Unipen

In one study,[1] 29 percent of patients with endocarditis were injection drug users. Injection drug use includes intravenous injection and "skin popping" (injection of the drug under the skin). Because right-sided endocarditis predominates in patients who use injection drugs, the classic left-sided findings of a new aortic or mitral murmur, fever, back pain, hematuria and peripheral lesions, such as Janeway's lesion, or Osler's nodes seen in subacute bacterial endocarditis, are often absent[23] (Table 1).

[TABULAR DATA OMITTED]

Clinical Presentation

Most injection drug users with endocarditis initially exhibit fever, often without localizing signs.[2,3] The diagnosis of infectious endocarditis in injection drug users is based on clinical suspicion and is confirmed with blood cultures and echocardiography. Three studies[4-6] have evaluated the incidence and presentation of infectious endocarditis in injection drug users with fever. Endocarditis was present in 6 to 13 percent of febrile patients,[4,5] while 25 to 32 percent had "trivial" or minor illnesses (viral syndrome, pharyngitis, fever of less than 48 hours, duration without diagnosis, hepatitis B or other illness not requiring hospitalization). Fifteen percent of patients who used injection drugs had skin findings that were presumed to be the primary source of infection.[4,6] In one study,[6] seven of 11 febrile injection drug users with endocarditis had clinically occult disease with positive blood cultures.

Generally, these studies showed that physicians were not able to predict which patients had endocarditis on the basis of classic signs and symptoms.[4-6] Symptoms such as chills, back pain and pleuritic chest pain, and findings such as systolic murmur or peripheral embolic events were not significantly associated with endocarditis, compared with other diagnoses, probably because of the predominance of acute infectious endocarditis and right-sided endocarditis in these patients. Cough, pleuritic chest pain and hemoptysis were the most common pulmonary symptoms. Furthermore, 30 percent of injection drug users with "trivial" illness had a murmur.[4] A higher likelihood of endocarditis was noted in febrile patients with a history of drug injection in the past five days.[6] Pulmonary emboli occurred in approximately one-third of patients with endocarditis.[5]

Physical Examination

The most common physical finding in patients with endocarditis associated with injection drug use is fever (higher than 38.8[degrees] to 39.2[degrees]C [102.0[degrees] to 102.6[degrees]F]).[4,6] Fever is absent in only 2 to 3 percent of all cases of endocarditis.[2,3] A pathologic murmur, often right-sided (Carvallo's sign), is heard on presentation in 18 to 40 percent of patients.[1,2,4] Twenty-five to 72 percent of patients with endocarditis associated with injection drug use will have a murmur at some time during the course of the disease,[1-4] compared with 86 percent of patients with endocarditis who do not use drugs.[2] Peripheral emboli presumably represent left-sided involvement.

Diagnostic Evaluation

Blood cultures are positive in more than 98 percent of cases of endocarditis associated with injection drug use.[2] Chest radiographs are abnormal in 55 to 76 percent of injection drug users with right-sided endocarditis.[1,3] Multiple lung lesions in different stages of evolution from infiltrates to abscesses are most predictive of right-sided endocarditis. A number of other laboratory abnormalities can occur with endocarditis, including urine abnormalities (hematuria, proteinuria or pyuria), electrolyte abnormalities (hyponatremia, hypokalemia) and elevated erythrocyte sedimentation rate.

Use of Echocardiography

Echocardiography is more sensitive in patients who use injection drugs because of the high frequency of right-sided endocarditis. Sensitivity for transthoracic echocardiography is approximately 88 to 94 percent.[5,7] The specificity is 96 percent; thus, false-positive results are rare. Although transesophageal echocardiography is more sensitive in patients with left-sided endocarditis and in the detection of myocardial abscesses, it has not been found to be more sensitive for right-sided endocarditis, and myocardial abscesses are rare in right-sided endocarditis.[7,8]

