CASE 66-4, QUESTION 2: What is the optimal dosage of gentamicin for G.S.?
Because patients with enterococcal endocarditis require prolonged therapy with
aminoglycosides, the optimal serum concentration should minimize toxicity without
jeopardizing clinical cure. Early in vitro data indicated that the bactericidal activity
of gentamicin against enterococci was not significantly different between peak
concentrations of 5 and 3 mcg/L; however, the differences between 3 and 1 mcg/mL
114 Animal models of endocarditis show discordant results in
bacterial counts per gram of vegetation in animals on low-dose versus high-dose
In experimental endocarditis, multiple daily dosing is more
effective than single daily dosing in reducing bacterial titers in vegetations.
contrast, viridans streptococci endocarditis can be managed with single daily
(see Case 66-1, Question 4). Thus, extended-interval dosing of
aminoglycosides cannot be recommended for the treatment of enterococcal
The only study comparing high-dose (>3 mg/kg/day) and low-dose (<3 mg/kg/day)
gentamicin with penicillin in humans with enterococcal endocarditis evaluated 56
patients during a 12-year period (36 with streptomycin-susceptible and 20 with
streptomycin-resistant infections).
122 The relapse rate of patients infected with
streptomycin-resistant organisms (n = 20) was not significantly different between the
high- and low-dose treatment groups (n = 10 each). Furthermore, patients who
received the higher doses of gentamicin experienced a greater prevalence of
nephrotoxicity (10 of 10 vs. 2 of 10; P<0.001). Mean peak and trough concentrations
of gentamicin in patients who received the high doses were 5 and 2.1 mcg/mL,
respectively; corresponding levels for patients receiving the low-dose regimen were
Given the available data, it would be reasonable to start G.S. on a gentamicin
dosage of 1 mg/kg every 8 hours (assuming her renal function is normal) and to
maintain peak concentrations of 3 to 5 mcg/mL and trough concentrations of less than
In Combination with Vancomycin
CASE 66-4, QUESTION 3: Why was vancomycin used in combination with gentamicin in G.S.? Is this
combination effective against enterococci?
G.S. has a history of penicillin allergy. Most clinicians favor a combination of
vancomycin and gentamicin for penicillin-allergic patients with enterococcal
endocarditis, although vancomycin plus streptomycin is a suitable alternative.
The combination of vancomycin and gentamicin demonstrates bactericidal synergy
for about 95% of enterococci strains. In contrast, the vancomycin and streptomycin
combination demonstrates bactericidal synergy for about 65% of enterococci.
Because G.S. has PVE, she should receive approximately 30 mg/kg/day, or roughly
1.5 g/day (750 mg every 12 hours), of vancomycin in combination with gentamicin (3
mg/kg/day). Serum levels of vancomycin and gentamicin should be monitored as
CASE 66-4, QUESTION 4: How long should G.S. be treated?
Historically, enterococcal endocarditis has been treated with penicillin plus an
aminoglycoside for 6 weeks; the overall cure rate with this regimen is about 85%.
Four weeks of therapy is probably adequate for most patients with enterococcal
123 One study evaluated the efficacy of a treatment regimen
involving shorter-course aminoglycoside therapy (median of 15 days) in combination
with a cell wall-active agent for a median of 42 days in patients with PVE and native
valve enterococcal endocarditis.
123 Clinical cure was observed in 75 of 93 (81%)
patients overall, 78% of patients with PVE, and 82% of patients with native valves.
Among those who had a clinical cure, 52% received a β-lactam, 12% received
vancomycin, and 36% received a combination of both. Ampicillin was given in 88%
of patients receiving a β-lactam. The causative organism was E. faecalis in 78
patients and E. faecium in five patients. Clinical success was also achieved in all
eight patients with native valve IE who received either vancomycin (50%),
ampicillin (25%), or combination of both (25%) without synergistic aminoglycoside
Patients with complicated courses should receive 6 weeks of therapy, including
patients infected with streptomycin-resistant organisms (such as G.S.), those who
have had symptoms for more than 3 months before the initiation of antibiotics, and
patients with PVE (such as G.S.).
12 Some clinicians recommend 6 weeks of therapy
for all patients in whom the duration of illness cannot be firmly established; this
accounts for many patients who present with subacute disease.
CASE 66-4, QUESTION 5: How do enterococci develop resistance to vancomycin? What are the
therapeutic implications if G.S. is infected with glycopeptide-resistant enterococci?
