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bacilli (gram-negative); Candida spp.

Early prosthetic valve endocarditis (<60 days after valve implantation): S. aureus, S. epidermidis (gram-positive); gram-negative bacilli; fungi: Candida spp., Aspergillus spp.

Late prosthetic valve endocarditis (>60 days after valve implantation): α- hemolytic streptococci, Enterococcus spp., S. epidermidis (gram-positive);

Candida spp., Aspergillus spp.

Culture-negative endocarditis: 10% of cases; Bartonella quintana (homeless);

Brucella spp., fungi, Coxiella burnetii (Q fever), Chlamydia trachomatis, Chlamydophila psittaci, HACEK organisms; Abiotrophia (formerly vitamin B6-deficient streptococci); use of antibiotics prior to blood cultures

Device-related endocarditis: coagulase-negative staphylococci or S. aureus

RISK FACTORS

Injection drug use, IV catheterization, certain malignancies (colon cancer), poor dentition, chronic hemodialysis

High-risk with:

–Prosthetic cardiac valve, implantable devices (pacemaker, automatic implantable cardioverter defibrillator [AICD]), total parenteral nutrition

–Previous infective endocarditis (IE)

–Congenital heart disease (CHD): unrepaired cyanotic CHD, including palliative shunts and conduits; repaired CHD with prosthetic device during the first 6 months; repaired CHD with residual defects at or near prosthetic site; cardiac transplant with valvulopathy (1)[B]

GENERALPREVENTION

Good oral hygiene.

Antibiotic prophylaxis is only recommended for high-risk cardiac conditions (1)[B]—prosthetic heart valve, history of endocarditis, transplant with abnormal valvular function, CHD (see “Risk Factors”).

Procedures requiring prophylaxis

–Oral/upper respiratory tract: any manipulation of gingival tissue or periapical region of teeth or perforation of the oral mucosa (1)[B]; invasive respiratory procedures involving incision; or biopsy of the respiratory mucosa merit prophylaxis. Amoxicillin 2 g PO (if penicillin allergic, clindamycin 600 mg PO) 30 to 60 minutes before procedure or ampicillin 2 g IV/IM are first-line prophylactic choices. For penicillin-allergic patients, use clindamycin 600 mg IV, or cephalexin 2 g PO, or

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azithromycin/clarithromycin 500 mg PO, or cefazolin/ceftriaxone 1 g

IV/IM 30 minutes before procedure. Pediatric doses are amoxicillin 50 mg/kg PO (max 2 g), cephalexin 50 mg/kg PO (max 2 g), clindamycin 20 mg/kg PO (max 600 mg), and ampicillin or ceftriaxone 50 mg/kg (maximum 1 g) IM/IV.

–GI/GU: Only consider coverage for Enterococcus (with penicillin, ampicillin, piperacillin, or vancomycin) for patients with an established infection undergoing procedures (1)[B].

–Cardiac valvular surgery or placement of prosthetic intracardiac/intravascular materials: perioperative cefazolin 1 to 2 g IV 30 minutes preop or vancomycin 15 mg/kg (maximum 1 g) (penicillin-allergic patients) 60 minutes preop (1)[B]

–Skin: incision and drainage of infected tissue; use agents active against skin pathogens (e.g., cefazolin 1 to 2 g IV q8h or vancomycin 15 mg/kg q12h; max 1 g) if penicillin-allergic or if methicillin-resistant S. aureus (MRSA) suspected.

DIAGNOSIS

Modified Duke Criteria (1)[B] (definite: 2 major criteria, or 1 major and 3 minor criteria, or 5 minor criteria; possible: 1 major and 1 minor criteria or 3 minor criteria)

Major clinical criteria

–Positive blood culture: isolation of typical microorganism for IE from two separate blood cultures or persistently positive blood culture

–Single positive blood culture for C. burnetii or anti–phase-1 IgG antibody titer >1:800

–Positive echocardiogram: presence of vegetation, abscess, or new partial dehiscence of prosthetic valve; must be performed rapidly if IE is suspected

–New valvular regurgitation (change in preexisting murmur not sufficient)

Minor criteria

–Predisposing heart condition or IV drug use

–Fever ≥38.0°C (100.4°F)

–Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions

–Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor (RF)

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–Microbiologic evidence: positive blood culture but not a major criterion

(excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis) or serologic evidence of infection likely to cause IE

HISTORY

Fever (>38°C), chills, cough, dyspnea, orthopnea; especially in subacute endocarditis: night sweats, weight loss, fatigue

Review risk factors.