VALVE INVOLVEMENT

Right-sided endocarditis occurs in 54 to 76 percent of injection drug users with endocarditis, tricuspid and aortic valve involvement is found in 18 percent, and 30 to 40 percent will have only left-sided involvement.[9,10] In contrast, 80 percent of cases of endocarditis not associated with injection drug use are left-sided. In one recent retrospective study,[9] 57 percent of injection drug users with endocarditis had left-sided abnormalities on echocardiography, while 40 percent had only right-sided involvement. The investigators postulated that echocardiography had improved since earlier studies, allowing them to see a greater number of left-sided lesions. The study also included more women with mitral valve prolapse, who presumably had a greater risk of mitral valve infection. The presence of prosthetic valves increases the risk of endocarditis; in one study,[1] prosthetic valves were found to be a risk factor in 10 percent of patients.

Microbiology

Staphylococcus aureus causes 50 to 75 percent of cases of endocarditis associated with injection drug use.[2] S. aureus involvement is most common with tricuspid valve disease. S. aureus infection resistant to methicillin (Staphcillin) is a common problem in some regions. Streptococcal species (including Enterococcus) account for 20 percent of cases, usually in left-sided valvular disease. Fungal infections (3 percent of cases) and polymicrobial infections (6 percent) are less common.[10] Other organisms associated with endocarditis related to injection drug use include Pseudomonas species, due to washing needles in contaminated water, and Neisseria sicca, associated with the practice of licking needles to clean them.[11,l2] Culture-negative endocarditis is rare in patients who are injecting drugs.

Significance of HIV Infection

The clinical presentation and spectrum of bacteria causing endocarditis in drug users who are seropositive for human immunodeficiency virus (HIV) infection or those with acquired immunodeficiency syndrome does not differ from that in patients who are not HIV-infected. Only one study to date directly compares HIV-seropositive and seronegative injection drug users with endocarditis. This study[13] showed that S. aureus infection occurs in up to 86 percent of HIV-positive patients, compared with 75 percent of HIV-negative patients. The mortality rate is 10 percent in persons with asymptomatic HIV infection and increases to 40 percent in individuals with symptomatic HIV infection.[13] Thus, endocarditis in HIV-positive drug users may be more difficult to treat, especially in the symptomatic stage of HIV infection, and mortality appears to be higher than in HIV-negative injection drug users.

Treatment

ANTIBIOTICS

The standard treatment for endocarditis is based on the prevalence of organisms seen in a particular group of patients. In the general population, infectious endocarditis is caused by streptococcal species in approximately 80 percent of cases.[10] In injection drug users, endocarditis is most commonly caused by S. aureus and, thus, an anti-staphylococcal penicillin (e.g., nafcillin [Unipen]) should be the empiric therapy of choice.[14] Vancomycin (Vancocin) may be substituted in patients with penicillin allergy, but some evidence shows more relapses in patients treated with vancomycin.[15] The addition of an aminoglycoside has been shown to decrease the length of time bacteremia is present in injection drug users with S. aureus tricuspid valve endocarditis (2.5 days versus 3.5 days), and it may allow for a shorter course of therapy.[16]

Although four to six weeks of therapy is standard for patients with left-sided infectious endocarditis, several studies have shown a cure rate greater than 95 percent for methicillin-sensitive S. aureus in drug users with uncomplicated right-sided endocarditis with two weeks of treatment using anti-staphylococcal penicillins (nafcillin or cloxacillin) plus an aminoglycoside.[16,17] These studies included patients with pulmonary emboli but excluded patients with evidence of systemic emboli. When Staphylococcus epidermidis or methicillin-resistant S. aureus are present, vancomycin with either an aminoglycoside or rifampin (Rifadin, Rimactane) should be used for four to six weeks.

