GRAM-NEGATIVE BACILLARY ENDOCARDITIS

CAUSED BY PSEUDOMONAS AERUGINOSA

Prevalence

CASE 66-5, QUESTION 4: Fourteen months after completing his course of antifungal therapy, B.G. was

readmitted to the hospital with a 48-hour history of fever, shaking chills, rigors, and night sweats. His vital signs

at that time were blood pressure, 100/60 mm Hg; pulse, 120 beats/minute; respirations, 24/minute; and

temperature, 103.7°F. A new-onset systolic murmur was noted on auscultation. Two-dimensional

echocardiography revealed two small vegetations on the prosthetic valve. Empiric therapy consisting of

amphotericin B, 5-FC, vancomycin, and gentamicin was initiated. Three blood cultures drawn on the day of

admission were positive for P. aeruginosa with the following antibiotic susceptibilities: gentamicin (8 mcg/mL),

tobramycin (2 mcg/mL), piperacillin–tazobactam (16 mcg/mL), and ceftazidime (2 mcg/mL). A presumptive

diagnosis of PVE caused by P. aeruginosa was made. Why was the finding of Pseudomonas expected in B.G.?

The prevalence of endocarditis caused by gram-negative organisms has increased

significantly over the years, especially in IV drug users such as B.G. and patients

with prosthetic heart valves. Gram-negative organisms are responsible for about

15% to 20% of endocarditis cases in these populations.

43 Most gram-negative

endocarditis cases are caused by Pseudomonas species, S. marcescens, and

Enterobacter species, although numerous other gram-negative organisms have been

known to cause endocarditis.

43

,

128

,

154–157

In narcotic addicts with gram-negative

endocarditis, the tricuspid, aortic, and mitral valves are involved in 50%, 45%, and

40% of cases, respectively.

128

p. 1400

p. 1401

Antimicrobial Therapy

CASE 66-5, QUESTION 5: How should B.G.’s gram-negative endocarditis be treated and monitored?

The previous empirical antimicrobials should be discontinued because P.

aeruginosa has been cultured from B.G.’s blood. A bactericidal combination of

antibiotics usually is required to provide in vivo synergy and to prevent resistant

subpopulations from emerging during therapy.

1

,

158 Endocarditis caused by P.

aeruginosa (as in B.G.) should be treated for at least 6 weeks with a combination of

an aminoglycoside and an antipseudomonal penicillin (piperacillin–tazobactam) or

cephalosporin (ceftazidime).

1

,

156

,

159–161 The combination of an antipseudomonal

penicillin and an aminoglycoside is synergistic in vitro and in the rabbit model of P.

aeruginosa endocarditis,

160

,

161 and clinical experience has confirmed this finding in

IV drug users. Combination therapy with high dosages of tobramycin or gentamicin (8

mg/kg/day) has been associated with a significantly higher cure rate and lower

mortality rate compared with an older, low-dose regimen (2.5–5 mg/kg/day).

43

,

156

,

159

B.G., therefore, should be treated with ceftazidime (2 g IV every 8 hours) with

concurrent high-dose tobramycin (3 mg/kg IV every 8 hours). Aminoglycosides

(tobramycin or gentamicin) should be dosed to produce peak and trough serum

concentrations of 15 to 20 mcg/mL and less than 2 mcg/mL, respectively, to ensure

maximum efficacy.

1 Finally, the infected valve should be surgically excised for the

reasons previously discussed.

Other antibiotics including imipenem, meropenem, aztreonam, cefepime, and

ciprofloxacin are active against many of the gram-negative organisms causing

endocarditis. Clinical data regarding their use in the treatment of endocarditis are

very limited, however.

162–165 Ceftolozane/tazobactam (Zerbaxa) is a novel

cephalosporin combination β-lactamase inhibitor with enhanced activity against

Pseudomonas and may be an alternative for treatment of multi-drug resistant

Pseudomonas infections. Its efficacy for the treatment of endocarditis is still being

investigated.

CULTURE-NEGATIVE ENDOCARDITIS

CASE 66-5, QUESTION 6: B.G.’s history, clinical presentation, and imaging studies are strongly suggestive

of IE. If his blood cultures had been negative after 48 hours of incubation, the working diagnosis would have

been culture-negative endocarditis. What are the possible reasons for culture-negative endocarditis, and what

measures should be taken to establish a microbiologic etiology?

The proportion of patients with culture-negative endocarditis has diminished

considerably, presumably as a result of improved microbiologic culture techniques.

Negative blood cultures are present in only 5% to 7% of patients who meet strict

criteria for the diagnosis of IE and have not recently received antibiotics.

166 The

prior administration of antimicrobials is thought to account for most cases of culturenegative endocarditis.

166 B.G.’s blood cultures may remain negative for several days

to weeks if he has taken antibiotics recently.

Slow-growing and fastidious organisms, such as gram-negative bacilli in the

Haemophilus–Actinobacillus–Cardiobacterium–Eikenella–Kingella group

(HACEK), Brucella, Coxiella, chlamydiae, strict anaerobes, and fungi, should be

pursued in culture-negative patients. This usually is accomplished by the use of

special culture media or by obtaining appropriate serologic acute and convalescent

titers. Blood cultures should be saved for at least 3 weeks to detect slow-growing

organisms.

