Carol A. Sulis, MD
CHAPTER OUTLINE
■ HOST DEFENSES
■ SKIN AND SOFT TISSUE INFECTIONS
■ GINGIVITIS
■ ENDOCARDITIS
■ NONCARDIAC VASCULAR INFECTIONS
■ RESPIRATORY INFECTIONS
■ HEPATIC AND GASTROINTESTINAL INFECTIONS
■ BONE AND JOINT INFECTIONS
■ NERVOUS SYSTEM INFECTIONS
■ EYE INFECTIONS
■ HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED IMMUNODEFICIENCY SYNDROME
■ SEXUALLY TRANSMITTED DISEASES
■ CONCLUSIONS
Infectious diseases are common complications of alcohol and other drug abuse (1–4). Infections can occur because of a breach in host defenses while a patient is intoxicated, by direct inoculation of blood-borne or environmental pathogens during injection drug use, or as the result of unsafe behaviors. Acute infection accounts for 60% of hospital admissions among injection drug users (referred to as IDUs in this chapter) in the United States each year and complicates a substantial proportion of hospital admissions among others who use drugs (5–8). Cellulitis, cutaneous abscesses, endocarditis, hepatitis, pneumonia, and tuberculosis have been common problems for people who use drugs for decades; malaria, wound botulism, and tetanus have become exceedingly rare; and the acquired immunodeficiency syndrome (AIDS) and infection with type II human T-cell lymphotropic virus (HTLV-II) are relative newcomers.
The two greatest challenges for the clinician are (a) to differentiate the occult or incipient infection from symptoms of intoxication or withdrawal and (b) to recognize an atypical presentation of an infection modified by defective host defenses (splenectomy or AIDS) or the patient’s self-medication with antibiotics or analgesics.
This chapter focuses on common infectious consequences of alcohol or other drug abuse. Standard texts and review articles should be consulted for detailed descriptions of the epidemiology, pathophysiology, clinical presentation, and management of infectious disorders.
HOST DEFENSES
Among IDUs, breach of local skin and mucosal barriers by the repeated injection of nonsterile materials and colonization with resistant organisms appears to be more important than deficiencies in phagocytic function or antibody response. Such repeated, nonspecific stimulation of the immune system leads to polyclonal elevation of immunoglobulin, which, in turn, can cause diagnostic confusion in caring for the patient who develops autoantibodies such as rheumatoid factor or who has a biologic false-positive test for syphilis or hepatitis C. Opioids appear to directly modulate immune response, though the magnitude of the effect and the clinical consequences remain uncertain (9–14).
Smokers have defective mucociliary function and are predisposed to the development of sinopulmonary infections caused by encapsulated organisms such as Streptococcus pneumoniaeor Klebsiella pneumoniae (15). A variety of immunomodulatory effects of alcohol have been postulated but not proven and appear to be influenced by the type and amount of alcohol ingested, duration of use, gender, genetic factors, and other comorbidities. In addition, malnutrition, micronutrient deficiency, and splenic dysfunction are common among people with alcoholism with cirrhosis, but the magnitude of their contribution to immune dysfunction is difficult to quantify. In contrast, the cell-mediated deficiencies that result from effects on T-lymphocyte function caused by infection with human immunodeficiency virus (HIV), tuberculosis, and other intracellular pathogens are well described (16).
SKIN AND SOFT TISSUE INFECTIONS
Skin and soft tissue infections are common among IDUs and often are the reason for hospital admission. The type of infection (cellulitis, abscess, or ulcer), its location and severity, and causative organisms usually are related to the duration and site of injection and local epidemiology (17–20). Clusters of infection caused by unusual pathogens have been reported from California (wound botulism and clostridial myonecrosis), Chicago (Pseudomonas aeruginosa), Detroit (Serratia marcescens), Great Britain (Clostridium novyi and Clostridium perfringens), and Western Europe (Bacillus anthracis). However, Staphylococcus aureus and groups A, C, F, and G beta-hemolytic streptococci are the organisms most often seen (1–3,21–34).