Symptoms of transient ischemic attack, cerebrovascular accident (CVA), or myocardial infarction (MI) on presentation

PHYSICALEXAM

Most patients with IE have new murmur or change in existing murmur; signs of heart failure (rales, edema) if valve function is compromised

Peripheral stigmata of IE: splinter hemorrhages in fingernail beds, Osler nodes on fleshy portions of extremities, “Roth spot” retinal hemorrhages, Janeway lesions (cutaneous evidence of septic emboli), palatal or conjunctival petechiae, splenomegaly, hematuria (due to emboli or glomerulonephritis)

Neurologic findings consistent with CVA, such as visual loss, motors weakness, and aphasia

DIFFERENTIALDIAGNOSIS

Fever of unknown origin, infected central venous catheter, marantic endocarditis, connective tissue diseases, intra-abdominal infections, rheumatic fever, salmonellosis, brucellosis, malignancy, tuberculosis, atrial myxoma, septic thrombophlebitis

DIAGNOSTIC TESTS & INTERPRETATION

If not critically ill; three sets of blood cultures drawn >2 hours apart from different sites before administration of antibiotics

If acutely ill, draw three sets of blood cultures over 1-hour prior to empiric therapy (1)[A]

Leukocytosis is common in acute endocarditis.

Anemia, decreased C3, C4, CH50, and RF in subacute endocarditis

ESR, C-reactive protein (CRP)

Hematuria, microscopic or macroscopic

Consider serologies for Chlamydia, Q fever, Legionella, and Bartonella in

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“culture-negative” endocarditis.

Transthoracic (TTE) or transesophageal echocardiogram (TEE) (TEE preferred) should be performed as soon as IE is suspected (1)[A].

CT scan may help locate embolic abscesses (e.g., splenic abscess).

Vegetations are composed of platelets, fibrin, and colonies of microorganisms. Destruction of valvular endocardium, perforation of valve leaflets, rupture of chordae tendineae, abscesses of myocardium, rupture of sinus of Valsalva, and pericarditis may occur.

Emboli, abscesses, and/or infarction of any system Immune-complex glomerulonephritis

TREATMENT

MEDICATION

First Line

Start empiric treatment after three sets of blood cultures have been drawn. Results guide treatment.

–Native valves: ampicillin-sulbactam 12 g/day IV divided into 4 doses with gentamicin 3 mg/kg/day IV/IM in 2 or 3 doses. If penicillin-allergic, use vancomycin 30 mg/kg/day IV in 2 doses with gentamicin 3 mg/kg/day IV/IM in 2 or 3 doses and with ciprofloxacin 1,000 mg/day PO or 800 mg/day IV, in 2 doses (2)[A].

–Prosthetic valves: vancomycin 30 mg/kg/day IV in 2 doses with gentamicin 3 mg/kg/day IV/IM in 2 doses and rifampin 1,200 mg/day PO in 2 doses, if <12 months postsurgery. If >12 months, use native valve regimen (2)[A].

Penicillin-susceptible viridans streptococci or S. bovis

–Native valve: penicillin G 12 to 18 million U/day IV continuously or in 4 to 6 doses or ceftriaxone 2 g/day IV/IM in 1 dose, both for 4 weeks (1)[B]

–Prosthetic valve: penicillin G 24 million U/day IV continuously or in 4 to 6 doses for 6 weeks or ceftriaxone 2 g/day IV/IM in 1 dose ± gentamicin 3 mg/kg IV/IM q24h for 2 weeks (peak gentamicin level 3 µg/mLand trough

<1 µg/mL) (1)[B]

Penicillin-resistant viridans streptococci or S. bovis

–Native valve: penicillin G 24 million U/day IV, either continuously or in 4 to 6 equally divided doses + gentamicin 3 mg/kg IV/IM q24h for 2 weeks

(peak gentamicin level 3 µg/mL and trough <1 µg/mL) (1)[B]

Prosthetic valve: penicillin G 24 million U/day IV, either continuously or in 4

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to 6 equally divided doses or ceftriaxone 2 g/day IV/IM in 1 dose for 6 weeks

+ gentamicin 3 mg/kg IV/IM q24h for 2 weeks (peak gentamicin level 3 µg/mL and trough <1 µg/mL) (1)[B] Staphylococcus

–Native valve: oxacillin or nafcillin 12 g IV/day in 4 to 6 equally divided doses 6 weeks. For oxacillin-resistant strains, use vancomycin 15 mg/kg/day IV q12h for 6 weeks for goal trough of 15 to 20 µg/mL (1)[B].

