OVERVIEW: What every practitioner needs to know
Are you sure your patient has infective endocarditis? What should you expect to find?
Injection drug use is a universal problem. It has been estimated that more than 200 million people (approximately 5%) use illicit drugs. In the United States, a survey shows that 19.5 million people 12 years of age or older (8.2% of the population) used illicit drugs in the month prior to the survey.
This imposes a higher risk for multiple infections, in particular endovascular, soft tissue and viral infections, such as HIV and Hepatitis C. Although infections in injection drug users (IDU) share similar characteristics to non-intravenous drug users, few special features are important to distinguish.
Infective endocarditis in an active intravenous (IV) drug user can be divided in different scenarios based on location:
Right-sided endocarditis is the most common presentation (70% of all cases), which involves the tricuspid valve, and a murmur is not always present. Symptomatology is non-specific and includes fever, pleuritic chest pain, dyspnea, and non-productive cough. It has a good prognosis, with a survival rate over 95%.
Left-sided endocarditis is very similar to disease in non-IV drug users, but it can be associated with systemic manifestations from embolic events. Special attention is necessary to renal, splenic and central nervous system involvement, as they can mask the initial presentation.
Arriving to the diagnosis of infective endocarditis requires a high index of suspicion, as this condition presents with very subtle symptoms and signs, especially early in the disease process.
How did the patient develop infective endocarditis? What was the primary source from which the infection spread?
The incidence of infective endocarditis in IDU is estimated to be 1-20 cases per 10000 injection users per year.
Infection is acquired from the drug user’s own flora via direct inoculation from skin or mucosa. This is associated with a lack of hygiene and insufficient cleaning prior to the injection, especially injections at body sites with high bacterial burden such as the inguinal and femoral regions. Other factors include inexperienced users, needle licking, use of running water that can contaminate the injection equipment, the drug itself, or adulterants.
An initial transient bacteremia, leading to seeding of a non-bacterial thrombotic vegetation at a previously injured endothelial surface, is the typical trigger for the initiation of infection.
Subsequently, the vegetation becomes colonized, developing and including fibrin, platelets, and bacteria adhering to the complex. Because of the composition of the vegetation, bacteria become protected from host defenses and tend to perpetuate the infectious process.
Over time, infection may progress with local destruction, distortion, and potential embolization to distant organs. An immunologic response can be seen with immune complex development. This phenomenon is usually seen in the subacute phase. However, such a response is less common now as the diagnosis of endocarditis is made earlier during the disease process.
In right-sided endocarditis, usually seen with a normal valve (based on autopsy series), it is postulated that intrinsic pulmonary hypertension secondary to lung parenchymal damage represents a risk factor, along with the direct effect of the injected substance. In females, the mitral valve is a common location if mitral valve prolapse is present prior to the infectious process.
Among injection drug users, which individuals are at greatest risk of developing infective endocarditis?
Risk factors include:
Concomitant infection at other sites
Previous history of infective endocarditis
Staphylococcus aureus colonization
HIV infection with CD4 count lower than 200 cells per cubic millimeter
Male gender (ratio varies from male to female ratio about 2:1 to 5:1)
Beware: there are other diseases that can mimic infective endocarditis in the injection drug user:
Acute rheumatic fever/rheumatic heart disease (RHD)
Systemic lupus erythematosus
Primary valvular and cardiac neoplasms
What laboratory studies should you order and what should you expect to find?
Results consistent with the diagnosis
Blood cultures: three sets of blood cultures over 24 hours, ideally prior to initiation of antibiotics (at least 2 sets of cultures prior to initiation of antibiotics) are consistent with the diagnosis. In the event of possible contamination or if antibiotics were initiated prior to culturing, more cultures may be useful to increase the likelihood of detecting a possible bacteremia. In general, newer techniques have improved the yield of positive cultures to more than 90%, and cultures tend to become positive in a shorter time.
Once an organism is identified, special attention to antimicrobial susceptibility is needed to select the best therapy. Ideally, the choice is based on determination of the minimal inhibitory concentration (MIC) of the antibiotic.
Results that confirm the diagnosis
For patients whose blood cultures fail to reveal the causative pathogen, some newer modalities, including molecular techniques such as PCR or checking serology for specific unusual pathogens may be helpful. Other useful tests, such as electrocardiogram, chest radiography, urinalysis, renal function, computed tomography (CT) Scans, or magnetic resonance imaging (MRI), contribute less to diagnosis but are helpful to determine the extent of the disease and to identify complications. Tests such as rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein, and cardiac troponins, are helpful for follow-up.