Beginning in 1999, there has been a dramatic increase in the incidence of methicillin-resistant S. aureus (MRSA) infection, increasing from 5% to 82% of cases in one study (35). Similar rates of resistance have been described in both community-onset and health care–associated invasive MRSA infection (36). Many of the community-onset isolates have discrete genetic and epidemiologic characteristics such as pulsed-field gel electrophoresis (PFGE) pattern USA 300 or 400, staphylococcal chromosome cassette methicillin resistance gene type IVa (SCCmec IVa), Panton-Valentine leukocidin production, and sensitivity to trimethoprim–sulfamethoxazole, clindamycin, and vancomycin. Up to 80% of these isolates have been associated with skin and soft tissue infections. Risk factors for acquisition include use of alcohol, methamphetamine, and injection drugs. The mainstay of therapy is incision and drainage of the wound, judicious use of appropriate antibiotics, and meticulous hygiene (37–42).
IDUs who mix their drugs with saliva or who lick their needles before injecting are particularly prone to the development of polymicrobial infections with viridans streptococci, Haemophilusspp., Eikenella corrodens, and oral anaerobes. Infection with these organisms also occurs in bite wounds and closed-fist injuries.
Repeated injection of nonsterile, potentially vasoactive opioids can cause ischemic necrosis at the injection site, rendering the damaged areas susceptible to superinfection. Similarly, both inhalation and injection of cocaine cause vasospasm with resulting areas of tissue necrosis serving as a nidus for infection. Streptococcal infection in areas of cocaine-induced tissue ischemia can cause large necrotic ulcers with extensive loss of tissue; such skin ulcers are extremely common among IDUs. Ulcers become colonized with a mixture of environmental pathogens, so surface cultures are not useful in guiding antibiotic selection.
The diagnosis of cellulitis is straightforward: Most patients have local signs of pain, redness, and swelling or induration of the skin. However, patients who delay seeking medical care while they attempt to self-medicate with antibiotics or lotions can develop extensive cellulitis, necrotizing fasciitis, or overwhelming sepsis.
Diagnosis of an abscess can be more challenging. Patients may complain of pain or tenderness at the site of a superficial cutaneous abscess and may have erythema, induration, or fluctuance of the overlying skin. A deeper abscess may surround blood vessels (especially in the neck and groin), causing local bland or suppurative thrombophlebitis, or be hidden deep in the mediastinum or epidural space. Deep neck abscess can cause internal jugular vein thrombosis, vocal cord paralysis, airway obstruction, or massive hemorrhage after eroding into the carotid artery. The presentation of deeper abscesses can be quite subtle, and diagnosis often requires radiologic imaging.
In IDUs, necrotizing fasciitis, an infection of the deep fascial structures, can be caused by Streptococcus pyogenes (group A beta-hemolytic streptococci) or a mixture of aerobic and anaerobic pathogens and most commonly originates at a soft tissue injection site. The most important diagnostic clue is the presence of pain or hemodynamic instability out of proportion to the physical findings, which may be quite trivial. Diagnosis can be delayed if the clinician discounts these complaints as evidence of drug-seeking behavior. Classic findings of high fever, crepitus, and progressive edema occur late in the course. Prompt surgical and radiologic evaluations for evidence of fasciitis are crucial for diagnosis. However, imaging studies such as plain films, computerized tomography, or magnetic resonance imaging may show only soft tissue edema and may be insufficiently sensitive to document extent of soft tissue involvement, even when gas is present. In patients with necrotizing fasciitis, treatment with antibiotics and urgent surgical exploration with débridement are required to minimize morbidity and maximize the patient’s chance for survival.
In all other cases of skin and soft tissue infection, empiric antibiotic therapy should be directed at the most likely pathogen and then modified when results of cultures of blood or aspirated pus become available. Early surgical evaluation and drainage can minimize morbidity and continued tissue destruction. However, the clinician should carefully evaluate lesions located in the vicinity of blood vessels (especially in the groin), because a mycotic aneurysm can masquerade as an abscess and should not be blindly incised due to the potential for massive hemorrhage.
