention.
METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS:
CASE 66-3, QUESTION 3: How would T.J.’s therapy differ if he were infected with MRSA?
Staphylococcus aureus IE involving methicillin-resistant strains has become
increasingly common and accounts for up to 40% of cases.
have more chronic comorbid conditions (e.g., diabetes mellitus, hemodialysis
dependency) and are more likely to have health-care-associated infection (76% vs.
37%) and an indwelling intravascular catheter or hemodialysis fistula as the
presumed source of infection (60% vs. 31%) when compared with patients infected
6 Persistent bacteremia was more common with MRSA IE, occurring in
43% versus 9% of patients infected with MSSA. Of interest, in this study, patients
with S. aureus IE from the United States were significantly more likely to be infected
with MRSA, to receive vancomycin therapy, and to develop persistent bacteremia.
In 20% of patients with MRSA IE, identifiable health-care contact was absent.
MRSA infection is traditionally associated with health-care contact in the
nosocomial setting, but is now becoming more prevalent in the community (CAMRSA).
6 Young and otherwise healthy individuals without the traditional risk factors
are infected in the community.
Panton-Valentine leukocidin (PVL). Expression of this pore-forming toxin that causes
severe necrosis in polymorphonuclear neutrophil cells in a rabbit model has been
implicated to cause invasive infections, including necrotizing pneumonia and skin
65–71 Specifically, CA-MRSA PVL-producing strains causing IE have been
Vancomycin has been the accepted standard of treatment for MRSA endocarditis.
Response to treatment, however, is slower than with semisynthetic penicillins (e.g.,
nafcillin) for MSSA endocarditis. The mean duration of bacteremia in patients with
MSSA endocarditis has been reported to be 3.4 days for nafcillin alone and 2.9 days
for the combination of nafcillin and gentamicin.
In contrast, the median duration of
bacteremia for MRSA endocarditis was 7 days for vancomycin alone. Failure rates
of up to 40% have been documented in patients even with right-sided involvement.
Of great concern is the emergence of resistant strains of S. aureus after repeated and
prolonged exposure to vancomycin therapy.
Either vancomycin or daptomycin at 8 mg/kg IV once daily (up to 12 mg/kg/day)
may be used to treat patients with MRSA endocarditis.
daptomycin 8mg/kg/dose. Vancomycin 30 mg/kg/day in two divided doses for a total
of 6 weeks is recommended for adults with normal renal function. Vancomycin peak
levels are not recommended. Given the emergence of MRSA strains with reduced
susceptibility to vancomycin, published guidelines from the Infectious Diseases
Society of America recommend a target trough of 15 to 20 mcg/mL
to overcome increasing MIC of clinical strains and limited tissue penetration.
Measurement of trough serum vancomycin concentrations is typically 30 minutes
prior to the fourth dose for patients receiving a dosing interval of every 12 hours. A
dosage regimen of vancomycin aimed to achieve an area under the curve-to-MIC
ratio of 400 or an unbound trough at 4 to 5 times MIC of the infected strain has been
proposed as the optimal pharmacodynamic target.
In a large multinational study of nearly 1,800 patients with definite IE, persistent
bacteremia, receipt of vancomycin, and healthcare contact were significantly more
common in patients with MRSA IE from the United States compared with those from
6 The authors speculated that the higher rates of persistent
bacteremia in US patients may be attributable in part to the receipt of vancomycin
Vancomycin MICs against S. aureus have been increasing over the years. At one
university medical center, vancomycin MICs were determined by broth microdilution
for 6,000 nosocomial MRSA isolates collected during a 5-year period. In the year
2000, 80% of the strains had vancomycin MIC of 0.5 mcg/mL; however, by 2004,
70% of isolates had MICs of 2 mcg/mL.
In response to increasing reports of
vancomycin failures caused by strains that are in the susceptible range, the
vancomycin breakpoint for susceptibility was reduced from 4 to 2 mcg/mL for S.
aureus in 2005 per the Clinical and Laboratory Standards Institute.
susceptibility to glycopeptides results from an increase in the production of
peptidoglycan precursors leading to a thickened cell wall and decreased penetration
of glycopeptides into the bacterial cell membrane.
hGISA strains may revert to glycopeptide susceptibility, making it difficult to detect
these strains in vitro. As such, several investigators have found that hGISA strains
have an MIC range that overlaps with the currently defined susceptible range and that
the prevalence among hospitalized patients is increasing.
testing methods performed in the clinical laboratory are unreliable in detecting
MRSA strains with hGISA phenotype.
