S pneumoniae

In the pre-antibiotic era, S. pneumoniae was responsible for approximately 15% of all cases of IE [84]. Since the advent of penicillin, pneu-mococcal IE has become a rare illness, causing 1-3% of all cases of NVE [84,85]. Despite the availability of penicillin, the mortality rate associated with this disease remains high, with case-fatality rates ranging from 28-60% [84].

Pneumococcal IE is usually preceded by pneumonia and is most commonly seen in alcoholic patients [84,85]. Underlying valvular heart disease is not a prerequisite for pneumococcal endocarditis [85]. Once IE is established, the course is typically aggressive, with rapid destruction of valvular tissue and subsequent CHF [84,86]. As well, this disease has a predilection to form large vegetations on the aortic valve, predisposing to embolization that can lead to pneumococcal meningitis [84,86]. In fact, the triad of pneumococcal pneumonia, complicated by endocarditis and meningitis, is referred to as Osler's triad as well as Austrian syndrome [84,85,87].

Patients with pneumococcal IE may be treated medically or with combined medical-surgical therapy. Evidence suggests, though, that persons with this disease be considered for early surgical intervention, as the mortality rate among patients who received medical therapy alone (63-80%) was much higher compared to the mortality rate of patients who received combination therapy (32%) [86]. This phenomenon was first noticed prior to the high prevalence of penicillin non-susceptibility among S. pneumo-niae that is widely appreciated today.

In the early 1990s, S. pneumoniae strains that had a high level of resistance to penicillin appeared in the United States [88]. Since then, rates worldwide have generally demonstrated an increase in penicillin non-susceptible strains (PNSP) [89-92]. By the end of the 1990s, approximately 25% of S. pneumoniae stains in the U.S. demonstrated intermediate (MIC 0.1-1 |g/mL) or high-level (MIC >2 |g/mL) resistance to penicillin, with similar trends described globally [93-96]. Furthermore, PNSP isolates have also demonstrated increasing resistance to other agents, most notably to macrolides, trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin, tetracyclines, and chlorampheni-col [90,91,97,98]. Fortunately, these latter antibiotics are not routinely used in the management of IE. Third-generation par-enteral cephalosporins (e.g., cefotaxime, ceftri-axone) and glycopeptides (e.g., vancomycin) currently possess significant activity against these multi-drug-resistant pneumococci [95,99-102]. Thus, these agents remain the recommended mainstay of empiric therapy for S. pneumoniae endocarditis as well as definitive therapy for IE due to intermediate- or high-level penicillin resistance [12,84] (see Table 9.5). If vancomycin monotherapy is selected for the management of pneumococcal IE, it is important that the possibility of meningitis be excluded, as there is concern about the penetration of vancomycin into cere-brospinal fluid in adults [103]. In patients with

Table 9.4. Antibiotic Treatment for NVE Due to Penicillin-Resistant (MIC >0.5 |g/mL) Streptococcus spp. (Non-Pneumococcus), Nutritionally Variant Streptococci

(NVS), and Enterococcus spp.

Category

First-line

Duration

Second-line

Duration

Comments

Penicillin-resistant

Ampicillin 2 g IV

4-6 weeks of

AHA recommends:4 weeks if

(MIC >0.5 |g/mL)

q4h + gentamicin

combined therapy

patient is symptomatic < 3

Streptococcus spp. (viridans

3 mg/kg/day IV

months; 6 weeks if

group streptococci and

symptomatic > 3 months.

S. bovis complex)

High-dose Penicillin

4-6 weeks of

High-dose penicillin G:3-4

G (e.g. 18—30

combined therapy

x105 U/kg

million units/day) IV

+ gentamicin

3 mg/kg/day IV

Vancomycin 30 mg/

6 weeks

kg/day IV q12h +

gentamicin 3 mg/

kg/day IV

Nutritionally variant

Ampicillin 2 g IV

4-6 weeks of

AHA recommends:4 weeks if

streptococci (NVS):

q4h + gentamicin

combined therapy

patient is symptomatic <3

Abiotrophie spp.

3 mg/kg/day IV

months; 6 weeks if

Granulicatella spp.

symptomatic >3 months

High-dose penicillin

4-6 weeks of

High-dose penicillin G:3-4 x

G (e.g., 18—30

combined therapy

105U/kg

million units/day) IV

+ gentamicin

3 mg/kg/day IV

Vancomycin 30 mg/

4-6 weeks of

BSAC recommends 6 weeks,

kg/day IV q12h +

combined therapy

because of the high rate of

gentamicin 3 mg/

relapse, as well as blood cultures

kg/day IV

weekly during therapy and

after completion of therapy.

Vancomycin alone is as effective

as penicillin G + gentamicin

in an experimental rabbit

model, and thus may be

considered if the risks of

gentamicin toxicity are high

Enterococcus spp.