166 Of note, previously NVS has been the cause of most of the cases of

endocarditis diagnosed as culture-negative, initially because of its requirement for

the addition of vitamin B6

(pyridoxal HCl) to the culture media for laboratory

growth; however, laboratory identification is no longer a significant problem with

current culture media and laboratory techniques.

9

Empiric Therapy

CASE 66-5, QUESTION 7: The causative organism remains unidentified. Recommend an antimicrobial

regimen for the empiric treatment of B.G.’s presumed culture-negative endocarditis.

In the hemodynamically stable patient, antibiotic therapy should be withheld until

positive blood cultures are obtained.

1 Based on B.G.’s clinical presentation and

echocardiographic findings, empiric antibiotics should be initiated as soon as

necessary cultures have been collected. Because staphylococci (often MRSA) and

gram-negative bacilli account for most cases of endocarditis in the narcotic addict

with a prosthetic heart valve, B.G. should be started on a four-drug regimen:

vancomycin targeting a trough of 15 to 20 mcg/mL, gentamicin targeting a peak of 3 to

4 mcg/mL, cefepime 2 g IV every 8 hours, and rifampin 300 mg IV/PO every 8

hours.

7 Because B.G. may be experiencing a relapse caused by C. albicans, the

addition of amphotericin B and 5-FC would be appropriate. Depending on the gramnegative pathogens common to the region and their anticipated susceptibilities, a

third-generation cephalosporin (ceftriaxone or ceftazidime) or piperacillin–

tazobactam could be used. The combination of an aminoglycoside and piperacillin–

tazobactam also will provide coverage for enterococci.

B.G.’s clinical status and the positive echocardiogram indicate that early surgical

valve excision and replacement are necessary. Cultures obtained from the excised

valve may allow for identification of the causative organism and subsequent

alteration of his antimicrobial regimen depending on susceptibilities.

PROPHYLACTIC THERAPY

Rationale and Recommendations

CASE 66-6

QUESTION 1: B.B., a 74-year-old man with poor dentition, is scheduled to have all of his remaining teeth

extracted for subsequent fitting of dentures. His medical history is significant for numerous infections of the oral

cavity and prosthetic valve replacement 2 years ago. His only current medications are oral digoxin (Lanoxin)

0.125 mg/day and furosemide (Lasix) 40 mg every morning. What is the rationale for antibiotic prophylaxis?

Because IE is associated with significant mortality and long-term morbidity,

prevention in susceptible patients is of paramount importance.

1 Estimates are,

however, that less than 10% of all cases are theoretically preventable.

167 The

incidence of endocarditis in patients undergoing procedures known to cause

significant bacteremia, even without antibiotic prophylaxis, is low. In addition,

endocarditis may develop after the administration of seemingly appropriate

chemoprophylaxis. Therefore, it is not surprising that the efficacy of prophylaxis has

never been established through

p. 1401

p. 1402

placebo-controlled clinical trials. Approximately 6,000 patients would be

necessary to demonstrate a statistical difference (if one exists) between untreated

controls and a group receiving prophylaxis.

168

Without conclusive clinical data from prospective trials, recommendations for

antibiotic prophylaxis have been based largely on in vitro susceptibility data,

evaluation of antibiotic regimens using animal models of endocarditis, and anecdotal

experiences.

168

Prophylactic antibiotics are thought to provide protection by decreasing the

number of organisms reaching the damaged heart valve from a primary source. Thus,

antibiotics theoretically prevent bacterial multiplication on the valve and interfere

with bacterial adherence to the cardiac lesion.

168

The 2007 AHA recommendations for antibiotic prophylaxis before common

medical procedures are outlined in Table 66-6.

168 Compared with the previous

(1997) guideline, the current guidelines only recommend the use of prophylaxis in

patients with specific cardiac conditions (associated with the highest risk of adverse

outcomes from endocarditis) who are undergoing only dental or respiratory tract

procedures. The use of prophylaxis for patients undergoing genitourinary or

gastrointestinal procedures is not recommended because of a continuing lack of

evidence to support efficacy.

DENTAL AND UPPER RESPIRATORY TRACT PROCEDURES

Analysis of published data shows that viridans streptococcal bacteremia can result

from any procedure that involves the manipulation of the gingival tissue or the

periapical region of the teeth or perforation of the oral mucosa. Placement or

removal of prosthodontic or orthodontic appliances, adjustment of orthodontic

appliances, taking dental radiographs, bleeding from trauma to the lips or oral

mucosa, and instantaneous shedding of deciduous teeth do not require

chemoprophylaxis. Endotracheal intubation also does not require prophylactic

therapy.