Management of skin ulcers requires antibiotics and aggressive wound care to minimize loss of function, especially when lesions are located on the hand.
An increasing incidence of infection in large skeletal muscles has been recognized, especially among patients with AIDS (43–47). The clinical presentation resembles that of tropical pyomyositis. Such infections usually are caused by S. aureus. Pyomyositis is characterized by the presence of a suppurative collection without myonecrosis, often without prior trauma or local drug injection at the site. Patients may have fever, pain, and swelling in the involved muscle, but often there is little evidence of local inflammation. Diagnosis is made by needle aspiration of pus, with subsequent antibiotic therapy directed by culture results.
Vibrio vulnificus is an unusual cause of cellulitis, soft tissue infection, and bacteremia in cirrhotic patients who have been exposed to saltwater or shellfish (48–50). Patients complain of nausea, vomiting, fever, hypotension, shock, and hemorrhagic skin bullae. Prognosis is poor, even with aggressive antibiotic and surgical management.
Complications related to infections with the Clostridium sp. that cause botulism and tetanus are discussed later, as are epidural and splenic abscess and mycotic aneurysm.
GINGIVITIS
Acute necrotizing ulcerative gingivitis (ANUG, trench mouth, Vincent angina) is characterized by severe pain, gingival necrosis, and bleeding. Patients often have fever, malaise, and fetid breath. Though associated with a variety of oral flora, the pathogenesis remains uncertain. Development of ANUG appears to be associated with smoking, stress, immunosuppression, and poor oral hygiene. Treatment may include use of antiseptic (chlorhexidine) mouthwash, systemic antibiotics such as penicillin or clindamycin, or débridement.
Oropharyngeal lesions are a common presenting complaint among people who have used cocaine adulterated with levamisole, a veterinary antihelminthic. Agranulocytosis, cutaneous vasculitis, soft tissue infections, and leukoencephalopathy have also been described (51).
Extensive tooth decay (“meth mouth”) is common among people who chronically use methamphetamine and is thought to be due to a combination of bruxism, decreased saliva production, and poor dental hygiene (52–54). Because aggressive intervention may be required to prevent disease progression, oral health should be evaluated at each visit to facilitate recognition and expedite early referral to a dentist.
ENDOCARDITIS
(Cardiovascular complications also are addressed in Chapter 73.)
Epidemiology and Pathogenesis
Infective endocarditis (IE) is the most common cardiac complication of injection drug use (1–3,55–61). IE usually begins during an episode of transient bacteremia. In most cases, microorganisms enter the bloodstream and lodge in a thrombus overlying previously damaged or denuded endothelium. Preexisting cardiac lesions are identified in about three-fourths of patients with IE; they include mitral valve prolapse, prosthetic cardiac valves, or congenital, degenerative, or rheumatic heart disease. In contrast, endocarditis that occurs in structurally normal valves is more likely to be nosocomial in origin, caused by more virulent organisms such as S. aureus, or occur in an IDU. The resulting lesion, called a vegetation, is composed of layers of platelets and fibrin covering clumps of relatively sequestered microorganisms. Though most vegetations are located on heart valves, they can occur on any endothelial surface.
The incidence of endocarditis in the general population is about 5 per 100,000 person-years, with regional variations that reflect the prevalence of risk factors in the population. Immunodeficiency (including HIV infection) does not appear to increase the incidence of endocarditis; however, morbidity and mortality from endocarditis increase with increasing immunosuppression (62).
In the non-IDU, IE most often is caused by viridans streptococci (30% to 50%), staphylococci (40%), and enterococci (10%). In contrast, in the IDU, IE most often is caused by S. aureus(more than 50%), of which variable proportions are methicillin resistant (36,63). Streptococci (13%), enterococci (7%), and fungi, particularly nonalbicans Candida species (5%), are much less commonly involved.
