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It

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

quinupristin/dalfopristin.

62 Selection of agent depends on organism susceptibility,

potential of drug–drug interactions, and host predisposition for development of

adverse effects.

Combination Therapy

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.

51 As expected,

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:

VANCOMYCIN

CASE 66-3, QUESTION 3: How would T.J.’s therapy differ if he were infected with MRSA?

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Staphylococcus aureus IE involving methicillin-resistant strains has become

increasingly common and accounts for up to 40% of cases.

4

,

6 MRSA-infected patients

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

with MSSA.

4

,

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.

63

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.

64 CA-MRSA strains are distinct from health-careassociated strains in that most possess a distinct virulence gene encoding for the

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

abscesses.

65–71 Specifically, CA-MRSA PVL-producing strains causing IE have been

reported.

72

Treatment Options

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.

54

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.

44

,

73

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.

63 The AHA recommends

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

7

,

63

,

74

in an attempt

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.

75–77

Persistent Bacteremia

CASE 66-3, QUESTION 4: T.J. has been treated with vancomycin 1 g IV every 12 hours for 5 days for his

MRSA endocarditis, but does not seem to be clinically improving. His blood cultures are still positive, and his

WBC count remains elevated at 12,500/μL with 55% polys and 7% bands. He continues to have a low-grade

fever since starting vancomycin. His vancomycin trough level on the second day of therapy was 17 mcg/mL.

The infected MRSA strain had a vancomycin MIC of 1.5 mcg/mL as determined by Epsilometer test (Etest).

What factors may be contributing to T.J.’s poor response to treatment? What other therapeutic options are

available for T.J.?

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

other geographic regions.

6 The authors speculated that the higher rates of persistent

bacteremia in US patients may be attributable in part to the receipt of vancomycin

therapy.

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.

78

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.

79

,

80

Widespread use of vancomycin has led to the emergence of glycopeptideintermediate S. aureus (GISA) or heteroresistant GISA (hGISA) strains.

44 Reduced

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.

81

In the absence of vancomycin,

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.

82–84 Routine susceptibility

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.

21

,

63

,

86

,

87

Experts have recommended a target vancomycin trough concentration of 15 to 20

mcg/mL to overcome increasing MIC when treating pneumonia or endocarditis

caused by MRSA.

63

,

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.

20 Notably,

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

MBC-to-MIC ratio of 32, and up to 10% exhibited heterogeneous vancomycinintermediate resistance phenotype (hVISA).

21

,

88 Vancomycin monotherapy of hVISA

was associated with treatment failure, whereas combination therapy responded

favorably.

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

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of choice for MRSA IE will need to be re-evaluated against other available

treatment options.

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

had treatment success.

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.

63

,

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

documented.

92

,

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.

63

Alternatively, daptomycin 10 mg/kg/dose IV once daily plus linezolid 600 mg PO

twice daily may be used, particularly with concomitant pneumonia.

95

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.

96–99 Daptomycin MIC

increase during therapy for S. aureus endocarditis was demonstrated in six patients.

97

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

reduced susceptibility to daptomycin, is the addition of an antistaphylococcal βlactam agent such as nafcillin or oxacillin to daptomycin based on in vitro synergy

studies and few case reports.

100

,

101

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

treatment failures, intolerability to standard therapy, or in infections with multidrugresistant gram-positive cocci.

102

In a review article that included 33 case reports of

endocarditis treated with linezolid, 63.6% of patients had successful outcomes at the

end of the follow-up period.

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.

103 The degree of

thrombocytopenia associated with linezolid correlates with the extent of drug

exposure, as measured by area under the concentration curve and duration of

treatment.

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

relapse of infection.

105

,

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

vancomycin or daptomycin.

107 At this time, tedizolid cannot be recommended as a

primary agent in treatment of endocarditis.