What imaging studies will be helpful in making or excluding the diagnosis of infective endocarditis in the patient?
The echocardiogram has become the most used imaging study to visualize the cardiac structures; it is readily available with no radiation exposure. There are two different modalities:
Transthoracic echocardiogram (TTE), wherein the transducer is placed on the chest wall. Pros include easy access, non-invasiveness and no need for sedation. Cons include lower yield detecting vegetations less than 5mm or “blind spots”. (Sensitivity is 46% and specificity 95%). Cost: $125-$500.
Transesophageal echocardiogram (TEE), which delivers better images as the transducer is placed at the retrocardiac space via the esophagus. Pros include visualization of smaller vegetations. Cons include required anesthesia and more advanced training of personnel. (Sensitivity is 93% and specificity is 96%). False negative rate is about 15%, especially with small vegetations, technical problems, or because of the location of vegetation in relation to the location of the transducer. Cost: $500-$1,000. Previous cost effectiveness analysis suggests that performing a TEE should be the first test, at least for patients with Staphylococcus aureus bacteremia as it helps with detection of small vegetations and complications that may lead to surgical treatment (such as valve perforation and intracardiac abscess).
Identification by histopathology remains the gold standard for diagnosis of vegetations (even this has a variable yield based on predisposing factors, location and causative pathogens).
What consult service or services would be helpful for making the diagnosis and assisting with treatment?
Management of antimicrobials by an infectious disease specialist
Consultations with a cardiologist and a cardiac surgeon (specially for patients with a previous mechanical valve and complicated cases including involvement of multiple valves, myocardial involvement, valve rupture, antimicrobial failure, major embolic events, multidrug resistant bacteria, persistent bloodstream infection and cardiac decompensation) should be considered early in the course of treatment.
If you decide the patient has infective endocarditis, what therapies should you initiate immediately?
The management of endocarditis becomes a multidisciplinary approach and includes the participation of specialties such as cardiology, infectious diseases and cardiac surgery. The latter should evaluate the patient early in the course to be prepared to operate in the event of local cardiac complications, such as large vegetations, prosthetic valve infections, involvement of multiple valves, mycotic abscesses, and valve or valve complex rupture. Surgery may also be required when there are major embolic events, failure of medical therapy, or infections unlikely to respond to medical management, such as those due to highly resistant pathogens or fungi.
The main therapy is parenteral antibiotics, which should be initiated after obtaining adequate blood cultures. In selected cases, urgent intervention is required for treatment of local cardiac complications.
1. Anti-infective agents
If I am not sure what pathogen is causing the infection, what anti-infective should I order?
First, obtaining cultures of multiple blood specimens before the initiation of antibiotic therapy is the optimal approach.
Vancomycin 15 mg/kg IV every 12 hours OR daptomycin 6-10 mg/kg IV every 24 hours should be given.
In settings in which methicillin resistant S. aureus (MRSA) is not present in the community, consider nafcillin or oxacillin, 2 g IV every 4 hours.
Consider broadening coverage (gram-negative, including anti-pseudomonal or fungal antibiotics) on the basis of patient risk factors. Once susceptibilities are known, therapy should be adjusted based on renal function (based on creatinine clearance).
Treatment for 4-6 weeks is recommended. Uncomplicated, right-sided endocarditis due to methicillin-sensitive S. aureus has been successfully treated with a 2 week regimen of combination intravenous beta-lactam plus aminoglycoside. An oral regimen of ciprofloxacin plus rifampin for 4 weeks was also demonstrated to be effective for susceptible S. aureus.
In the following situations, a full treatment with 6 weeks should be provided, regardless of the location: MRSA infection, vegetations over 2cm, embolic events, poor response based on symptoms or persistent bacteremia at 96 hours, and HIV patients with CD4 count lower than 200.
See Table 1. Treatment of specific types of endocarditis.
2. Other key therapeutic modalities
Surgery may be indicated in patients with native valve endocarditis and one or more of the following complications:
Heart failure, moderate to severe related to valvular dysfunction
Severe aortic or mitral regurgitation with abnormal hemodynamics
Endocarditis due to fungal organisms
Endocarditis due to highly resistant organisms or bacteria that respond poorly to antibiotics
Perivalvular infection with abscess or fistula formation
Extrapulmonary embolic events while on appropriate antibiotic regimen OR associated with a large vegetation (larger than 1 cm in diameter)
Ethical and practice problems can be encountered in surgical candidates, as this group represents a high risk for complications if a prosthetic device is infected after valve replacement. In some instances, it is advised to defer surgery. Also, it is important to consider evaluation for a drug rehabilitation program.