85 MIC determined by Etest best predicts
treatment outcome with vancomycin.
Experts have recommended a target vancomycin trough concentration of 15 to 20
mcg/mL to overcome increasing MIC when treating pneumonia or endocarditis
87 A published study of adult infections with MRSA reported that
54% (51 of 95) of clinical isolates had vancomycin MIC of 2 mcg/mL.
invasive infections, such as bacteremia and pneumonia, were linked to higher MIC.
Infections caused by those strains were associated with lower end of treatment
responses (62% vs. 85%) and increased mortality (24% vs. 10%) compared with
strains with MIC of 1 mcg/mL or less, irrespective of attaining a goal trough of 15 to
20 mcg/mL (achieving the goal of 4 to 5 times greater than MIC of an infected strain
that has an MIC of 2 mcg/mL). Borderline susceptibility (MIC 2 mcg/mL) and
severity of underlying disease were independent predictors of poor treatment
response. Many strains demonstrated tolerance to vancomycin as defined by the
88 Vancomycin monotherapy of hVISA
was associated with treatment failure, whereas combination therapy responded
88 Combination regimens included vancomycin plus rifampin, linezolid, or
daptomycin. These findings suggest a role for combination therapy or alternative
agents when treating invasive infections caused by MRSA strains with borderline
susceptibility. However, the above study was not designed to compare the efficacy of
vancomycin monotherapy with combination therapy for the treatment of MRSA
infections, and the sample size of patients infected with hVISA in this study was
small. Therefore, the role of vancomycin as the treatment
of choice for MRSA IE will need to be re-evaluated against other available
Despite attaining a pharmacodynamic goal of unbound vancomycin trough level of
at least 4 times MIC of the infected strain, T.J. fails to clinically improve and has
persistent bacteremia. It is possible that T.J. is infected with a hVISA strain; thus, a
change in therapy is warranted.
Daptomycin (Cubicin) is a cyclic lipopeptide that has been approved for treatment
of S. aureus bacteremia and right-sided endocarditis. In vivo, it has a wide spectrum
of activity against gram-positive bacteria, including S. aureus (including MRSA),
Enterococcus faecalis, Enterococcus faecium, streptococci, and most other species of
aerobic and anaerobic gram-positive bacteria. It was approved for the treatment of S.
aureus bacteremia and endocarditis in a noninferiority study in patients receiving
daptomycin or standard therapy consisting of an antistaphylococcal penicillin or
vancomycin in addition to low-dose gentamicin.
89 Successful outcome was seen in
46% (41 of 90) of patients who had presumed or definite staphylococcal
endocarditis at their baseline diagnosis. Of those, MRSA endocarditis was
successfully treated in 42% (15 of 36) of cases. In patients with confirmed
uncomplicated and complicated right-sided endocarditis, treatment success was
similar between the daptomycin group (8 of 18) and the group receiving standard
therapy (7 of 16) at 44%. Microbiologic failure occurred in seven patients in the
daptomycin group and in five patients receiving standard therapy. Overall, the most
common cause of daptomycin failure was persistent or relapsing infections,
accounting for 16% of failures. In contrast, failure of standard therapy was more
often the result of treatment-limiting adverse events, accounting for 15% of failures.
Increase in the MIC of the infected strain was observed more often in the daptomycin
group compared with standard treatment (six in the daptomycin group vs. one patient
in the standard therapy group). The use of daptomycin for treatment of left-sided
endocarditis is not established because only nine patients were treated and only one
Daptomycin at >8 mg/kg/day for a total duration of 6 weeks should be used for the
treatment of endocarditis. Considering its concentration-dependent effects, some
recommended higher doses (up to 12 mg/kg/day) which appear to be safe.
90 Highdose daptomycin should be considered in patients who have previously failed
vancomycin treatment, who are severely ill, or who are infected with an isolate with
elevated vancomycin MICs. Daptomycin should be dosed based on total body weight
because obese patients have a larger volume of distribution as well as increased
clearance compared with the nonobese population.
