Figure 66-2 Splinter hemorrhages in the nail bed.
Figure 66-3 Petechialskin lesions in a case of acute staphylococcal endocarditis.
Several laboratory findings are consistent with IE in A.G. A low Hgb and Hct with
normal red cell indices suggest anemia of chronic disease. Of patients with subacute
disease, 70% to 90% will have a normochromic, normocytic anemia. Leukocytosis
with a left shift, although not evident in A.G., commonly is seen in those with acute,
fulminant disease such as staphylococcal endocarditis. The ESR nearly always is
elevated in IE, but this finding is nonspecific and can be associated with several
other disease entities. RF (an immunoglobulin M antiglobulin) and circulating
immune complexes can be detected in most patients with long-standing disease, but
both are nonspecific findings.
Major embolic episodes and infarction involving the kidney, spleen, lung, and
brain may develop as secondary complications in up to one-third of cases.
exhibits some degree of renal damage, as evidenced by moderate hematuria and
proteinuria. Alterations in A.G.’s renal function (increased BUN and creatinine)
probably are a result of immune complex deposition (diffuse glomerulonephritis) or
secondary to renal embolization (focal glomerulonephritis). Erythrocyte and
leukocyte cast formation also may be present. Renal impairment usually is reversible
with the institution of effective antimicrobial therapy.
Cardiac complications occur most frequently. CHF from infection-induced
valvular damage is the most common cause of death in IE and is the most common
10 As many as two-thirds of patients with endocarditis
develop CHF. Aortic valve infection is more frequently associated with CHF than
mitral valve infection. Other manifestations include paravalvular abscesses,
pulmonary edema, and pericarditis.
10 Mitral valve injury caused by viridans
streptococci generally is better tolerated hemodynamically than aortic valve injury
caused by staphylococci. Although A.G. has no apparent signs of overt heart failure,
he should be monitored closely for the development of hemodynamic instability.
Neurologic complications, most commonly stroke, rank second to cardiac
complications in frequency, but they may be the leading cause of death in patients
10 A stroke syndrome in a patient with underlying valvular
abnormalities should prompt the clinician to rule out IE. Other clinical manifestations
include headache, mental status change, transient ischemic attack, seizures, brain
abscess, or intracranial mycotic aneurysms.
10 Neurologic symptoms associated with
high mortality can be observed in up to 35% of S. aureus endocarditis patients who
Metastatic abscesses can develop in virtually any organ secondary to systemic
septic embolization. The most commonly involved metastatic foci are the spleen,
kidney, liver, and iliac and mesenteric arteries.
10 Splenomegaly, although not part of
A.G.’s findings, occurs in 20% to 60% of all cases and is more common in subacute
CASE 66-1, QUESTION 2: How was the diagnosis of IE established in A.G.?
Although A.G.’s medical history (mitral valve prolapse, recent dental procedure) and
clinical presentation are highly suggestive of IE, blood culture is the single most
important diagnostic workup for IE.
1 Bacteremia (when present) secondary to
endocarditis is continuous and low grade; more than 50% of the cultures show only 1
to 30 bacteria/mL. Despite the low concentration of organisms, at least one of the
first two blood cultures is positive in 95% of cases.
In order to achieve a high yield,
at least three sets of blood cultures collected by separate venipunctures should be
obtained during the first 24 hours of presentation.
1 Administration of antibiotics
within the previous 2 weeks may significantly decrease this yield.
It is also important to establish the exact microbiologic cause before initiating
antimicrobial therapy. In patients who are acutely ill, empiric therapy should start as
soon as the appropriate cultures are obtained to avoid further valvular damage or
Echocardiography is a valuable tool in establishing early diagnosis (e.g., the
presence and size of vegetations), identifying patients at high risk for complications,
and optimizing the timing and mode of surgical intervention by detecting and
monitoring associated pathologic changes such as valvular abscess.
transducer may be placed on the chest (transthoracic echocardiogram [TTE]) or in
the esophagus (transesophageal echocardiogram [TEE]).
noninvasive procedure with 98% specificity for vegetations. Sensitivity for
vegetations may be less than 60% to 70%, however, for adult patients with obesity,
hyperinflated lungs caused by emphysema, or a prosthetic valve. TEE is more costly
and invasive, but is significantly more sensitive in detecting vegetations while
maintaining high specificity. All patients with suspected IE should have
echocardiography on admission and repeated during their course, to help guide future
medical management and timing of intervention.