What complications could arise as a consequence of Infective endocarditis in the infection drug user?
What should you tell the family about the patient's prognosis?
Septic pulmonary emboli (with right-sided endocarditis)
Pneumothorax (associated with septic pulmonary emboli)
Pneumonic consolidations and pleural effusions
Congestive heart failure
Myocardial infarction due to coronary emboli
Spinal epidural abscess
Immune-complex mediated glomerulonephritis
Osteomyelitis and septic arthritis
The family should be informed that:
Right-sided endocarditis carries a good prognosis with a survival rate greater than 90%.
Left-sided endocarditis has a worse prognosis.
Vegetations larger than 2 cm are associated with worse outcomes.
Fungal infections have a higher mortality.
It is unclear if the presence of comorbidities lead to a worse outcome.
What if blood cultures are negative?
Most of the studies refer to non-IDU endocarditis cohorts.
This group of patients represents a major diagnostic challenge for antibiotic regimen and duration of therapy.
In a previous study, up to 20% of cases diagnosed by strict criteria had negative cultures.
This is because of one or more of the following scenarios:
Inadequate microbiological techniques
Previous administration of antibiotics prior to blood cultures are obtained (this can reduce the yield of a positive result to 35-40%)
Antibiotics should be selected based on clinical presentation, course of illness, and epidemiological features.
Duration of antibiotics should be continued for at least 6 weeks.
Based on current IE management guidelines, patients can be divided into the following groups:
Native valve IE
Acute presentation of native valve endocarditis: coverage for S. aureus
Subacute presentation: coverage for S. aureus, viridans group streptococci, and enterococci
Based on the previous, also consider coverage for HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species)
Prosthetic valve present
Less than 1 year from valve replacement: coverage for S. aureus
If within 2 months of replacement, consider coverage for possible hospital acquired gram-negative bacteria.
More than 1 year of valve replacement: coverage for S. aureus, viridans group Streptococcus
Most common organisms in IDU are Staphylococcus aureus, Coagulase-negative staphylococci, β-hemolytic Streptococci, fungi, aerobic gram-negative bacilli (including Pseudomonas spp), polymicrobial.
Another group to consider is uncommon or rare pathogens
Bartonella species (>3% of all culture negative endocarditis in previous reports), Chlamydia, Coxiella burnetii, Brucella species, Legionella species, Tropheryma whippleii, non-candida fungi
Non-infectious causes include neoplasia associated, autoimmune associated (especially anti-phospholipid syndrome), post valvular surgery, and miscellaneous causes.
Serologic and tissue testing (i.e., polymerase chain reaction [PCR] techniques) can help in diagnosis for this group.
How does the patient contract infective endocarditis and how frequent is this disease?
Estimated incidence is 1.5-3.3 cases per 1000 injection drug users per year. There is no seasonal variation.
Direct inoculation from skin and mucosa with the injection drug user’s own flora or associated to injection paraphernalia or drug contamination is the mode of spread. Wilson and colleagues showed that IE is more common among IDU with advanced HIV even after accounting for injection drug use behaviors, (Odds Ratio of 3.61). Similar results are seen in a study from Miro and colleagues.
What pathogens are responsible for Infective endocarditis in the injection drug user?
Most infections are caused by S. aureus and streptococcus species. In a series from the Detroit Medical Center:
S. aureus 60.8% (both MSSA and MRSA)
Streptococcus species isolated in 16.2% of cases (including S. pyogenes, Group B and G Streptococcus, and Enterococcus)
Gram-negative bacteria: Pseudomonas aeruginosa (up to 13.5% of cases) and Serratia marcescens; Pseudomonas was associated with the use of tripelennamine and pentazocine (known as the “Ts and the blues” or TaBs) and tap water use.
Infective endocarditis is known to be one of the few entities that can be associated with a polymicrobial infection. In one series from the Detroit Medical Center, 8% of cases were due to multiple pathogens.
Licking the needle may predispose to infections with oral flora, including Eikenella spp, Neisseria sicca, and Rothia dentocariosa.
Anaerobes, including Eikenella, Fusobacterium spp, Clostridium, and bacteroides. Other causative agents are less common, including Corynebacterium (Archanobacterium) hemolyticum, C. jeikenium, and C. diphtheriae.
There are increasing reports of fungal infections of Candida spp, in particular C. parapsilosis and C. tropicalis.