Both IDUs and people with alcoholism have a higher proportion of IE caused by gram-negative bacilli such as P. aeruginosa, Pseudomonas cepacia, and S. marcescens, although their relative prevalence has significant regional variation (22,59–61,64–79). A cluster of P. aeruginosa endocarditis occurred in Chicago among patients who abused pentazocine and tripelennamine (“T’s and blues”) (74,75). This cluster was found to be associated with selective survival of the patients’ own bacterial isolates when grown in the presence of these drugs. Outbreaks of S. marcescens infection have been reported in Detroit and California, but the reason for the increased prevalence in these locations remains obscure. In one California cluster of S. marcescens endocarditis reported in the 1970s, cases were characterized by the development of enormous vegetations that caused almost complete occlusion of the valve orifice in the absence of concurrent valve destruction. Mortality in this outbreak was 70% (77,78). Underlying alcoholism is identified as a risk factor in 40% of episodes of pneumococcal endocarditis, and concurrent meningitis is present in 70% of this subgroup of patients (80–83).
Endocarditis caused by Bartonella henselae has been described in homeless people with alcoholism, IDUs, and patients with HIV (84–88). Endocarditis caused by a vast array of additional pathogens has been described in case reports (89–92).
The sustained bacteremia that characterizes IE occurs when microorganisms are released as the vegetation fragments, and the size of the vegetation is related to the type of pathogen. Organisms such as S. marcescens and C. albicans tend to produce large friable vegetations and bulky emboli.
Clinical Presentation
Clinical features usually include fever, accompanied by a panoply of cardiac abnormalities (murmur, conduction delay, congestive heart failure, and valvular dysfunction), complications from emboli or from metastatic seeding of other structures during the bacteremia (causing meningitis, brain abscess, osteomyelitis, or splenic abscess), and a wide spectrum of immune complex–mediated phenomena (arthritis, glomerulonephritis, aseptic meningitis, Osler nodes, Roth spots, splinter hemorrhages, and other manifestations of vasculitis) (93–97). Patients may complain of fever, night sweats, anorexia, arthralgias, myalgias (especially in the low back and upper thighs), and weight loss. However, the presence of IE cannot be predicted in a febrile IDU on the basis of signs and symptoms alone (98,99). Unexplained fever should prompt evaluation for endocarditis.
The most reliable clues are the presence of embolic phenomenon and visualization of vegetations on echocardiography. IDUs have a high incidence of acute IE involving a previously normal tricuspid valve (100,101). As a result, patients have pulmonary symptoms, including cough and pleuritic chest pain from septic pulmonary emboli. Pulmonary infiltrate or effusion occurs in 75% to 85%, and evidence of septic pulmonary embolization eventually is present on 90% of chest x-rays. These emboli appear as rounded infiltrates (“cannon balls”) early in the course, often in showers, and may undergo central cavitation or be complicated by empyema. Murmurs and congestive heart failure usually are absent in these patients. In contrast, IDUs with left-sided endocarditis have murmur, congestive heart failure, and stigmata of systemic embolization.
Mycotic aneurysms complicate IE in 15% of patients. Most are asymptomatic and resolve with treatment.
Diagnosis
After performing a careful history and physical examination, patients should have two or three blood cultures drawn. Hospitalization and treatment with empiric antibiotics often are recommended when adequate outpatient follow-up is uncertain.
Definitive diagnosis requires microbiologic or pathologic proof of infection by histology or by culture of a sample of the vegetation or embolus obtained at surgery or autopsy (102–105). A possible diagnosis is established by demonstrating a characteristic vegetation, valve ring abscess, or dehiscence of a prosthetic valve with echocardiography in a patient with multiple positive blood cultures obtained over an extended period (105–108). However, even a negative transesophageal echocardiogram (TEE) does not exclude the diagnosis. The probability that endocarditis is present is estimated by using major and minor criteria, as shown in Table 79-1 (105).