In particular, compared with TTE,
TEE is superior in the diagnosis of pacemaker IE and IE in the elderly. A.G. has a
negative TTE result on admission. Given the high clinical suspicion for IE in A.G., a
follow-up TEE is recommended to rule out a false-negative TTE result.
In summary, IE should be suspected in any patient who has a documented fever and
heart murmur and a preceding risk of bacteremia. Prior cardiac disease, peripheral
manifestations, splenomegaly, various laboratory abnormalities, and a positive
echocardiogram strengthen the diagnosis, but microbiologic documentation is the
most important factor in confirming IE. Disease entities with overlapping clinical
presentation and laboratory abnormalities should be excluded using the appropriate
Diagnostic criteria for IE which integrate clinical, laboratory, microbiologic, and
echocardiographic data are listed in Tables 66-1 and 66-2.
evidence involving nearly 2,000 patients, the 2015 AHA guidelines suggest that the
modified Duke criteria be used as the primary diagnostic schema to evaluate patients
Definition of Infective Endocarditis (IE) According to the Modified Duke
embolized, or an intracardiac abscess specimen; or
One major criterion and one minor criterion; or three minor criteria
Firm alternative diagnosis explaining evidence of IE; or
Resolution of IE syndrome with antibiotic therapy for <4 days; or
infective endocarditis. Clin Infect Dis. 2000;30:633.
Definitions of Terminology Used in the Modified Duke Criteria for the Diagnosis
of Infective Endocarditis (IE)
Typical microorganisms consistent with IE from two separate blood cultures:
Viridans streptococci, Streptococcus bovis, HACEK group; or
Staphylococcus aureus or community-acquired enterococci in the absence of a primary focus; or
Microorganisms consistent with IE from persistently positive blood cultures defined as follows:
At least two positive blood cultures drawn >12 hours apart; or
Single positive blood culture for Coxiella burnetii or antiphase 1 IgG antibody titer >1:800
EVIDENCE OF ENDOCARDIAL INVOLVEMENT
Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least
“possible IE” by clinical criteria or complicated IE [paravalvular abscess]; TEE as first test in
other patients) defined as follows:
implanted material in the absence of an alternative anatomic explanation; or
New partial dehiscence of prosthetic valve
New valvular regurgitation (worsening or changing of preexisting murmur not sufficient)
Predisposition: Predisposing heart condition or IV drug use
Vascular Phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial
hemorrhage, conjunctival hemorrhages, Janeway lesions
Immunologic Phenomena: glomerulonephritis, Osler nodes, Roth spots, RF
Microbiologic Evidence: positive blood culture but not meeting major criterion as noted above
evidence of active infection with organism consistent with IE
Echocardiographic minor criteria eliminated
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella
species, and Kingella kingae; TEE, transesophageal echocardiography.
infective endocarditis. Clin Infect Dis. 2000;30:633.
A.G. possesses one major criterion (positive blood cultures) and three minor
criteria (fever, predisposing heart condition, vascular and immunologic phenomena);
therefore, he meets the diagnostic criteria for definite IE.
CASE 66-1, QUESTION 3: What would be a reasonable duration of antibiotic therapy for A.G.? When is
determination of minimum bactericidal concentration (MBC) useful in treating bacterial endocarditis?
The avascular nature of the vegetation results in an environment that is devoid of
normal host defenses (e.g., phagocytic cells and complement); this permits
uninhibited growth of bacteria.
2 Therefore, to eradicate the causative organism, high
doses of an IV bactericidal antibiotic generally are administered for 4 to 6 weeks.