–Prosthetic valve: oxacillin or nafcillin 12 g/day IV in 4 to 6 doses + rifampin 300 mg IV/PO q8h, for 6 weeks, + gentamicin 3 mg/kg/day IV for first 2 weeks (peak gentamicin level 3 µg/mL and trough <1 µg/mL). For oxacillin-resistant strains, use vancomycin 15 mg/kg IV q12h, + rifampin 300 mg IV/PO q8h, both for 6 weeks, + gentamicin 3 mg/kg/day IV/IM in 2 to 3 doses for the first 2 weeks (peak gentamicin level 3 µg/mLand trough

<1 µg/mL) (1)[B].

Penicillin-sensitive Enterococcus, native or prosthetic valve: ampicillin 2 g IV q4h or penicillin G 18 to 30 million U/day IV continuously or in 6 doses + gentamicin 3 mg/kg IV q8h for 4 to 6 weeks (peak gentamicin level 3 µg/mL and trough <1 µg/mL) (1)[B]. Consider expert consultation for penicillinresistant enterococci.

HACEK organisms: ceftriaxone 2 g IM or IV q24h for 4 weeks (1)[B] or ampicillin-sulbactam 12 g IV q4h for 4 weeks or ciprofloxacin 1 g/day PO or 800 mg/day IV in 2 equally divided doses for 4 weeks (1)[B]

– Cardiac device–related endocarditis: device removal followed by antibiotic therapy based on organism susceptibility (3)[B]

Precautions: Adjust dosage of penicillin G, gentamicin, cefazolin, ampicillin, ampicillin/sulbactam, ciprofloxacin, and vancomycin in patients with renal impairment. Rapid infusion of vancomycin <1 hour may cause “red-man syndrome” due to histamine release (not an allergic reaction). Treat with antihistamines and decrease infusion rate.

Interactions: Vancomycin + gentamicin increases renal toxicity. Rifampin alters warfarin and oral hypoglycemic metabolism.

Second Line

For patients allergic to penicillin:

Penicillin-susceptible or resistant viridans group streptococci or S. bovis: vancomycin 30 mg/kg/day (not to exceed 2 g/day) IV in 2 equal doses for 4 weeks (6 weeks for prosthetic valve endocarditis) for goal trough of 10 to 15 µg/mL (1)[B]

Enterococcus, native or prosthetic valve: Desensitization to penicillin should

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be considered. Vancomycin 15 mg/kg (usual dose, 1 g) IVq12h, + gentamicin or streptomycin (peak gentamicin level 3 µg/mL and trough <1 µg/mL) for 4 to 6 weeks (6 weeks for prosthetic valve endocarditis) (1)[B]

Staphylococcus of native valve: cefazolin 2 g IV q8h (not to be used in patients with immediate-type hypersensitivity to penicillin) for 6 weeks or vancomycin 30 mg/kg (usual dose, 1 g) IV q12h for a goal trough of 15 to 20 µg/mL for 6 weeks (1)[B]

SURGERY/OTHER PROCEDURES

Surgery is required in 50% of IE cases. Indications (2)[A]: Heart failure due to aortic or mitral valve disease

–Prevention of embolism: aortic or mitral valve vegetations >10 mm with prior embolic episodes; isolated very large vegetation >15 mm; in patients

with major ischemic stroke, surgery is delayed for at least 4 weeks, if possible (4)[C].

Uncontrolled infection: persistent fever and positive cultures >7 to 10 days; infection caused by fungi or resistant organism; presence of abscess, fistula, false aneurysm, or enlarging vegetations

Early prosthetic valve IE

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

Check gentamicin peak (~3 µg/mL) and trough (<1 µg/mL) levels if used for >5 days and with renal dysfunction. Perform twice-weekly BUN and serum creatinine while on gentamicin. Consider audiometry baseline and follow-up during long-term aminoglycoside therapy.

Check vancomycin trough (15 to 20 µg/mL) levels in all patients (typically prior to fourth dose) (2)[B].

Baseline ECG; monitor ECG for conduction disturbances/MI in initial weeks of therapy.

TTE at the conclusion of therapy

Blood cultures q48h until negative

PROGNOSIS

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Late complications contribute to poor prognosis. These include heart failure, reinfection, and cerebral emboli. 10-year survival is 60–90% (5)[A].

COMPLICATIONS

Cerebral complications are the most frequent and severe, occurring in 15–20% of patients (1)[A].

Emboli: arterial (e.g., MI, mesenteric, splenic, cerebral infarction), infectious (e.g., abscesses of heart, lung, brain, meninges, bone, pericardium)

–Neurologic events are the most frequent complications in patients with IE requiring ICU admission. Ischemic stroke is the presenting symptom of IE in 20% of cases (5)[A].