91 Creatine kinase levels should be
obtained at baseline and weekly to monitor for elevations, and more frequently in
patients who may be at risk for developing skeletal muscle dysfunction. High-dose
daptomycin at 8 to 12 mg/kg daily should be considered as alternative therapy in T.J.
Emergence of cross-resistance to daptomycin after vancomycin exposure has been
93 Similar to a thickened cell wall contributing to decreased
susceptibility to vancomycin, the same mechanism is thought to contribute to
daptomycin resistance in S. aureus.
94 Therefore, it is important to confirm MRSA
susceptibility to daptomycin when used in a patient who had prior vancomycin
exposure. Either gentamicin (at 1 mg/kg every 8 hours or 5 mg/kg daily) or rifampin
300 to 450 mg orally (PO) twice daily or both may be used in combination with
daptomycin as in vitro synergy has been demonstrated for the combinations.
Alternatively, daptomycin 10 mg/kg/dose IV once daily plus linezolid 600 mg PO
twice daily may be used, particularly with concomitant pneumonia.
Once daptomycin therapy is initiated, continued monitoring of clinical response
and organism susceptibility to daptomycin is warranted because resistance
development has been reported during prolonged therapy.
increase during therapy for S. aureus endocarditis was demonstrated in six patients.
Baseline MIC increased from 0.25 to 2 mcg/mL in five isolates and from 0.5 to 4
mcg/mL in one isolate. Five of those six isolates were MRSA.
A potential treatment option for T.J., if his infected MRSA strain demonstrates
Linezolid (Zyvox), an oxazolidinone, is not approved by the US Food and Drug
Administration (FDA) for the treatment of endocarditis, but has been used in cases of
In a review article that included 33 case reports of
endocarditis treated with linezolid, 63.6% of patients had successful outcomes at the
102 MRSA and vancomycin-intermediate S. aureus were
the most common pathogens, accounting for 24% and 30% of cases, respectively.
Failure with linezolid treatment was documented in seven cases, including four
deaths attributed to endocarditis and three owing to persistent positive blood
cultures. Thrombocytopenia was the most common adverse effect, occurring in eight
of nine patients. In a compassionate-use program, linezolid achieved 50% clinical
and microbiologic cure rates at 6-month follow-up in 32 patients with definite IE;
MRSA was the causative agent in seven of those patients. The most common adverse
events reported in this group were gastrointestinal system effects and
thrombocytopenia, each occurring in 15% of patients.
thrombocytopenia associated with linezolid correlates with the extent of drug
exposure, as measured by area under the concentration curve and duration of
104 Of note, treatment failure with linezolid for MRSA endocarditis caused
by persistent bacteremia has been described in two patients and in one patient with
106 Thus, additional efficacy data are needed before linezolid
can be recommended for the treatment of IE caused by MRSA. Tedizolid (Sivextro),
a novel oxazolidinone, was shown to have only moderate bactericidal activity in
vivo in a rabbit model of MRSA endocarditis and was less active than either
107 At this time, tedizolid cannot be recommended as a
primary agent in treatment of endocarditis.
penicillin (rash, urticaria, and wheezing). The working clinical
enterococcal endocarditis in G.S.?
Enterococci, unlike streptococci, are inhibited but not killed by penicillin or
109 The synergistic combination of penicillin (or ampicillin,
piperacillin, or vancomycin) with an aminoglycoside is required to produce the
109 One definition of synergy is when a combination of
antibiotics lowers the MIC to at least one-fourth the MIC of either drug alone.
mechanism of synergy against enterococci is explained by an increased cellular
111 Because G.S. is allergic to penicillin, vancomycin was
prescribed with an aminoglycoside. Relapse rates are unacceptably high if penicillin
is used alone for the treatment of enterococcal endocarditis.
111 and clinical studies have confirmed the in vitro synergy for penicillin in
combination with streptomycin or gentamicin for enterococcal endocarditis.