For some infections, it may be necessary to use two antibiotics to achieve synergistic
activity against the organism. Once an organism has been identified, its in vitro
susceptibility pattern is determined by the minimum inhibitory concentration (MIC)
for various antibiotics. Standard Kirby-Bauer disk diffusion testing is inadequate in
the setting of IE to aid in selection of antibiotics without the quantitative information
In addition, the MBC may be useful in detecting tolerant
strains, particularly in the setting of unexplained slow response or treatment failure.
Routine MBC determination is not recommended, however.
endocarditis requires antibiotics with bactericidal activity; therefore, the serum
concentration of the antibiotic must greatly exceed the MBC for the particular
organism. For endocarditis caused by viridans streptococci acquired from the
community, this usually is achieved without much difficulty because most isolates are
sensitive to penicillin at an MIC of less than 0.12 mcg/mL
are, at most, one or two tube dilutions higher.
demonstrating resistance to penicillin and related β-lactams, such as ceftriaxone, is a
significant problem, particularly among bloodstream isolates obtained from the
nosocomial setting and neutropenic cancer patients.
o f β-lactam-resistant clinical isolates highlights the importance of determining the
MIC and continued close monitoring of the antibiotic susceptibility of viridans
streptococci. An increasing number of reports have described suboptimal response to
19 Many such strains demonstrated tolerance to vancomycin as defined by
a high MBC-to-MIC ratio (≥32).
20 Thus, these data support the need to determine
MBC, especially in the setting in which the treatment option for IE caused by S.
aureus is limited to vancomycin and suboptimal response is observed.
CASE 66-1, QUESTION 4: What factors must be considered in selecting a regimen for A.G.? Which
regimen should be used for A.G.?
Patients with endocarditis caused by penicillin-sensitive strains of viridans
streptococci and nonenterococcal group D streptococci (e.g., Streptococcus
gallolyticus; MIC <0.1 mcg/mL) can be treated with any one of three regimens as
outlined in the 2015 AHA treatment guidelines.
7 The suggested regimens (Table 66-
3) are associated with cure rates of up to 98% and include (a) high-dose parenteral
penicillin for 4 weeks, (b) high-dose parenteral ceftriaxone for 4 weeks, and (c) 2
weeks of combined therapy with high-dose parenteral penicillin and an
21–27 Ceftriaxone with an aminoglycoside for 2 weeks appears to be
Suggested Regimens for Therapy of Native Valve Endocarditis Caused by
Streptococcus viridans group and Streptococcus gallolyticus
Penicillin-Susceptible [minimum inhibitory concentration (MIC) ≤0.12 mcg/mL]
Adult: 12–18 million units/24 hour IV either continuously or in four to six
Pediatric: 200,000 units/kg/24 hour IV (max: 20 million units/24 hour) either
continuously or in four to six equally divided doses
c Adult: 2 g once daily IV or IM 4 weeks
Pediatric: 100 mg/kg once daily IV or IM
See penicillin-susceptible dosing for penicillin above 2 weeks
CWeftriaxone sodium See penicillin-susceptible dosing for ceftriaxone above 2 weeks
Adult: 3 mg/kg once daily IV or IM 2 weeks
Pediatric: 3 mg/kg once daily IV or IM or in three equally divided doses
Relatively Penicillin G Resistant (MIC >0.12 mcg/mL and <0.5 mcg/mL)
Adult: 24 million units/24 hour IV either continuously or in four to six equally
Pediatric: 200,000–300,000 units/kg/24 hour IV (max: 20 million units/24 hour)
either continuously or in four to six equally divided doses
Adult: 3 mg/kg once daily IV or IM
Pediatric: 3 mg/kg once daily IV or IM or in three equally divided doses
Ceftriaxone sodium Adult: 2 g once daily IV or IM
Pediatric: 100 mg/kg once daily IV or IM
Adult: 30 mg/kg/24 hour IV in two equally divided doses (max: 2 g/24 hour
unless serum concentrations are monitored)
Pediatric: 40 mg/kg/24 hour IV in two or three equally divided doses (max: 2
g/24 hour unless serum concentrations are monitored)
aPediatric doses should not exceed that of a normal adult.
bAntibiotic doses for patients with impaired renal function should be modified appropriately.
obtained within half an hour of the next dose and be in the range of 10–15 mcg/mL.