Inflammatory/immune disorders (e.g., arthritis, myositis, glomerulonephritis)

Other complications: congestive heart failure (CHF), ruptured valve cusp, sinus of Valsalva aneurysm, arrhythmia, and mycotic aneurysms

REFERENCES

1.Baddour LM, Wilson WR, Bayer AS, et al; for American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435–1486.

2.Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med. 2013;368(15):1425–1433.

3.Baddour LM, Epstein AE, Erickson CC, et al; for American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation. 2010;121(3):458–477.

4.Byrne JG, Rezai K, Sanchez JA, et al. Surgical management of endocarditis: the society of thoracic surgeons clinical practice guideline. Ann Thorac Surg. 2011;91(6):2012–2019.

5.Sonneville R, Mirabel M, Hajage D, et al. Neurologic complications and outcomes of infective endocarditis in critically ill patients: the ENDOcardite en REAnimation prospective multicenter study. Crit Care Med. 2011;39(6):1474–1481.

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CODES

ICD10

I33.0 Acute and subacute infective endocarditis

I39 Endocarditis and heart valve disord in dis classd elswhr A54.83 Gonococcal heart infection

CLINICALPEARLS

Antibiotic prophylaxis is recommended for patients with artificial heart valves, history of infective endocarditis, CHD, and cardiac transplants with valvulopathy.

TEE/TTE and blood cultures are the mainstays for the diagnosis of IE.

Most common organisms are viridans Streptococcus species and

Staphylococcus.

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ENDOMETRIALCANCER AND UTERINE

SARCOMA

Christina N. Kufel, DO, MS Michael P. Hopkins, MD,

MEd

BASICS

DESCRIPTION

Endometrial cancer: malignancy of the endometrial lining of the uterus

–Two types

Type I: estrogen-dependent, grade 1 or grade 2, better prognosis, endometrioid histology

Type II: estrogen-independent, higher grade, more aggressive, includes grade 3 endometrioid and nonendometrioid: serous, clear cell, mucinous, poor prognosis (1)[A]

Cell types: adenocarcinoma, adenosquamous (malignant squamous elements), clear cell, and papillary serous

Sarcomas: malignancy of the uterine mesenchyme and mixed tumors

–Mixed müllerian sarcoma (carcinosarcoma): Heterologous sarcoma elements are not native to the müllerian system (e.g., cartilage or bone); homologous sarcoma elements are native to the müllerian system (40–50% prevalence of all sarcomas).

–Leiomyosarcoma develops in the myometrium, characterized by cellular atypic mitoses and coagulative necrosis (30% prevalence of all sarcomas).

–Endometrial stromal sarcoma develops from the stromal component of the endometrium (15% prevalence of all sarcomas).

–Poorer prognosis (2)[C]

Predominant age

–Endometrial cancer: Most patients are postmenopausal: Average age of diagnosis: 63 years old

–Sarcomas: occur in both preand postmenopausal:

Average age of diagnosis: 40 to 69 years old (2)[C]

70% of endometrial cancer is stage I at the time of diagnosis.

System(s) affected: reproductive

Synonym(s): uterine cancer; endometrial cancer; corpus cancer

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Pregnancy Considerations

This malignancy is not associated with pregnancy.

EPIDEMIOLOGY

Incidence

Endometrial cancer is the most common gynecologic malignancy, fourth most common cancer in women, and eighth leading cause of cancer-related death in women worldwide.

In the United States, it is estimated that endometrial cancer will account for 61,380 new cases and 10,920 deaths in 2017 according to SEER database.

Incidence higher in Caucasian than African American, but African Americans have stage matched higher mortality (3).

Prevalence

Approximately 500,000 women in the United States

ETIOLOGYAND PATHOPHYSIOLOGY

Continuous estrogen stimulation unopposed by progesterone Endometrial: unopposed estrogen

–Estrogen replacement therapy without concomitant progesterone increases the risk. Addition of progesterone decreases risk to that of general

population.

Sarcomas: etiology unknown

Genetics

Endometrial: Lynch syndrome (hereditary nonpolyposis colorectal cancer); lifetime risk up to 30% (3); Cowden syndrome (4,5)

Sarcoma: African American, higher incidence of leiomyosarcoma, childhood retinoblastoma survivors

RISK FACTORS

Early menarche/late menopause

Nulliparity

Personal or family history of colon or reproductive system cancer

Obesity

Diabetes mellitus

Hypertension

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