Penicillin S

Ampicillin 2 g IV

4-6 weeks of

Gentamicin S

q4h + gentamicin

combined therapy

Vancomycin S

3 mg/kg/day IV

High-dose penicillin

4-6 weeks of

G (e.g., 18—30

combined therapy

million units/day) IV

+ gentamicin

3 mg/kg/day IV

Vancomycin 30 mg/

> 4 weeks of

Indicated only for patients

kg/day IV q12h +

combined therapy

unable to tolerate P-lactams

gentamicin 3 mg/

(BSAC);

kg/day IV

6 weeks of combined

therapy (AHA)

Penicillin S

Ampicillin 2 g IV

4-6 weeks of

For streptomycin, aim for

Gentamicin R

q4h + Streptomycin

combined therapy

peak serum concentration of

Streptomycin S

7.5 mg/kg IV q12h

20-35 |g/mL and trough

Vancomycin S

<10 |g/mL

Penicillin G 24

4-6 weeks of

million units/day) IV

ombined therapy

+ Streptomycin

7.5 mg/kg IV q12h

Vancomycin 30 mg/

> 4 weeks of

Vancomycin indicated only for

kg/day IV q12h +

combined

patients unable to tolerate

Streptomycin 7.5 mg/

therapy (BSAC)

P-lactams

kg IVq12h

6 weeks of

combined therapy

(AHA)

(Continued)

Table 9.4.—Continued

Category

First-line

Duration

Second-line

Duration

Comments

Penicillin S

Ampicillin 2 g

8 weeks (BSAC);

Surgical intervention may be

Gentamicin R

IV q4h

> 6 weeks (AHA)

necessary

(MIC >500 |g/mL)

High-dose penicillin

Streptomycin R

G (e.g.,24-30

(MIC >2000 |g/mL)

million units/

(i.e., high-level aminogly

day) IV

Vancomycin 30 mg/kg/

8 weeks (BSAC);

coside resistance)

day IV q12h

> 6 weeks (AHA)

Vancomycin S

Penicillin R

Ampicillin-

6 weeks

Usually gentamicin resistant,

(ß-lactamase +)

sulbactam 2 g IV

in which case >6 weeks of

Gentamicin S

q4h + gentamicin

ampicillin-sulbactam is

Vancomycin S

3 mg/kg/day IV

needed

Vancomycin 30 mg/

> 4 weeks of

kg/day IV q12h +

combined

gentamicin 3 mg/

therapy (BSAC);

kg/day IV

6 weeks of

combined therapy

(AHA)

Penicillin R (intrinsic

Vancomycin 30 mg/

> 4 weeks of

resistance)

kg/day IV q12h +

combined therapy

Gentamicin S

Gentamicin 3 mg/

(BSAC);

Vancomycin S

kg/day IV

6 weeks of combined

therapy (AHA)

Penicillin R

Vancomycin 30 mg/

8 weeks (BSAC)

Surgical intervention may be

Gentamicin R

kg/day IVq12h

> 6 weeks (AHA)

necessary for cure

Vancomycin S

Penicillin variable

E. faecalis—

> 8 weeks

Strongly consider

Gentamicin R

Ampicillin 2 g IV

consultation with an

Vancomycin R

q4h + Ceftriaxone

Infectious Disease specialist.

2 g IVq12h

Surgical intervention may be

OR

necessary for cure.

Ampicillin 2 g IV

Prolonged (>2 weeks)

q4h + Imipenem/

therapy with Linezolid may

cilastatin 500 mg

be associated with

IV q6h

thrombocytopenia (see text)

E. faecium—

> 8 weeks

Linezolid 600 mg

po/IV q12h

OR

Quinupristin/

Dalfopristin

7.5 mg/kg IV q8h

S = susceptible; R = resistant

S. pneumoniae IE and meningitis, high-doses of a third-generation cephalosporin should be used [52]. If the isolate is resistant to third-generation cephalosporins (e.g., cefotaxime MIC > 2 |g/mL), then vancomycin and rifampin should be added [52].

Given the aggressive nature of this disease, including the associated risk of meningitis and the high mortality rates with medical therapy alone, the preferable treatment of patients with pneumococcal IE may be a combined medical-surgical approach. This recommendation is largely based on a meta-analysis of 197 cases reported in the English literature of this disease among adult patients in the penicillin era [84]. The mortality rate among 91 patients treated with antibiotics alone was 62%, compared to 32% among 37 patients managed with a com-

Table 9.5. Antibiotic Treatment for NVE Due to S.pneumoniae and ß-Hemolytic Streptococci

Category

First-line

Duration

Second-line

Duration

Comments

Penicillin-sensitive

Penicillin G 24 million

4 weeks

Note: S. pneumoniae IE may

S. pneumoniae

units/day IV

require combined medical-

(MIC <0.1 |g/mL)

surgical therapy for cure

Ampicillin 2 g IV q4h

4 weeks

Third-generation

4 weeks

cephalosporins:

ceftriaxone 2 g IV q12h

OR

Cefotaxime 2 g IV q4 to 6h

Cefazolin 2 g IV q8h

4 weeks

Recommended by AHA, but not

by BSAC

Vancomycin 30 mg/

4 weeks

Vancomycin indicated only for

kg/day IVq12h

patients unable to tolerate

P-lactams

Penicillin-non-

susceptible

S. pneumoniae (PNSP):

Intermediate resistance

Penicillin G 24 million

4 weeks

Recommended by AHA, but

(MIC 0.1-1 |g/mL)

units/day IV

not by BSAC; data derived from

with NO meningitis

animal model,with concern

about its clinical significance [84]