Antimicrobial prophylaxis should be directed against the viridans group of

streptococci because these organisms are the most common cause of endocarditis

after dental procedures. Invasive surgical procedures involving the upper respiratory

tract, such as incision or biopsy of the respiratory mucosa (e.g., tonsillectomy,

adenoidectomy), can cause transient bacteremia with organisms that have similar

antibiotic susceptibilities to those that occur after dental procedures; therefore, the

same regimens are suggested. Prophylaxis is not recommended for bronchoscopies

unless the procedure involves incision of the respiratory mucosa. Amoxicillin is

currently recommended for oral prophylaxis in susceptible persons having dental or

upper respiratory tract surgery. Oral clindamycin, clarithromycin, or azithromycin is

recommended for patients with immediate-type hypersensitivity reaction to

penicillins. Only patients with outlined cardiac conditions should receive

prophylactic antibiotics.

Table 66-6

Cardiac Conditions for Which Prophylaxis is Recommended

Cardiac Conditions

Prophylaxis Recommended

Prosthetic cardiac valves

Previous bacterial endocarditis

Congenital heart disease

Unrepaired cyanotic CHD, including palliative shunts and conduits

Completely repaired congenital heart defect with prosthetic material device during the first 6 months after

the procedure

Repaired CHD with residual defects at or adjacent to the site of the prosthetic device or patch

Mitral valve prolapse with valvular regurgitation and/or thickened leaflets

Cardiac transplantation recipients who develop cardiac valvulopathy

CHD, congenital heart disease.

Source: Wilson W et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a

guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease

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

Cardiovascular Surgery and Anesthesia, and the Quality of Care an Outcomes Research Interdisciplinary Working

Group. American Heart Association [published correction appears in Circulation. 2007;116:e376]. Circulation.

2007;116:1736.

Most cases of endocarditis caused by bacterial flora from the mouth do not follow

dental procedures but rather are the result of poor oral hygiene. The cumulative

exposure to random bacteremias from daily oral activities is estimated to be 5,730

minutes during a 1-month period compared with only 6 to 30 minutes for a dental

procedure. Furthermore, it is estimated that the cumulative exposure to bacteremia

from routine daily activities may be up to 5.6 million times greater than a single tooth

extraction.

168 Based on the study results, concerns for antimicrobial resistance, and

cost, changes to restrict the use of antibiotic prophylaxis before dental procedures to

the highest-risk patients may be expected with future guidelines issued by the AHA.

Indications and Choice of Agent

CASE 66-6, QUESTION 2: Is prophylactic antibiotic therapy indicated for B.B.? If so, which antibiotic(s)

should be used?

Based on the current recommendations, B.B. is a candidate for antibiotic

prophylaxis. Presence of a prosthetic aortic valve while undergoing multiple tooth

extractions places him at risk for experiencing endocarditis. He also is scheduled to

have all of his remaining teeth extracted, a procedure likely to result in bacteremia.

According to Table 66-7, B.B. should receive a single 2-g oral dose of amoxicillin 1

hour before the procedure.

p. 1402

p. 1403

Table 66-7

Endocarditis Prophylaxis Regimen Indicated for Patients with Cardiac

Conditions

Drug

a Dose

Dental or upper respiratory tract procedures Single dose 30–60 minutes before procedure

Standard Regimen

Amoxicillin Adult: 2 g

Pediatric: 50 mg/kg

Allergic to Penicillin or Ampicillin

Clindamycin Adult: 600 mg

Pediatric: 20 mg/kg

Cephalexin

b

,

c Adult: 2 g

Pediatric: 50 mg/kg

Azithromycin or clarithromycin Adult: 500 mg

Pediatric: 15 mg/kg

Unable to Take Oral Medications

Ampicillin Adult: 2 g IM or IV

Pediatric: 50 mg/kg IM or IV

Allergic to Penicillin or Ampicillin

Clindamycin Adult: 600 mg IM or IV

Pediatric: 20 mg/kg IV

Cefazolin

b Adult: 1 g IM or IV

Pediatric: 50 mg/kg IM or IV

aSee Table 66-6.

bCephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (e.g., urticaria,

angioedema, or anaphylaxis) to penicillins or ampicillin.

cOther first- or second-generation oral cephalosporins in equivalent adult or pediatric dose.

IM, intramuscular; IV, intravenous.

Source: Wilson W et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a

guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease

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

Cardiovascular Surgery and Anesthesia, and the Quality of Care an Outcomes Research Interdisciplinary Working

Group. American Heart Association [published correction appears in Circulation. 2007;116:e376]. Circulation.

2007;116:1736.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and website for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

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Circulation. 2015;132:1435–1486.

Fowler VJ, Jr et al. Endocarditis and intravascular infections. In: Mandell GL et al, eds. Mandell, Douglas, and

Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.

Chapter 77. (1)

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Li JS et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis.

2000;30:633. (15)

Le T, Bayer AS. Combination antibiotic therapy for infective endocarditis. Clin Infect Dis. 2003;36:615. (16)

Liu C et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of

methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18. (63)

Palraj R. Prosthetic valve endocarditis. In: Mandell GL et al., eds. Mandell, Douglas, and Bennett’s Principles and

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Wilson W et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline

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

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Working Group. American Heart Association [published correction appears in Circulation. 2007;116:e376].

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Key Websites

www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/infectious-disease/infectiveendocarditis/

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