Compliance with lengthy therapy is often a major issue for injection drug users. Several investigators have looked at alternatives such as twice-daily intramuscular ceforanide[18] or two-week intravenous therapy followed by two-week oral regimens such as ciprofloxacin (C)pro) or rifampin for treatment of right-sided endocarditis.[19] Although these small studies provide hope for the future, these regimens should not be considered unless standard regimens are not possible. Ciprofloxacin resistance during therapy has been reported in one patient treated with oral ciprofloxacin alone.[20]

SURGERY

As for persons in the general population with endocarditis, surgery should be considered for injection drug users with endocarditis who have valvular insufficiency and acute heart failure, central nervous system emboli, multiple systemic emboli or myocardial abscesses. Most injection drug users with right-sided endocarditis will improve with medical therapy alone, and surgery should be reserved for cases in which refractory bacteremia develops or fungal infection is present. Even then, tricuspid valvulectomy may be preferable to valve replacement in patients who may continue to inject drugs, thereby increasing their risk for prosthetic valve endocarditis. The five- to 10-year survival rate for injection drug users who undergo valve replacement is 10 percent.[21] Most patients will do well without a tricuspid valve in place.

Outcome

Mortality is higher for left-sided infectious endocarditis (14.0 to 21.4 percent) than for right-sided endocarditis (2.0 to 7.0 percent in patients who inject drugs).[3,10] This difference is due to the poor prognosis for patients with cerebral emboli as well as increased mortality in patients with significant left-sided cardiac failure. Predictors for poor outcome in patients with right-sided endocarditis include systemic emboli (excluding the lungs) and refractory bacteremia. One study[3] documented a 33.0 percent mortality rate for patients with vegetations larger than 2.0 cm, compared with 1.3 percent for patients with smaller vegetations. Prolonged fever (greater than one week) increased overall mortality, but not for injection drug users with right-sided endocarditis.[3] Embolic strokes occur in approximately 20 percent of cases of left-sided endocarditis.[22] Symptomatic HIV infection is also a risk factor for mortality.[13]

Prevention

The risk of endocarditis can be reduced by cleaning the skin before injection, and there is some evidence that eliminating nasal carriage of Staphylococcus in injection drug users may reduce infection rates.[23] The rate of recurrent endocarditis in injection drug users is between 24 and 40 percent.[24] The most important risk factor for recurrent endocarditis is continued injection drug use. Injection drug users who have their native valve replaced with a prosthetic valve and continue to use drugs have a high recurrence rate for endocarditis, which is usually fatal.[24]

Final Comment

Patients who use injection drugs and who present with fever higher than 38.5[degrees]C (101.[degrees]F) should be strongly considered for hospital admission, unless another source of benign illness is clearly present. Physical examination may be helpful if a right-sided murmur is heard or if there is evidence of left-sided involvement. Three sets of blood cultures should be obtained. The patient should be started on empiric therapy with an anti-staphylococcal penicillin with consideration of the addition of an aminoglycoside. Echocardiography should be considered. When involvement is only right-sided and uncomplicated, two-week therapy may be sufficient and surgery is usually not needed. Left-sided involvement mandates four to six weeks of treatment, and immediate surgery should be considered in patients with evidence of heart failure or significant systemic emboli. Patients with recurrent infectious endocarditis or prosthetic valves should receive four to six weeks of treatment and special efforts, such as inpatient drug treatment, should be made to prevent recurrence.