TABLE 79-1 CRITERIA FOR THE DIAGNOSIS OF IE (MODIFIED DUKE UNIVERSITY CRITERIA)
Adapted from Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke Criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–638.
Treatment
Effective antimicrobial therapy requires identification of the specific pathogen and assessment of its susceptibility to various antimicrobial agents. Empiric therapy should be targeted to the most likely pathogens in the clinical setting (108). Initial therapy with an antistaphylococcal antibiotic is appropriate for most IDUs. Use of vancomycin should be considered in areas with a high prevalence of MRSA or penicillin-resistant Pneumococcus. Addition of antibiotics directed against gram-negative pathogens should be considered in geographic regions where an increased prevalence of gram-negative endocarditis has been identified by local epidemiology (109).
The chosen antibiotic should be bactericidal and must achieve sufficient levels to permit passive diffusion deep into the vegetation, where microcolonies of the pathogen are located. Ultimately, antibiotic selection should be based on final culture and sensitivity results. The duration of therapy should follow standard guidelines. Most patients require a minimum of 4 weeks of intravenous antibiotics, though shorter courses can be effective in IDUs with uncomplicated tricuspid valve endocarditis. An active IDU should not be discharged with an intravascular access device. Encouraging the patient to remain in a monitored setting for the duration of therapy is one of the most challenging aspects of achieving a successful outcome.
Once effective antimicrobial therapy has been initiated, symptoms of fever and fatigue improve coincident with clearance of bacteremia. Blood cultures for streptococci and enterococci should become sterile after 1 to 2 days. Blood cultures for staphylococci should become sterile after 3 to 5 days, but can take 10 to 14 days to become sterile in patients treated with vancomycin. As a result, short-course therapy cannot be used in regimens containing vancomycin. Blood cultures should be obtained daily, until sterile. If initial blood cultures remain negative, the possibility of culture-negative endocarditis, an undrained focus of infection such as splenic abscess, or an alternative diagnosis should be explored. Diagnostic possibilities are quite extensive and are best assessed with the assistance of an infectious diseases specialist.
When sequelae of endocarditis progress despite appropriate antibiotic management, surgical evaluation is warranted. Surgical intervention should be considered for patients who demonstrate congestive heart failure because of valvular dysfunction that is refractory to medical therapy, multiple clinically relevant emboli despite antibiotic therapy for more than 2 weeks, infection caused by certain pathogens such as fungi or resistant organisms (which rarely respond to medical therapy alone), extension of myocardial abscess, inability to sterilize blood cultures, or infection or dehiscence of a prosthetic valve (110,111). Patients with valve ring abscess should be monitored for the development of conduction abnormalities. These patients may require placement of a temporary pacemaker because of the risk of developing high-grade heart block.
Outcome and Prevention
The outcome of an episode of IE is based on many factors, including age of the patient, virulence of the organism, site of the infection, presence of complications (such as congestive heart failure, renal failure, rupture of a mycotic aneurysm, cardiac arrhythmia, conduction abnormalities, or cerebral embolization), and the presence of comorbid conditions such as HIV infection. Left-sided endocarditis is associated with a worse prognosis, as is infection with gram-negative bacilli or fungi. Heart failure remains the leading cause of death.
After cure, patients remain at a substantially increased risk of reinfection, and injection drug use is the most common risk factor for recurrent native valve endocarditis. As a result, patients should follow the American Heart Association guidelines and be given prophylactic antibiotics when undergoing certain invasive procedures (112). Current guidelines recommend prophylaxis only for patients with specific high-risk cardiac conditions who undergo dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. High-risk cardiac conditions include prior endocarditis, prosthetic valve, prosthetic material used to repair valve, congenital heart disease (unrepaired, repaired within 6 months, or repaired with residual defect), or valvulopathy after cardiac transplant. Administration of antibiotics solely to prevent endocarditis is no longer recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. In addition, patients should be counseled about the importance of adopting strategies to reduce the likelihood of transient bacteremia. Other preventative measures include aggressive treatment of skin infections, emphasis on maintaining good dental hygiene, and discussion of the overall benefits of discontinuing illicit drug use.