IM, intramuscular; IV, intravenous.
Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.
HIGH-DOSE PENICILLIN FOR 4 WEEKS
Ten to 20 million units/day of IV penicillin G for 4 weeks resulted in a cure rate of
100% for 66 patients with nonenterococcal streptococcal endocarditis.
study using penicillin monotherapy reported relapse in only 2 of 49 patients;
however, both of these patients received less than 4 weeks of therapy.
range of 12 to 18 million units/day of penicillin is recommended to allow flexibility
in dosing based on the patient’s renal function and disease severity. Ampicillin 2 g
every four hours is a reasonable alternative.
SINGLE DAILY CEFTRIAXONE FOR 4 WEEKS
Ceftriaxone is active against viridans streptococcal strains isolated from patients
with endocarditis. In one study, all 49 strains of viridans streptococci and 11 strains
o f S. bovis were inhibited at <0.125 mcg/mL of ceftriaxone; one strain of
Streptococcus sanguinis was inhibited at an MIC of 0.25 mcg/mL.
comparable to high-dose penicillin when treatment is given for 4 weeks.
70 assessable patients who received ceftriaxone 2 g as a single daily dose for 4
weeks, all were cured, except for one patient who had a probable relapse 3 months
after completion of therapy. All strains of viridans streptococci were inhibited by
ceftriaxone at an MIC of 0.25 mcg/mL in both studies. Although the simplicity of
single daily treatment with ceftriaxone is attractive for outpatient use, careful patient
selection based on microbiologic, clinical, and host factors is critical to the success
of treatment and the proper and timely management of potential complications. (See
Case 66-6, Question 1, for a detailed discussion of outpatient therapy.)
HIGH-DOSE PENICILLIN OR CEFTRIAXONE PLUS AN
The combination of 2 weeks of streptomycin (or gentamicin) with 4 weeks of
penicillin is synergistically bactericidal for most streptococci, including enterococci
33 This in vitro synergy also has been correlated with a
more rapid rate of eradication of viridans streptococci from cardiac vegetations in
25 A shortened combination regimen consisting of high-dose
penicillin G and streptomycin for 2 weeks is an effective alternative to the previously
described regimens. The reported cure rate in 104 patients treated at the Mayo Clinic
Although clinical experience with combination therapy has been primarily with
penicillin and streptomycin, in vitro and animal data support that streptomycin and
gentamicin are reasonably interchangeable. Administration of gentamicin once daily
versus thrice daily when added to penicillin appears equally effective in the
treatment of viridans streptococcal endocarditis.
Combination therapy with ceftriaxone and aminoglycoside for 2 weeks has also
28 Clinical cure rates of 87% to 96% were observed in patients
infected with penicillin-susceptible streptococci when given once daily ceftriaxone 2
g plus netilmicin or gentamicin at 3 mg/kg. This study excluded patients with
suspected or documented cardiac or extracardiac abscesses and those with PVE.
Although the aminoglycoside agent (netilmicin or gentamicin) was administered as a
single daily dose in both studies, all of the patients had measurable serum trough
levels. Therefore, the efficacy of “extended-interval dosing” of aminoglycoside
Based on available data, the 2-week regimen of penicillin or ceftriaxone plus an
patients with extracardiac complications or intracardiac abscesses. Patients infected
w i t h Abiotrophia species (formerly known as nutritionally variant viridans
streptococci) or viridans streptococci with a penicillin MIC greater than 0.1 mcg/mL
or patients who have prosthetic valve infections should not receive short-course
The risk of relapse may be higher in patients who have had symptoms for more than 3
months before the initiation of treatment.
31 These patients should be treated with 4
to 6 weeks of penicillin combined with an aminoglycoside for the first 2 weeks.
Nutritionally deficient or variant streptococci (NVS) have been reclassified into a
new genus, Abiotrophia, which includes Abiotrophia defectiva, Abiotrophia
adiacens (renamed again as Granulicatella adiacens), and Abiotrophia elegans.