REFERENCES

[1.] Lederman MM, Sprague L, Wallis RS, Ellner JJ. Duration of fever during treatment of infective endocarditis. Medicine 1992;71:52-7. [2.] Chambers HF, Korzeniowki OM, Sande MA. Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts. Medicine 1983;62:170-7. [3.] Hecht SR, Berger M. Right-sided endocarditis in intravenous drug users. Prognostic features in 102 episodes. Ann Intern Med 1992;117:560-6. [4.] Marantz PR, Linzer M, Feiner CJ, Feinstein SA, Kozin AM, Friedland GH. Inability to predict diagnosis in febrile intravenous drug abusers. Ann Intern Med 1987;106:823-8. [5.] Weisse AB, Heller DR, Schimenti RJ, Montgomery RL, Kapila R. The febrile parenteral drug user: a prospective study in 121 patients. Am J Med 1993;94:274-80. [6.] Samet JH, Shevitz A, Fowle J, Singer DE. Hospitalization decision in febrile intravenous drug users. Am J Med 1990;89:53-7. [7.] Dubois RW, Ginzton LE. Role of echocardiography in suspected infective endocarditis in intravenous drug abusers. Am J Cardiol 1986;58:649-50. [8.] San Roman JA, Vilacosta I, Zamorano JL, Almeria C, Sanchez-Harguindey L. Transesophageal echocardiography in right-sided endocarditis. J Am Coll Cardiol 1993;21:1226-30. [9.] Graves MK, Soto L. Left-sided endocarditis in parenteral drug abusers: recent experience at a large community hospital. South Med J 1992;85:378-80. [10.] Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 19801990. A review of 210 episodes. Medicine 1993;72:90-102. [11.] Cherubin CE, Sapira JD. The medical complications of drug addiction and the medical assessment of the intravenous drug user: 25 years later. Ann Intern Med 1993;119:1017-28. [12.] Valenzuela GA, Davis TD, Pizzani E, McGroarty D. Infective endocarditis due to Neisseria sicca and associated with intravenous drug abuse. South Med J 1992;85:929. [13.] Nahass RG, Weinstein MP, Bartels J, Gocke DJ. Infective endocarditis in intravenous drug users: a comparison of human immunodeficiency virus type 1-negative and -positive patients. J Infect Dis 1990;162:967-70. [14.] Sande MA, Scheld WM. Combination antibiotic therapy of bacterial endocarditis. Ann Intern Med 1980;92:390-5. [15.] Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother 1990; 34:1227-31. [16.] Chambers HF, Miller RT, Newman MD. Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: two-week combination therapy Ann Intern Med 1988;109:619-24. [17.] DiNubile MJ. Short-course antibiotic therapy for right-sided endocarditis caused by Staphylococcus aureus in injection drug users. Ann Intern Med 1994;121 :873-6. [18.] Greenman RL, Arcey SM, Gutterman DA, Zweig RM. Twice-daily intramuscular ceforanide therapy of Staphylococcus aureus endocarditis in parenteral drug abusers. Antimicrob Agents Chemother 1984;25:16-9. [19.] Dworkin RJ, Lee BL, Sande MA Chambers HF. Treatment of right-sided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampicin. Lancet 1989;2(8671):1071-3. [20.] Ciprofloxacin resistance and staphylococcal endocarditis [Letter!. Lancet 1989;2(8678-9):1525-6. [21.] DiNubile M. Surgery for addiction-related tricuspid valve endocarditis: caveat emptor. Am J Med 1987;82:811-3. [22.] Hart RG, Foster JW, Luther MF, Kanter MC. Stroke in infective endocarditis. Stroke 1990;21:695-700. [23.] Tuazon CU, Sheagren JN. Staphylococcal endocarditis in parenteral drug abusers: source of the organism. Ann Intern Med 1975;82:788-90. [24.] Welton DE, Young JB, Gentry WO, Raizner AK, Alexander JK, Chahine RA, et al. Recurrent infective endocarditis: analysis of predisposing factors and clinical features. Am J Med 1979;66:932-7.

DAWN E. DEWITT, M.D. is acting assistant professor in general internal medicine at the University of Washington School of Medicine, Seattle. She is the ambulatory student clerkship coordinator at the University Medical Center and coordinates community and rural residency rotations. Dr. DeWitt received a medical degree from Harvard Medical School, Boston, and served a residency in internal medicine at the University of Washington.

DOUGLAS S. PAAUW, M.D. is associate professor in general internal medicine and serves as the medicine clerkship director at the University of Washington School of Medicine. He received his medical degree from the University of Michigan Medical School, Ann Arbor.

Address correspondence to Dawn E. DeWitt, M.D., Department of Medicine, University of Washington Medical Center-Roosevelt, 4245 Roosevelt Way, NE, Seattle, WA 98105.

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