NONCARDIAC VASCULAR INFECTIONS
Epidemiology and Pathogenesis
Both direct injury to blood vessels during injection drug use and vasospasm from cocaine use are associated with endothelial injury and thrombus formation. Bacterial seeding of the thrombus can result in septic thrombophlebitis. Alternatively, a hematoma adjacent to the traumatized or ischemic blood vessel may serve as a nidus for superinfection. An arteriovenous fistula can occur either as a result of a direct injury or from extension of local infection.
A mycotic aneurysm results when emboli to the vasa vasorum cause a mushroom-shaped swelling, especially at arterial bifurcations. Mycotic aneurysm formation classically occurs during episodes of bacterial endocarditis. The damaged arterial wall is seeded during a concurrent or subsequent bacteremia. Mycotic aneurysms complicate 15% of cases of IE. They usually are silent but may become symptomatic in 3% to 5% of patients months or years after completion of appropriate therapy (113–115).
For most noncardiac endovascular lesions, the predominant pathogen is S. aureus; however, gram-negative bacilli (especially P. aeruginosa) are reported with increased frequency in IDUs.
Clinical Presentation
When peripheral blood vessels are involved, clinical findings include fever with local pain, swelling, warmth, and induration. A bruit may be present. Infections of the peripheral vasculature can masquerade as cellulitis or subcutaneous abscess, and blind surgical incision should be avoided (116,117). Thrombosis of larger vessels can be associated with either pulmonary embolization or distal ischemia and may be confused with IE.
A patient with a mycotic aneurysm in the neck or groin may describe a painful, tender, enlarging, pulsatile mass with overlying bruit or thrill, accompanied by various constitutional symptoms. Ischemia of a distal extremity or signs of nerve compression may be present. Two important complications include extension of infection into surrounding soft tissue with abscess formation and massive hemorrhage from aneurysmal rupture. Mycotic aneurysms in the brain complicate 2% to 4% of cases of left-sided endocarditis. Patients complain of unremitting headache, visual disturbances, or cranial nerve palsy.
Patients with endovascular infection may have sustained bacteremia and signs of clinical sepsis. Management of septic thrombophlebitis is controversial but generally includes treatment with both intravenous antibiotics and short-term anticoagulation.
Diagnosis
Successful management of a mycotic aneurysm requires early diagnosis before rupture occurs. Misdiagnosis is common, and a high index of suspicion is essential. Arteriographic confirmation remains the standard diagnostic test, though newer radiologic tools such as computed tomographic angiography with contrast enhancement and magnetic resonance angiography are being used with increased frequency.
Treatment
Empiric antibiotics can be given after blood cultures have been obtained. Antibiotic choice should reflect local epidemiology and should include an antistaphylococcal agent with additional gram-negative coverage in geographic regions where an increased prevalence of gram-negative endovascular infection has been identified by local epidemiology. The antibiotic regimen should be modified on the basis of culture and sensitivity results and usually is continued for 4 to 6 weeks.
Surgical excision of an enlarging mycotic aneurysm and surrounding infected tissue may be necessary to avoid the catastrophic sequelae of a rupture. Intrathoracic, intraabdominal, and peripheral mycotic aneurysms often require surgical excision. Cerebral mycotic aneurysms usually heal with medical therapy alone but may require neurosurgical intervention if enlarging or bleeding (118).
RESPIRATORY INFECTIONS
(Respiratory problems also are discussed in Chapter 77.)