As many as 55% of all enterococcal blood isolates are highly resistant to
streptomycin (MIC >2,000 mcg/mL), and the combination of streptomycin with
penicillin is not synergistic for those isolates. In contrast, gentamicin in combination
with penicillin, ampicillin, or vancomycin is synergistic for most blood isolates of
enterococci, regardless of their susceptibility to streptomycin.
ototoxicity in the form of vestibular dysfunction secondary to streptomycin therapy
occurs in nearly 30% of patients in the treatment of enterococcal endocarditis and is
most often irreversible. High peak concentrations and prolonged drug therapy have
been associated with ototoxicity, but laboratory assays for streptomycin levels are
not readily available. For these reasons, gentamicin in combination with penicillin
(or ampicillin) or vancomycin is recommended by most authorities for the treatment
of aminoglycoside-susceptible and, in particular, streptomycin-resistant enterococcal
endocarditis, as it was for G.S.
7 Of note, other aminoglycosides cannot be used to
substitute for gentamicin or streptomycin because of the uncertain correlation
between in vitro synergy and in vivo efficacy.
7 Table 66-5 lists the suggested
regimens for the treatment of enterococcal endocarditis.
Of the aminoglycosides, gentamicin and streptomycin are often tested with penicillin
(or ampicillin) for synergistic bactericidal activity. About 10% to 25% of the
clinical isolates of E. faecalis and up to 50% of E. faecium are resistant to
113 Without conclusive data, some groups favor long-term (8–12
weeks) therapy with high-dose penicillin (18–30 million units/day IV in six divided
doses) or ampicillin (2–3 g IV every 4 hours) for treatment of resistant enterococci.
Ampicillin plus the β-lactamase inhibitor sulbactam (Unasyn) would be substituted
for β-lactamase-producing, high-level gentamicin-resistant enterococci. In light of the
increasing prevalence of enterococci with high-level aminoglycoside resistance, the
A bactericidal synergistic effect was shown between amoxicillin and cefotaxime
against 50 strains of E. faecalis. Amoxicillin MIC decreased from 0.25 to 1 mcg/mL
to 0.01 to 0.25 mcg/mL for 48 of 50 strains tested.
115 Additionally, Brandt et al.
demonstrated a synergistic bactericidal effect for amoxicillin in combination with
imipenem against vancomycin–aminoglycoside-resistant E. faecium strains. The
authors speculated that saturation of different penicillin-binding proteins by different
β-lactam agents may be the underlying mechanism for the synergy observed. In an
observational, nonrandomized multi-center study, 159 patients were treated with
ampicillin (2 g IV every 4 hours) and ceftriaxone (2 g IV every 12 hours) and 87
were treated with ampicillin and gentamicin.
23 There were no differences in mortality
(while on antibiotics and at 3-month follow-up), treatment failure, and relapses. The
2015 AHA guidelines recommend double β-lactam therapy with ampicillin and
ceftriaxone as a reasonable option for infections caused by aminoglycoside-resistant
Therapy for Endocarditis Caused by Enterococci (or Streptococci viridans with
Nonpenicillin-Allergic Patient
Penicillin G Adult: 18-30 million units/24 hour IV given continuously or in six
Pediatric: 300,000 units/kg/24 hour IV (max: 30 million units/24
hour) given continuously or in four to six equally divided doses
d Adult: 1 mg/kg IM or IV every 8 hours 4–6
Pediatric: 1 mg/kg IM or IV every 8 hours 4–6
Ampicillin Adult: 12 g/24 hour IV given continuously or in six equally divided
Pediatric: 300 mg/kg/24 hour IV (max: 12 g/24 hour) in four to six
d See nonpenicillin-allergic dosing for gentamicin above 4–6
With ceftriaxone 4 g/24 hour IV in two equally divided doses 6 weeks
e Adult: 30 mg/kg/24 hour IV in two equally divided doses (max: 2
g/24 hour unless serum levels monitored)
Pediatric: 40 mg/kg/24 hour IV in two to three equally divided
doses (max: 2 g/24 hour unless serum levels monitored)
d Adult: 1 mg/kg IM or IV (max: 80 mg) every 8 hours 6 weeks
Pediatric: 1 mg/kg IM or IV (max: 80 mg) every 8 hours 6 weeks
aAntibiotic doses should be modified appropriately in patients with impaired renal function.
bEnterococcishould be tested for high-level resistance (gentamicin: MIC ≥500 mcg/mL).
cSerum concentration of gentamicin should be monitored and dosage adjusted to obtain a peak level of
because of decreased activity against enterococci.
fDesensitization should be considered; cephalosporins are not satisfactory alternatives.
IM, intramuscular; IV, intravenous; MIC, minimum inhibitory concentration.
Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.
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