How do these pathogens cause infective endocarditis in the injection drug user?
The pathophysiology of endocarditis typically involves a transient bacteremia from the oral cavity, genitourinary tract, or peripheral sites of infection with consequent seeding at a previously damaged endothelial surface, including normal heart valves, congenitally altered valves or at the site of foreign bodies. Among injection drug users this sequence may occur with particular risk for infection of valve sites damaged during prior episodes of drug abuse-related endocarditis. Nevertheless, the major risk source of transient bacteremia among injection drug users leading to both initial and subsequent episodes of endocarditis is the non-sterile injection of a drug itself. Transient bacteremia with seeding of a normal or damaged valve leads to formation of a vegetation, a structure composed of fibrin, platelets, and bacteria that becomes protected from host defenses. With time, the process can progress to local destruction and distortion of affected structures. Embolization of vegetation fragments to the pulmonary or systemic circulation can occur. Immunologic response is also seen with immune complex development.
What other clinical manifestations may help me to diagnose and manage infective endocarditis in the injection drug user?
Most of the initial symptoms are not specific and include fever (this can be absent in cases of severe malnutrition, immunosuppression, or infection with a bacteria of low virulence), weight loss, anorexia, weakness or fatigue, chest pain, shortness of breath (due to both heart failure from valvular dysfunction and septic emboli), or genitourinary symptoms, including hematuria, flank pain, and glomerulonephritis. Musculoskeletal pain that can be localized or generalized, altered mental status, or focalization.
Recent use of intravenous drugs or damage of nasal mucosa from drug use.
Previous history of infective endocarditis and IV drug use.
IDUs tend to present earlier during the disease presentation (<1 week) than non-drug users (>2 weeks).
Cardiac exam includes a NEW murmur or a change in the characteristic of a murmur present prior to the disease. This has a variable sensitivity ranging from 35-70%. Chest radiographs can show complications related to infective endocarditis, ranging from heart failure signs, pulmonary findings that can suggest embolization or concomitant infection (a cavitation can represent pulmonary tuberculosis), and soft tissue infections.
Extracardiac findings, such as Roth’s spots, Osler nodes, and Janeway lesions, are rarely seen in this group of patients.
Splenomegaly has been reported in 10-15% of cases.
What other additional laboratory findings may be ordered?
Diagnosis requires a high level of suspicion, knowing that injection drug use increases the risk for bacteremia. The combination of risk factors, positive blood cultures, positive imaging, plus embolic events is confirmatory of an endovascular process.
The modified Duke criteria are the most commonly accepted algorithm to validate the diagnosis and have a sensitivity ranging from 66 to 100%. Infection is considered acute or chronic based on duration of symptoms and is diagnosed as right- or left-sided based on location of the valves involved. (See Table 2 and Table 3)
|Criteria||Definite Infective Endocarditis||Possible Infective Endocarditis||Not-Infective Endocarditis|
|Histologic||Vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis||Short of definite, but not rejected||No pathologic evidence of infective endocarditis with antibiotic therapy for 4 days or less|
|Bacteria||Demonstrated by culture or histology in a vegetation, or in a vegetation that has embolized, or in an intracardiac abscess||Short of definite, but not rejected||No pathologic evidence of infective endocarditis with antibiotic therapy for 4 days or less|
|Clinical- any one of following:|
|Major||2||Does not apply||Resolution of manifestations of endocarditis, with antibiotic therapy for 4 days or less or firm alternate diagnosis for manifestations of endocarditis. Does not meet criteria for possible infective endocarditis|
|Major and minor||1 major / 3 minor||1 major / 1 minor|
How can endocarditis be prevented in the injection drug user?
Stopping intravenous drug use is the best way to prevent associated infections, but achieving this goal is not always possible. Nevertheless, treating endocarditis in injection drug users provides an opportunity to intercede in this self-destructive behaviour. Recent studies have illustrated that while care of endocarditis itself in this population may be highly appropriate the opportunity to intervene in the addiction process is often inadequate. Strenuous efforts to refer these patients into programs that provide medication-assisted treatment (methadone, buprenorphine-naloxone [Suboxone]) are an imperative part of treating injection drug-related endocarditis.
Those patients with prior endocarditis who overcome addiction and cease injection drug use are candidates for endocarditis prophylaxis as recommended by the American Heart Association (see Chapter Prevention of Infective Endocarditis).
In those instances where addiction treatment is rejected, risk reducing strategies (syringe-exchange programs, educational interventions for improvement of techniques and use of paraphernalia) and providing naloxone for overdose treatment can help reduce future infections and death due to overdose.