Epidemiology and Pathogenesis
Many factors interfere with host defenses and predispose the patient to infection (7,8,15,119–129). Two important examples include cigarette smoke, which disrupts mucociliary function and macrophage activation, and alteration in the level of consciousness accompanied by depressed the gag reflex, which compromises airway protection and permits aspiration of oropharyngeal flora. In addition, alcoholism is associated with oropharyngeal colonization with enteric gram-negative bacilli and abnormal phagocyte function. Injection drug use is associated with a large number of insults, including drug-induced bronchospasm, pulmonary edema, and the development of various types of foreign-body granuloma (cotton, starch, or talc) from contaminants in injected materials. Such nonspecific abnormalities on chest radiograph contribute to diagnostic confusion in a febrile patient with cough. An increased risk of exposure to certain pathogens because of lifestyle (e.g., homelessness or incarceration) and the increased prevalence of HIV infection in this group contribute to the increased risk of infection.
Pneumonia
Pneumonia is present in up to one-third of IDUs evaluated for fever and complicates a variable percentage of admissions for treatment of alcohol withdrawal or cocaine intoxication (130,131). Septic pulmonary emboli associated with right-sided endocarditis or septic thrombophlebitis and tuberculosis infection are common. Most pulmonary infections are community-acquired episodes of pneumonia, caused by common respiratory pathogens such as S. pneumoniae, atypical bacteria (such as Legionella or Chlamydia), oral anaerobes, or viruses (132–134). IDUs have an increased incidence of pneumonia caused by Haemophilus influenzae, S. aureus, and P. aeruginosa, especially those coinfected with HIV (125–129,135–140).
Patients with HIV are at higher risk of developing pneumonia. Though Pneumocystis (carinii) jiroveci is the major pulmonary pathogen in patients with AIDS, pneumonia caused by Mycobacterium tuberculosis, Mycobacterium avium–intracellulare, cytomegalovirus, and common bacterial and viral pathogens occurs with increased frequency in this group. Lung abscesses can complicate aspiration pneumonia, necrotizing bacterial pneumonia, or septic emboli. Left-sided pulmonic effusion may be a clue to an underlying splenic abscess or bacterial or tuberculous pleuritis.
Evaluation of a febrile person who uses drugs with respiratory symptoms should follow standard guidelines, with empiric management directed at likely pathogens (132,141).
Tuberculosis
Tuberculosis is a leading cause of infectious morbidity and mortality worldwide, and one-third of the world population is latently infected. In the United States, only 4% to 6% of the population has latent infections (142). Rates of active disease fell steadily until the mid-1980s, when there was a brief resurgence coincident with immigration patterns and the spread of HIV. HIV infection has contributed to the rising case rates because of the higher likelihood of reactivation as immune function decreases and because of the risk of unusually rapid progression to active disease following new (primary) infection. In addition, patients with HIV have a higher prevalence of extrapulmonary and drug-resistant disease (143–156). People who use drugs, especially people with alcoholism and IDUs, have an increased incidence of reactivation tuberculosis for reasons that are unknown (157–159). Injection drug use has been implicated in a large outbreak of multiresistant tuberculosis in New York City, where most transmission occurred in hospitals and jails (160–164). Difficulties in controlling this outbreak were compounded by homelessness and noncompliance with medical therapy.
Infection is spread by the aerosolization of acid-fast bacilli in respiratory secretions. Patients with cavitary disease are particularly infectious because of the high concentration of bacilli in their sputum. Cough-inducing procedures such as bronchoscopy, administration of aerosolized medications (including bronchodilators), and smoking (cigarettes, crack cocaine, and marijuana) can increase transmission.
The classic symptoms of pulmonary tuberculosis include cough with purulent, blood-tinged sputum and increasing malaise, with the development of night sweats and weight loss as the disease progresses. High fever, especially in the evening, is seen with decreasing frequency as the level of immunosuppression increases. Diagnosis is made by culturing M. tuberculosisfrom expectorated sputum. Nucleic acid amplification tests are promising but lack standardization. Tuberculin skin tests generally turn positive 4 to 6 weeks after primary infection but can be negative in up to 25% of patients at the time of diagnosis. Interpretation of the tuberculin test is stratified to reflect a combination of risk factors, including severity of underlying immunosuppression, and should follow standard algorithms (165–172). In vitro testing using interferon gamma release assays (IGRAs) shows promise, but concordance with tuberculin skin test results has not been established in this population (173). Various IGRAs are available, but interpretation is hampered by false-positive and false-negative results. Since no diagnostic strategy has been proven superior for the evaluation of latent tuberculosis in the HIV-infected host, decisions about which test to use may be influenced by availability, cost, and convenience. IGRAs should not be used for diagnosis of active tuberculosis because of poor sensitivity and specificity. To avoid nosocomial transmission, patients with a suspicious presentation should be isolated until the diagnosis is excluded.
