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GENTAMICIN

Dosing

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

were significant.

114 Animal models of endocarditis show discordant results in

bacterial counts per gram of vegetation in animals on low-dose versus high-dose

aminoglycosides.

117

,

118

In experimental endocarditis, multiple daily dosing is more

effective than single daily dosing in reducing bacterial titers in vegetations.

119–121

In

contrast, viridans streptococci endocarditis can be managed with single daily

dosing

28

(see Case 66-1, Question 4). Thus, extended-interval dosing of

aminoglycosides cannot be recommended for the treatment of enterococcal

endocarditis at this time.

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

3.1 and 1 mcg/mL.

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

1 mcg/mL.

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.

7

,

108

,

122

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

previously discussed.

DURATION OF THERAPY

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%.

7

Four weeks of therapy is probably adequate for most patients with enterococcal

endocarditis.

7

,

122

,

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

therapy.

123

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.).

7

,

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

the United States since 1987.

124

,

125 The increased use of vancomycin since the mid1980s has coincided with the increased resistance to this class of compounds.

Between 1989 and 1993, the percentage of nosocomial enterococci reported as

resistant to vancomycin in the United States rose more than 20-fold, from

p. 1398

p. 1399

0.3% to 7.9%.

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

to 12% in 2003.

126

,

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

mortality.

126

,

127

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.

124 VRE

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).

124 Most

(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

infections.

Vancomycin, and also extended-spectrum cephalosporins and drugs with potent

antianaerobic activity are risk factors for VRE.

124

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

gentamicin.

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

128 pump conferring

resistance to dalfopristin.

Linezolid has bacteriostatic activity against enterococci, including vancomycinresistant E. faecium and E. faecalis. It is also active against other gram-positive

cocci, including Streptococcus pneumoniae and methicillin-resistant staphylococci.

129

Vancomycin-resistant E. faecium isolates resistant to linezolid have been

isolated.

130

,

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).

129 Linezolid

given orally or via enteral feedings is completely bioavailable.

132 A dosage of 600

mg twice daily is recommended for adults.

Daptomycin

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.

133

,

134

In a case report of

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.

135

Clinical experience with daptomycin for vancomycin-resistant E. faecium

endocarditis is limited, and treatment failure has been reported.

136

If daptomycin

therapy is chosen, a dose of 10–12 mg/kg/day is recommended.

7

FUNGAL ENDOCARDITIS CAUSED BY CANDIDA

ALBICANS

Prognosis and Treatment

CASE 66-5

QUESTION 1: B.G., a 35-year-old male heroin addict, was admitted to the hospital with chief complaints of

pleuritic chest pain and dyspnea on exertion. Physical examination revealed a cachectic man with a temperature

of 104°F, a diastolic regurgitant heart murmur heard loudest during inspiration, splenomegaly, and pharyngeal

petechiae. Funduscopic examination was noncontributory. On the chest radiograph, several pulmonary infiltrates

with cavitation were evident. UA was significant for microscopic hematuria and RBC casts. A TEE

demonstrated vegetations on both the tricuspid and aortic heart valves. B.G. had evidence of moderate heart

failure, although his hemodynamic status at that time was “stable.” Six sets of blood cultures were drawn over

the course of 2 days, and broad-spectrum empiric coverage consisting of vancomycin, gentamicin, and

ceftazidime was initiated. Two days later, two of the cultures grew Candida albicans, and a diagnosis of fungal

endocarditis was established. What is B.G.’s prognosis, and how should his fungal endocarditis be treated?

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.

137–140

Management of fungal endocarditis generally requires early valve replacement and

aggressive fungicidal therapy with amphotericin deoxycholate B 0.6 to 1 mg/kg/day

with or without

p. 1399

p. 1400

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

alternative.

141

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.

137 Despite

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

B.G.

1

In addition, replacement of a heart valve for fungal endocarditis in a heroin

addict carries a significant risk of late morbidity and mortality.

137

COMBINATION THERAPY WITH 5-FLUCYTOSINE AND AMPHOTERICIN

B

CASE 66-5, QUESTION 2: Why is it important to treat B.G.’s fungal endocarditis with the combination of 5-

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

combination.

142

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

considered.

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.

143

In patients with fungal PVE,

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

of the high rates of relapse.

1

,

137

,

139

,

142–145

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

reports.

137

,

139

,

142

,

143

,

147 Alternative antifungal agents, including echinocandins and

azoles, are potential options in patients who experience significant renal toxicities.

ALTERNATIVE ANTIFUNGALS

CASE 66-5, QUESTION 3: If B.G. experiences significant toxicities because of prolonged combination

treatment with amphotericin and 5-FC, what alternative antifungal agent(s) can be used to treat his fungal

endocarditis?

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.

148

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.

153