Abiotrophia species are slow-growing, fastidious organisms that are responsible for
34 Previously, NVS were the cause of most of the cases
of endocarditis diagnosed as “culture-negative,” initially owing to its requirement for
(pyridoxal HCl) to the culture media for laboratory
growth. Laboratory identification is no longer a significant problem, however,
because of current culture media and laboratory techniques.
NVS are less susceptible to penicillin when compared with other streptococci.
Many NVS have a relatively high MIC to penicillin (0.2–2.0 mcg/mL), and some
show high-level resistance to penicillin (MIC >4 mcg/mL).
penicillin has been described in many strains.
9 An animal model of endocarditis
indicates that a penicillin–aminoglycoside (streptomycin or gentamicin) combination
is significantly better than penicillin alone in reducing bacterial counts.
of bacteriologic failure and relapse may be expected in patients despite completion
of the treatment course for strains highly susceptible to penicillin.
infected with NVS or Abiotrophia should receive 4 to 6 weeks of high-dose
penicillin (or ampicillin) in combination with gentamicin.
combination therapy with penicillin and gentamicin is recommended for patients with
symptoms longer than 3 months in duration and those with PVE caused by these
9 Patients with endocarditis caused by relatively resistant viridans
streptococci with penicillin MIC of greater than 0.5 mcg/mL or enterococci should
receive a similar treatment regimen, as described above.
Patients allergic to β-lactams should receive vancomycin 30 mg/kg/day divided
into two doses for 4 to 6 weeks. Although the addition of an aminoglycoside to
vancomycin enhances bactericidal activity in vitro, it is unknown whether the
addition of an aminoglycoside confers any additional clinical benefit.
viridans streptococci isolated from A.G. are not resistant to penicillin and he has no
other complicating factors, any of the suggested regimens would be appropriate.
Because no compelling reason exists to use the 4-week regimens, the 2-week
penicillin–aminoglycoside regimen could be the optimal choice. Although A.G. has
mild renal impairment, this is most likely secondary to the endocarditis and should
improve once adequate antimicrobial therapy has been instituted. A.G. was begun on
12 million units/day of penicillin G, which would be reasonable for his age and mild
renal impairment. If nephrotoxicity were a major concern in A.G., penicillin or
ceftriaxone alone for 4 weeks is reasonable. If gentamicin is used, A.G.’s renal
function should be monitored and the dose should be adjusted appropriately if not
using a single daily regimen. Multiple aminoglycoside dosing requires frequent
monitoring for signs of toxicity by taking periodic peak and trough aminoglycoside
PVE. What are the most likely organisms responsible for PVE in F.T.?
PVE is a life-threatening infectious complication of artificial heart valve
implantation that accounts for 7% to 25% of cases of IE in developed countries.
The prevalence of complications resulting in death has been as high as 20% to
37 The risk of PVE after surgery is approximately 1% at 12 months and 2% to
3% at 60 months. PVE is categorized as early or late, depending on the onset of
clinical manifestations after cardiac surgery.
37 Early PVE occurs within 2 months
after surgery and is thought to represent infection acquired during valve placement. It
usually is caused by skin organisms that were implanted into the valve annulus
(suture site where the valve is attached to cardiac muscle) at the time of surgery.
The most common organisms cultured from patients such as F.T. with early PVE are
coagulase-negative staphylococci (primarily S. epidermidis [>30%], most of which
are resistant to methicillin), followed by S. aureus (20%), and gram-negative bacilli
(10%–15%). Miscellaneous organisms, such as diphtheroids and fungi, account for
the remainder. In contrast, streptococci are a more common cause of late PVE (>2
Nosocomial bacteremia and fungemia in a patient with prosthetic heart valves
contribute to a significant risk for the development of PVE. One study noted that
bacteremia caused by staphylococci and gram-negative bacilli resulted in 55% and
33% of subsequent PVE cases, respectively.
development of PVE in 25% (11 of 44) of patients after nosocomial candidemia.