GLYCOPEPTIDE RESISTANCE IN ENTEROCOCCI
Vancomycin resistant enterococci (VRE), particularly E. faecium, have emerged in
Between 1989 and 1993, the percentage of nosocomial enterococci reported as
resistant to vancomycin in the United States rose more than 20-fold, from
125 Enterococcal isolates from intensive care units increased even more
dramatically, from 0.4% to 13.6%, during that time. Data from the Centers for
Disease Control and Prevention National Nosocomial Infections Surveillance
(NNIS) system indicate that the rate of increase has slowed down from 31% in 2000
127 A 12% increase was found in VRE infections in intensive care
units between 2003 and the prior 5-year period (1998–2002). Nonetheless,
epidemiologic studies conducted by the NNIS system, as well as others, have shown
that VRE bacteremia is associated with significantly increased morbidity and
Although E. faecalis is responsible for 80% to 90% of infections caused by
enterococci, E. faecium is more likely to exhibit resistance to glycopeptides
compared with E. faecalis; more than 95% of VRE recovered in the United States are
E. faecium. Glycopeptide-resistant enterococci synthesize abnormal peptidoglycan
precursors that lower the binding affinity of glycopeptides to peptidoglycans.
can be broadly classified into three separate phenotypes (A, B, and C) based on three
structurally different genes and gene products (e.g., altered ligases).
(approximately 70%) of resistant enterococci are of the VanA phenotype, which are
resistant to high levels of vancomycin (MIC >256 mcg/mL). Expression of resistance
is inducible, usually plasmid mediated, and transferable to other organisms via
conjugation. The VanB strains exhibit moderate vancomycin resistance (MIC 16–64
mcg/mL), and the VanC strains are the least resistant (vancomycin MIC 8–16
mcg/mL, because of chromosomal-mediated constitutive expression (i.e., not
inducible as are VanA and VanB); however, VanC isolates usually are associated
with the much less common Enterococcus gallinarum and Enterococcus casseliflavus
Vancomycin, and also extended-spectrum cephalosporins and drugs with potent
antianaerobic activity are risk factors for VRE.
Few therapeutic alternatives exist for VRE, and synergistic combinations are
required for bactericidal activity and clinical cure in endocarditis. Consequently, the
treatment of choice is unknown. As a result, practitioners must make decisions using
the available data from in vitro synergy studies, experimental models of endocarditis,
and scattered case reports. Of additional concern, glycopeptide-resistant isolates
often exhibit concomitant high-level resistance to aminoglycosides and β-lactams
(e.g., ampicillin, penicillin) secondary to either β-lactamase production or alteration
in the target penicillin-binding proteins.
Several antibiotic combinations appear promising in vitro and in preliminary
animal models of endocarditis, but few data are currently available in humans. Those
combinations include high-dose ampicillin (20 g/day) or ampicillin/sulbactam plus
an aminoglycoside; vancomycin, penicillin or ceftriaxone, and gentamicin; ampicillin
and imipenem; ciprofloxacin and ampicillin; and ciprofloxacin, rifampin, and
Streptogramin and Oxazolidinone
Quinupristin/dalfopristin (Synercid) and linezolid (Zyvox) are two agents with
activity and proven efficacy against some infections caused by VRE.
Quinupristin/dalfopristin received accelerated approval by the FDA in late 1999
specifically for the treatment of vancomycin-resistant E. faecium bacteremia.
However, in 2010, with other therapies available for the treatment of VRE, this
FDA-labeled indication was removed. The fixed product is generally bactericidal
against susceptible streptococci and staphylococci (including methicillin-resistant
strains), but it is bacteriostatic against E. faecium. Specifically, E. faecalis is not
susceptible to the agent because of the presence of an efflux
cocci, including Streptococcus pneumoniae and methicillin-resistant staphylococci.
Vancomycin-resistant E. faecium isolates resistant to linezolid have been
131 Treatment experience with linezolid under the compassionate-use
protocol reported clinical and microbiologic cure rates of 50% at 6-month follow-up
for patients with endocarditis. Vancomycin-resistant E. faecium was the causative
organism for 19 of the 32 patients treated.
103 Common adverse effects associated with
linezolid include nausea, headache, diarrhea, rash, and altered taste. Of greater
concern is its potential to cause myelosuppression. Thrombocytopenia, leukopenia,
anemia, and pancytopenia have all been reported. Up to 30% of patients treated
experience thrombocytopenia (platelet counts <100,000 platelets/μL).
given orally or via enteral feedings is completely bioavailable.
mg twice daily is recommended for adults.
Daptomycin is active against enterococci in vitro, with a MIC range of 0.25 to 4
mcg/mL and MIC90 of 4 mcg/mL for 219 vancomycin-resistant E. faecium isolates
from the United States. For 40 vancomycin-resistant E. faecalis isolates, the MIC
range is 0.015 to 2 mcg/mL, with a MIC90 of 2 mcg/mL. Of concern is the emergence
of daptomycin resistance during therapy for VRE infections.
a patient with vancomycin-resistant E. faecium pyelonephritis, the initial isolate had
an MIC of 2 mcg/mL; however, after 17 days of treatment, a blood culture yielded
growth of vancomycin-resistant E. faecium with an MIC increase to 32 mcg/mL.
Clinical experience with daptomycin for vancomycin-resistant E. faecium
endocarditis is limited, and treatment failure has been reported.
therapy is chosen, a dose of 10–12 mg/kg/day is recommended.
FUNGAL ENDOCARDITIS CAUSED BY CANDIDA
with cavitation were evident. UA was significant for microscopic hematuria and RBC casts. A TEE
the course of 2 days, and broad-spectrum empiric coverage consisting of vancomycin, gentamicin, and
Fungal endocarditis is a rare but life-threatening infection that is difficult to
diagnose and even more difficult to treat.