ENTEROCOCCAL ENDOCARDITIS

Antimicrobial Therapy

ANTIBIOTIC SYNERGY

CASE 66-4

QUESTION 1: G.S., a 35-year-old woman, has been complaining of anorexia, weight loss, and fever for the

past 2 months. Her medical history is significant for an aortic aneurysm with insufficiency that resulted in an

aortic valve replacement (porcine) 3 years before admission. Approximately 2 months before admission, G.S.

had a cesarean section followed by a tubal ligation. She did not receive antibiotic prophylaxis for either

procedure. Physical examination revealed a thin woman (5 foot 0 inches, 48 kg) in no acute distress with

evidence of a systolic heart murmur, splinter hemorrhages, and petechiae on her soft palate. Her temperature

was 100.2°F. Her WBC count was 14,000/μL (SI unit, 14 × 10/L) with a slight left shift; all other laboratory

results were within normal limits. She was not taking any medications, and she has a documented allergy to

penicillin (rash, urticaria, and wheezing). The working clinical

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diagnosis was probable bacterial endocarditis, which was confirmed when four sets of blood cultures grew

gram-positive cocci. Antibiotic therapy with gentamicin (50 mg IV every 8 hours) and vancomycin (1,000 mg

IV every 12 hours) was begun. Biochemical testing subsequently identified the organism as E. faecalis, highly

resistant to streptomycin (MIC >2,000 mcg/mL). Why were two antibiotics prescribed for the treatment of

enterococcal endocarditis in G.S.?

Enterococci, unlike streptococci, are inhibited but not killed by penicillin or

vancomycin alone.

108

,

109 The synergistic combination of penicillin (or ampicillin,

piperacillin, or vancomycin) with an aminoglycoside is required to produce the

desired bactericidal effect.

108

,

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.

110 The

mechanism of synergy against enterococci is explained by an increased cellular

uptake of the aminoglycoside with agents that inhibit cell wall synthesis (e.g., βlactams and vancomycin).

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.

7

,

108

,

110

,

111 Numerous in

vivo

110

,

111 and clinical studies have confirmed the in vitro synergy for penicillin in

combination with streptomycin or gentamicin for enterococcal endocarditis.

16

Streptomycin Resistance

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.

1

,

108

,

112

In addition,

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.

Gentamicin Resistance

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

gentamicin.

112

,

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

potential synergistic interaction between ampicillin or amoxicillin and a thirdgeneration cephalosporin was explored in vitro and in experimental models of IE.

114

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.

116

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

E. faecalis strains.

Table 66-5

Therapy for Endocarditis Caused by Enterococci (or Streptococci viridans with

an MIC ≥0.5 mcg/mL)

Antibiotic

a,b Dose and Route Duration

Nonpenicillin-Allergic Patient

Penicillin G Adult: 18-30 million units/24 hour IV given continuously or in six

equally divided doses

4–6

weeks

Pediatric: 300,000 units/kg/24 hour IV (max: 30 million units/24

hour) given continuously or in four to six equally divided doses

4–6

weeks

With gentamicin

c

,

d Adult: 1 mg/kg IM or IV every 8 hours 4–6

weeks

Pediatric: 1 mg/kg IM or IV every 8 hours 4–6

weeks

Ampicillin Adult: 12 g/24 hour IV given continuously or in six equally divided

doses

4–6

weeks

Pediatric: 300 mg/kg/24 hour IV (max: 12 g/24 hour) in four to six

equally divided doses

4–6

weeks

With gentamicin

c

,

d See nonpenicillin-allergic dosing for gentamicin above 4–6

weeks

With ceftriaxone 4 g/24 hour IV in two equally divided doses 6 weeks

Penicillin-Allergic Patients

f

Vancomycin

e Adult: 30 mg/kg/24 hour IV in two equally divided doses (max: 2

g/24 hour unless serum levels monitored)

6 weeks

Pediatric: 40 mg/kg/24 hour IV in two to three equally divided

doses (max: 2 g/24 hour unless serum levels monitored)

6 weeks

With gentamicin

c

,

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

approximately 3 mcg/mL. (For shorter-course gentamicin therapy for enterococcal endocarditis, see comment in

text.)

dDosing of aminoglycosides and vancomycin on a mg/kg basis gives higher serum concentrations in obese than in

lean patients.

eTrough serum concentrations should be obtained within half an hour of the next dose and should be in the range

of 10 to 20 mcg/mL. Each dose should be infused over 1 hour; 6 weeks of vancomycin therapy recommended

because of decreased activity against enterococci.

fDesensitization should be considered; cephalosporins are not satisfactory alternatives.

IM, intramuscular; IV, intravenous; MIC, minimum inhibitory concentration.

Source: Baddour LM et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of

complications. A Scientific Statement for Healthcare Professionals from the American Heart Association (AHA);

on behalf of the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on

Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and

Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.

2015;132:1435–1486..

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