Third-generation

4 weeks

cephalosporins: ceftriaxone

2 g IV q12h OR Cefotaxime

2 g IV q4 to 6h

Vancomycin 30 mg/

4-6 weeks [521]

Vancomycin indicated only for

kg/day IV q12h

patients unable to tolerate

P-lactams or if isolate is

resistant to third-generation

cephalosporins

Intermediate resistance

Third-generation

4 weeks

(MIC 0.1-1 |g/mL)

cephalosporins: ceftriaxone

WITH meningitis

2 g IV q12h OR Cefotaxime

2 g IV q4 to 6h

Vancomycin 30 mg/

4-6 weeks

Vancomycin indicated only for

kg/day IVq12h +

patients unable to tolerate

Rifampin [522]

P-lactams or if isolate is

resistant to third-generation

High-level (MIC > 2

Vancomycin 30 mg/kg/day

4-6 weeks

Fluoroquinolones as

|g/mL)

IV q12h + rifampin [522]

combination therapy may be of

use [86]

ß-hemolytic

Surgical intervention may be

streptococci:

necessary for cure

Group A streptococci

High-dose penicillin G

4 weeks

(S. pyogenes)

(e.g., 24 million units/

day IV)

Cefazolin 2 g IV q8h

4 weeks

Ceftriaxone 2 g IV q12h

4 weeks

Vancomycin 30 mg/

4 weeks

kg/day IV q12h

Groups B,C,G

High-dose penicillin G

Combination

(e.g., 24 million units/

therapy for >

day IV) + gentamicin

2 weeks, then

3 mg/kg/day IV

penicillin G for

2-4 weeks [107]

Vancomycin 30 mg/

Combination therapy

kg/day IV q12h +

for >2 weeks, then

gentamicin 3 mg/

vancomycin for

kg/day IV

2-4 weeks

bined modality approach. Similar studies with smaller samples sizes of patients with definite pneumococcal IE support this suggestion [104,105]. The optimal timing of surgical intervention in this disease remains unknown; perhaps trans-esophageal echocardiography (TEE) may play a role. The optimal duration of antimicrobial therapy, either alone or after surgical intervention, also remains unclear, but four to six weeks is recommended [12,84].

The role of pneumococcal vaccination in providing primary protection against pneumococ-cal IE is unknown. In one study, S. pneumoniae IE developed in two patients who had been previously immunized: one patient developed disease due to a serotype that was represented in the vaccine, whereas the second patient had a history of alcoholism and chronic obstructive pulmonary disease and developed IE due to a strain that was not serotyped (105]. Although no conclusion can be made regarding the efficacy of immunization in primary prevention, it is important to note the possibility of developing pneumococcal disease (endocarditis or otherwise) despite a history of vaccination, as most people develop a humoral response to only ~75% of the antigens in the vaccine [84]. Recurrence of disease is extremely rare [106] and so the role of immunization for secondary prevention is unknown.

do not have allergy to this antibiotic [11,12]. For the remaining BHS (Lancefield groups B, C, and G), for which the penicillin MICs can be higher than for Streptococcus pyogenes, there is some evidence regarding the benefit of combined therapy (i.e., penicillin with an aminoglycoside), and is therefore recommended [11,12]. The antibiotic regimens for the treatment of BHS IE are provided in Table 9.5. The duration of antimicrobial therapy remains ill-defined. Recommendations of four weeks for group A streptococcus and four to six weeks for groups B, C, and G streptococci have been made, in the absence of any complications [52]. Microbiological evidence of sterilization of excised cardiac valves after four weeks of a fi-lactam, with or without aminoglycoside for the first two weeks, supports this recommendation [110].

A significant proportion (50-60%) of patients have required adjunctive surgical intervention [107,108]. The most frequent indication for cardiac surgery was acute valve insufficiency. The authors of the two largest series to date on BHS IE believe that a more aggressive surgical intervention is associated with diminished mortality rates, although the benefit of surgery could not be clearly demonstrated [107,108]. Nonetheless, consultation with a cardiac surgeon should be considered early in the course of management.

^-Hemolytic Streptococci

IE due to P-hemolytic streptococci (BHS) is extremely uncommon, accounting for < 5% of cases [107]. The major pathogens are groups A (S. pyogenes), B (S. agalactiae), C, and G, with group B being the most common cause of BHS IE [107,108].

The typical clinical characteristics is one of an acute infection, often occurring on normal heart valves, producing large valvular vegetations, and frequently complicated by embolic phenomena [107,108]. Most patients have underlying conditions, including diabetes mel-litus, malignancy, chronic alcoholism/cirrhosis, varicella, and HIV [107-109].

Few studies have been published regarding the optimal treatment of this uncommon condition. Because penicillin resistance by the BHS remains uncommon, it remains the cornerstone of therapy, and is recommended as monother-apy in group A streptococcal IE in patients that

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