1 Most cases are caused by Candida and
Aspergillus species. Fungal endocarditis occurs primarily in IV drug users, patients
with prosthetic heart valves, immunocompromised patients, those with IV catheters,
or patients receiving broad-spectrum antibiotics.
Management of fungal endocarditis generally requires early valve replacement and
aggressive fungicidal therapy with amphotericin deoxycholate B 0.6 to 1 mg/kg/day
5-flucytosine (5-FC) 25 mg/kg orally QID. If B.G. had poor renal function,
liposomal formulations of amphotericin B 3 to 5 mg/kg daily can be used as an
These antifungal agents should be prescribed for B.G., and his broad-spectrum
antibiotic should be discontinued. B.G.’s clinical presentation and chest radiograph
indicate that fragments of vegetation have already embolized to his lungs and
possibly to other vital organs (e.g., spleen, kidneys). Because of the morbidity and
mortality associated with major emboli and valvular insufficiency, B.G. should
undergo surgery within 48 to 72 hours after antifungal therapy has been initiated. The
prognosis for B.G. is dismal even with proper medical and surgical treatment. In a
series analyzing 270 cases of fungal IE occurring during a 30-year period, mortality
for those who received combined medical and surgical management was 45%,
compared with 64% for those who received antifungal therapy alone.
initial response to treatment, the rate of relapse is high (30%–40%), and relapse can
occur up to 9 years after the initial episode of infection.
137–140 Most deaths in IV drug
users with endocarditis are secondary to heart failure, a finding already evident in
In addition, replacement of a heart valve for fungal endocarditis in a heroin
addict carries a significant risk of late morbidity and mortality.
COMBINATION THERAPY WITH 5-FLUCYTOSINE AND AMPHOTERICIN
FC and conventional or lipid-based amphotericin B? What is the optimal duration of therapy?
The poor prognosis associated with fungal endocarditis warrants the
administration of 5-FC in combination with amphotericin B, despite its potential for
causing bone marrow suppression and hepatotoxicity.
137 The vegetations from B.G.’s
tricuspid or aortic heart valves already have broken off and caused pulmonary
cavitation and possibly splenomegaly. His clinical presentation is consistent with a
potentially fatal outcome; therefore, his blood isolates should be tested for in vitro
susceptibility to amphotericin, 5-FC, and azoles. Fungi resistant to 5-FC alone may
still be susceptible to the synergistic effect of the 5-FC–amphotericin B
If the organism is resistant to 5-FC, in vitro synergy between these
two antifungals should be performed or therapy with an echinocandin should be
The optimal dose and duration of antifungal therapy for fungal endocarditis have
not been determined by clinical studies; however, postoperative treatment with
amphotericin B and 5-FC (if it has in vitro activity) for a minimum of 6 weeks (total
dose, 1.5–3 g of amphotericin B) is recommended and is supported by the poor
penetration of amphotericin B into heart valve tissue.
some experts advocate secondary prophylaxis for a minimum of 2 years or lifelong
suppressive treatment with an oral antifungal agent for nonsurgical candidates in light
Nephrotoxicity caused by amphotericin B is often a serious dose-limiting factor to
completion of therapy, particularly in patients who require a prolonged treatment
course. Renal dysfunction secondary to the conventional formulation of amphotericin
B may stabilize or improve with the switch to lipid-formulated amphotericin B
products (i.e., Abelcet, AmBisome).
146 The efficacy of the new formulations in the
treatment of endocarditis has been demonstrated only in anecdotal
147 Alternative antifungal agents, including echinocandins and
azoles, are potential options in patients who experience significant renal toxicities.
CASE 66-5, QUESTION 3: If B.G. experiences significant toxicities because of prolonged combination
Fluconazole (Diflucan) is a triazole compound active against Candida species,
particularly C. albicans and Candida parapsilosis. It also has a favorable toxicity
profile compared with amphotericin and 5-FC.
Successful experience with fluconazole treatment of fungal endocarditis in humans
has been described in only a few case reports.
149–152 Patients with various Candida
species were treated with 200 to 600 mg of fluconazole daily for 45 days to 6 months
or until death. Fluconazole therapy reduced or completely removed all cardiac
vegetations and resolved clinical symptoms. Because of the lack of adequate clinical
experience, however, the use of fluconazole in treating fungal endocarditis cannot be
advocated except in patients who require lifelong therapy because of the following
situations: (a) The patient is a poor surgical candidate, (b) the patient has relapsed at
least once since the initial infection episode, or (c) the patient has PVE.
Another alternative treatment option is the echinocandins which are fungicidal
against most Candida species, including those in biofilms. A limited but growing
body of literature primarily in case reports describes the successful outcomes with
use of the echinocandins in Candida IE. Echinocandin-based regimens including
caspofungin, micafungin, and anidulafungin were found to be as effective and to have
similar mortality rate as amphotericin-based therapies based on a subgroup analysis
of 25 patients in a prospective international cohort of patients with Candida IE.
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