CASE 66-2, QUESTION 2: What measures can be taken to prevent early PVE?
The overall frequency of early PVE, despite antibiotic prophylaxis, is 1% to 4%.
Complications are severe and include valve dehiscence, acute heart failure,
arrhythmias, and outflow obstruction. Although antibiotic prophylaxis before valve
surgery (a “clean” procedure) has not been proved to reduce the frequency of early
PVE, it is indicated nevertheless because the complications of infection are
catastrophic. The antimicrobial regimen used most commonly for cardiac surgery
prophylaxis (see Chapter 63, Antimicrobial Prophylaxis for Surgical Procedures)
consists of an antistaphylococcal cephalosporin, such as cefazolin, given in the
operating room at the time of induction of anesthesia or within 60 minutes before the
procedure. Vancomycin could be considered the prophylactic agent of choice for
cardiovascular procedures, including prosthetic valve replacement and implantation
of prosthetic grafts, in the presence of any of the following: (a) documented penicillin
allergy, (b) prior receipt of broad-spectrum antimicrobial therapy and high
likelihood of being colonized with cephalosporin-resistant staphylococci or
enterococci, or (c) performance of the procedure in a center experiencing
outbreaks or a high endemic rate of surgical infection with methicillin-resistant
CASE 66-2, QUESTION 3: What are the treatment options for F.T.?
As noted earlier, F.T. most likely is infected with coagulase-negative
staphylococci. For those rare coagulase-negative staphylococci that remain sensitive
to β-lactams (<20%), a penicillinase-resistant penicillin (nafcillin or oxacillin) is the
staphylococci are sensitive to vancomycin at concentrations of 2 mcg/mL or less;
however, strains of staphylococci with intermediate susceptibility to vancomycin
44 Refer to the IDSA guidelines for vancomycin dosing and drug
The AHA currently recommends the use of triple-drug combination (vancomycin,
resistant to all available aminoglycosides, aminoglycoside treatment should be
omitted. A fluoroquinolone active against the isolate may be considered as substitute
for the aminoglycoside in the three-drug regimen. In addition to medical therapy,
most patients also required valve replacement surgery.
Treatment of Staphylococcal Endocarditis
Antibiotic Dosage and Route Duration
OXACILLIN/METHICILLIN–SUSCEPTIBLE STAPHYLOCOCCI
NONPENICILLIN-ALLERGIC PATIENTS
Nafcillin or oxacillin Adult: 2 g IV every 4 hours 6 weeks
Pediatric: 150–200 mg/kg/24 hour IV (max: 12 g/24
hour) in four to six equally divided doses
d Adult: 2 g IV every 8 hours 6 weeks
Pediatric: 100 mg/kg/24 hour IV (max: 6 g/24 hour) in
equally divided doses every 8 hours
f Adult: 30 mg/kg/24 hour IV in two or four equally
(max: 2 g/24 hour unless serum levels monitored)
Pediatric: 40 mg/kg/24 hour IV in two or four equally
(max: 2 g/24 hour unless serum levels monitored)
OXACILLIN/METHICILLIN–RESISTANT STAPHYLOCOCCI
f Adult: 30 mg/kg/24 hour IV in two or four equally
(max: 2 g/24 hour unless serum levels monitored)
Pediatric: 40 mg/kg/24 hour IV in two or four equally
(max: 2 g/24 hour unless serum levels monitored)
With Prosthetic Valve or Other Prosthetic Material
OXACILLIN/METHICILLIN–RESISTANT STAPHYLOCOCCI
g Adult: 30 mg/kg/24 hour IV in two or four equally
(max: 2 g/24 hour unless serum levels monitored)
Pediatric: 40 mg/kg/24 h IV in two or four equally
(max: 2 g/24 h unless serum levels monitored)
h Adult: 300 mg IV/PO every 8 hours ≥6 weeks
Pediatric: 20 mg/kg/24 hour PO (max: 900 mg/24 hour)
in three equally divided doses
j Adult: 3 mg/kg IV or IM in two or three equally divided
Pediatric: 3 mg/kg IV or IM in three equally divided
OXACILLIN/METHICILLIN–SUSCEPTIBLE STAPHYLOCOCCI
k Adult: 2 g IV every 4 hours ≥6 weeks
Pediatric: 150–200 mg/kg/24 hour IV (max: 12 g/24
hour) in four to six equally divided doses
h See prosthetic valve dosing for rifampin above ≥6 weeks
j See prosthetic valve dosing for gentamicin above 2 weeks
comments on the use of daptomycin and rifampin.)