WHAT'S THE EVIDENCE for specific management and treatment recommendations?
Baddour, LM, Wilson, WR, Bayer, AS. “Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association: endorsed by the Infectious Diseases Society of America”. Circulation. vol. 132. 2015. pp. 00-00. (This document is the most recent clinical guideline used by practitioners for the management of infective endocarditis.)
Gordon, R, Lowy. “Bacterial Infections in Drug Users”. N Engl J Med. vol. 353. 2005. pp. 1945-54. (Excellent overview of bacterial infection in those who use illicit drugs.)
“Infections in Injection Drug Users”. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2010. pp. 3875-90. (Nice textbook chapter on the subject.)
Brown, PD, Levine, DP. “Infections in Injection Drug Users”. Infectious Disease Clinics of North America. vol. 16. 2002 Sept. pp. 735-92. (Details the Detroit experience and nice review of the topic, in general.)
Crane, LR, Levine, DP, Zervos, MJ, Cummings, G. “Bacteremia in narcotic addicts at the Detroit Medical Center. I. Microbiology, epidemiology, risk factors, and empiric therapy”. Rev Infect Dis. vol. 8. 1986. pp. 364-73. (Older paper, but a classic one showing the risks for bacteremia in those who use intravenous drugs.)
Wilson, LE, Thomas, DL, Astemborski, J, Freedman, TL, Vlahov, D. “Prospective study of infective endocarditis among injection drug users”. J Infect Dis. vol. 185. 2002. pp. 1761-6.
Chambers, HF, Morris, DL, Tauber, MG, Modin, G. “Cocaine use and the risk for endocarditis in intravenous drug users”. Ann Intern Med. vol. 106. 1987. pp. 833-6. (Paper dealing with cocaine use and risk of endocarditis.)
Chambers, HF, Miller, RT, Newman, MD. “Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: two-week combination therapy”. Ann Intern Med. vol. 109. 1988. pp. 619-24. (Novel approach shown to be effective in intravenous drug users who classically left the hospital before standard regimens of 6 weeks of anti-staphylococcal therapy could be accomplished. However, only valid for right-sided endocarditis.)
Rosenthal, ES, Karchmer, AW, Theisen-Toupal, J, Castillo, RA, Rowley, CE. “Suboptimal Addiction Intervention for Patients Hospitalized with Injection Drug Use-Associated Endocarditis”. Am J Med. vol. 129. 2016. pp. 481-485. (This paper illustrates the missed opportunity for intervention in the addiction process that occurs commonly when patients are treated for injection drug use–associated endocarditis. This is an essential component of care if future episodes of endocarditis and the ravages of narcotic addiction are to be minimized.)
DRG CODES and expected length of stay
421 – Acute and subacute endocarditis
421.0 – Acute and subacute bacterial endocarditis
421.1 – Acute and subacute infective endocarditis in diseases classified elsewhere
421.9 – Acute endocarditis, unspecified
424.9 – Endocarditis, valve unspecified
424.90 – Endocarditis, valve unspecified, unspecified cause
424.91 – Endocarditis in disease classified elsewhere
424.99 – Endocarditis, other
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has infective endocarditis? What should you expect to find?
- How did the patient develop infective endocarditis? What was the primary source from which the infection spread?
- Among injection drug users, which individuals are at greatest risk of developing infective endocarditis?
- Beware: there are other diseases that can mimic infective endocarditis in the injection drug user:
- What laboratory studies should you order and what should you expect to find?
- What imaging studies will be helpful in making or excluding the diagnosis of infective endocarditis in the patient?
- What consult service or services would be helpful for making the diagnosis and assisting with treatment?
- If you decide the patient has infective endocarditis, what therapies should you initiate immediately?
- If I am not sure what pathogen is causing the infection, what anti-infective should I order?
- What complications could arise as a consequence of Infective endocarditis in the infection drug user?
- What should you tell the family about the patient's prognosis?
- What if blood cultures are negative?
- How does the patient contract infective endocarditis and how frequent is this disease?
- What pathogens are responsible for Infective endocarditis in the injection drug user?
- How do these pathogens cause infective endocarditis in the injection drug user?
- What other clinical manifestations may help me to diagnose and manage infective endocarditis in the injection drug user?
- What other additional laboratory findings may be ordered?
- How can endocarditis be prevented in the injection drug user?
- WHAT'S THE EVIDENCE for specific management and treatment recommendations?
- DRG CODES and expected length of stay