bDosing of aminoglycosides and vancomycin on a milligram per kilogram basis will give higher serum
concentrations in obese than in lean patients.
agents is increased in patients >65 years of age or those with renal or eighth nerve impairment.
patients with immediate-type hypersensitivity to penicillin.
fVancomycin and gentamicin doses must be modified appropriately in patients with renal failure.
required for antithrombotic therapy.
IM, intramuscular; IV, intravenous; PO, orally.
Anesthesia, and Stroke Council: Endorsed by the Infectious Diseases Society of America. Circulation.
Although alternative agents such as quinupristin/dalfopristin, linezolid,
daptomycin, telavancin, ceftaroline, dalbavancin, and oritavancin have shown potent
in vitro activity against coagulase-negative staphylococci, clinical experience in the
treatment of IE caused by these strains is lacking.
STAPHYLOCOCCUS AUREUS ENDOCARDITIS
Intravenous Drug User Versus Nonuser
results included the following:
WBC count, 14,000/μL with 65% polys and 5% bands (SI units, 14 × 10/L with 0.65 polys and 0.05 bands
[normal, 3.2–9.8 with 0.54–0.62 polys and 0.03–0.05 bands])
Hgb, 13.1 g/dL (SI units, 131 g/L [normal, 140–180])
Hct, 39% (SI units, 0.39 [normal, 0.39–0.49])
ESR, 55 mm/hour (Westergren) [normal, ≤30 mm/minute]
infection have on the risk and outcomes of endocarditis in the IV drug user?
The annual incidence of endocarditis among IV drug users is estimated at 1% to
5%; parenteral cocaine addicts have the highest risk.
pathophysiology, and prognosis of endocarditis in those who acquire the disease
secondary to IV drug use differ from those in nonusers.
likely than other pathogens to cause infection in this population.
the normal skin flora and is introduced when the illicit drug is injected. The
following are differences between addicts and nonaddicts with S. aureus
endocarditis: Addicts are significantly younger; they have fewer underlying diseases
nervous system complications; and they exhibit fewer signs of peripheral
involvement and have a lower incidence of death.
48 Among patients without history
of IV drug use, MRSA was involved in one-third of a cohort of 424 patients with
definite S. aureus IE. Clinical features that characterized MRSA IE were persistent
bacteremia, chronic immunosuppressive therapy, health-care-associated infection, a
presumed intravascular device source, and diabetes mellitus.
The prevalence of HIV seropositivity is 40% to 90% among IV drug users with
49 HIV-related immunosuppression may be an independent risk factor for the
METHICILLIN-SENSITIVE STAPHYLOCOCCUS AUREUS
CASE 66-3, QUESTION 2: What are the therapeutic options for treating S. aureus endocarditis in T.J.?
The susceptibility of S. aureus to methicillin is the major determinant of which
antibiotic is selected to treat T.J.’s endocarditis. T.J. is infected with MSSA.
Therapy of choice for methicillin-sensitive strains is a penicillinase-resistant
penicillin, such as nafcillin or oxacillin.
(Table 66-4). Penicillin G rarely is
appropriate because nearly all isolates of S. aureus produce penicillinase. A 6-week
course of therapy with high-dose (12 g/day) nafcillin is the therapy of choice.
Vancomycin may be less efficacious than nafcillin as an antistaphylococcal agent.
IV drug addicts, for the reasons previously identified, have a higher response rate to
appropriate therapy compared with nonaddicts. In one study, 31 addicts were
successfully treated with 16 days of parenteral therapy followed by 26 days of oral
Addicts with uncomplicated right-sided endocarditis caused by MSSA have been
treated successfully with a 2-week course of combination therapy with a
penicillinase-resistant penicillin and an aminoglycoside.
patients (94%) were cured after treatment with the combination of IV nafcillin (1.5 g
every 4 hours) and tobramycin (1 mg/kg every 8 hours) for a total of 2 weeks.
Notably, 2 of 3 patients treated with vancomycin relapsed, resulting in early
termination of this arm of study. Thus, vancomycin should not be used to substitute
for nafcillin in this regimen. An abbreviated course of treatment can be used in a
defined group of IV drug users with right-sided endocarditis. These patients should
have the following characteristics: (a) clinical and bacteriologic response within 96
hours of initiation of therapy; (b) no evidence of hemodynamic compromise,
metastatic infection, or neurologic or systemic embolic complications at either the
initiation or completion of 2 weeks of therapy; (c) no echocardiographically
demonstrable vegetations larger than 2 cm3
; (d) not infected with MRSA; and (e) not
55 HIV-seropositive patients (CD4
6 cells) with tricuspid involvement included in the above studies
also responded favorably to these short-course regimens; thus, a short-course
Recent studies suggest that the addition of an aminoglycoside to the treatment
regimen does not improve overall response for patients who meet the above criteria
for short-course therapy and is associated with increased toxicity. Therefore, the
AHA guidelines do not favor the antibiotic combination anymore. Also, all patients
receiving the short regimen should be carefully evaluated for evidence of continuing
infection or complications before discontinuing therapy at the end of the 2-week
treatment course; extension of therapy with a β-lactam agent to at least a 4 to 6-week
duration is recommended with any evidence of active disease or complications.
Although response to antibiotic therapy has been shown to be similar between
asymptomatic HIV-seropositive and HIV-seronegative IV drug users, short-course
therapy should be avoided in more immunosuppressed individuals (CD4 cell counts
<200 μL) until more definitive outcome data are available in this subgroup.
An oral treatment regimen consisting of ciprofloxacin (750 mg every 12 hours) plus
rifampin (300 mg every 12 hours) has also been evaluated in addicts with
uncomplicated right-sided endocarditis. In one small, noncomparative study, 10
addicts were successfully treated with the combination of ciprofloxacin and rifampin
58 Ciprofloxacin was given IV (400 mg every 12 hours) for the first 7
days, followed by oral administration (750 mg every 12 hours) for the remaining 21
days of therapy. Another study prospectively compared the oral regimen with
standard parenteral therapy for this subgroup.
59 Patients were randomly assigned to
receive 28 days of therapy with oral ciprofloxacin plus rifampin or oxacillin (2 g IV
every 4 hours) plus gentamicin (2 mg/kg IV every 8 hours). Vancomycin (1 g IV
every 12 hours) was substituted for oxacillin in the penicillin-allergic patients. One
of 19 patients in the oral group versus 3 of 25 in the IV group failed treatment;
however, approximately half of the study patients in either group had possible
endocarditis. Given the small number of patients who completed treatment,
therapeutic equivalency between the oral and parenteral regimens will need to be
confirmed in larger trials. In addition, emerging quinolone resistance in S. aureus and
the compliance and monitoring required of this regimen when administered in the
outpatient setting are of concern. Nonetheless, it appears that a 4-week oral regimen
with ciprofloxacin and rifampin may be a useful alternative treatment option in
addicts with uncomplicated right-sided endocarditis.
Treatment of penicillin-allergic patients with S. aureus endocarditis is somewhat
controversial. First-generation cephalosporins have been used with some success for
the treatment of patients with mild penicillin allergy, but treatment failures with
cefazolin are difficult to explain.
60 The stability of cefazolin when exposed to
staphylococcal β-lactamase has been proposed as a mechanism for these failures.
Notably, staphylococci are capable of producing four penicillinase subtypes, to
which the stability of cefazolin varies. These susceptibility differences are apparent
on MIC testing only if a larger-than-usual inoculum is used (i.e., >10
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