Extrapulmonary tuberculosis occurs in one-sixth of normal adults and up to 60% to 80% of patients with HIV. Diagnosis is challenging because of the paucity of bacilli in the extrapulmonary sites. Histopathology classically shows giant cell granulomas with central caseating necrosis. Extrapulmonary seeding commonly causes empyema, meningitis, and vertebral osteomyelitis, and diagnosis generally requires biopsy.
Because of the long delay to obtain culture and sensitivity results, treatment usually is initiated before a definitive diagnosis has been established. Treatment should follow the American Thoracic Society Guidelines (166–172). Many patients are started on a four-drug regimen that includes isoniazid, rifampin, pyrazinamide, and ethambutol. Patients should be closely monitored for evidence of disease progression and for the development of treatment-related side effects, such as hepatitis or rash (174–179). The initial regimen is adjusted once sensitivities are known. Duration of therapy is based on the severity of immunosuppression and extent of disease. IDUs are at increased risk of multidrug-resistant tuberculosis (resistant to both isoniazid and rifampin). For these patients, results of sensitivity testing are crucial in planning an effective treatment regimen that should include at least two active agents.
Medication selection can be particularly troublesome in treating patients with HIV. Drugs may be poorly absorbed because of underlying enteropathy or may have significant interactions with other medications. For example, rifampin should not be used with protease inhibitors or many other medications because of its effect on hepatic catabolism. Directly observed therapy is strongly encouraged when non-adherence is anticipated and often is preferred for patients with risk factors, such as homelessness or addictive disorders. HIV-infected patients, especially those with CD4 cell counts less than 200, should be monitored closely for the development of immune reconstitution inflammatory syndrome.
Most people who use drugs are at increased risk of tuberculosis infection and should have routine tuberculin skin testing. Interpretation of the skin test result and selection of a treatment regimen should follow standard guidelines (165–172). For example, IDUs with more than 10-mm induration on skin testing might be given 6 to 12 months of chemoprophylaxis with isoniazid after active disease is excluded. IDUs with HIV might be given 12 months of isoniazid when there is more than a 5-mm induration on skin testing or after close contact with a case of infectious tuberculosis, regardless of skin test results. Many drug combinations and dosing schedules are available. Peripheral neuropathy can occur in patients treated with isoniazid, especially in those with preexisting nutritional deficiency, alcohol use, pregnancy, diabetes, renal failure, and HIV infection, and can be minimized by using pyridoxine at a dose of 25 to 50 mg per day. Rifampin can reduce methadone levels, and patients often require adjustment of their maintenance dose. IDUs with underlying hepatitis or who use hepatotoxins such as alcohol have an increased risk of developing hepatitis when using isoniazid, rifampin, or pyrazinamide. These patients should be monitored for the development of anorexia, abdominal pain, nausea, vomiting, change in color of urine or stool, or jaundice.
Most patients with underlying lung disease are at risk of increased morbidity from influenza and should be offered annual immunization (180). The efficacy of pneumococcal vaccine to prevent invasive disease varies with the population studied. Because there is a clear benefit for most patients with HIV infection and for many patients age 50 or older, pneumococcal vaccine should be administered as well, particularly in the patient with alcoholism or who smokes (181).
HEPATIC AND GASTROINTESTINAL INFECTIONS
(Hepatic and gastrointestinal disorders also are addressed in Chapters 74 and 76, respectively.)
Viral hepatitis is common among people who use injection drugs, noninjection drugs, and alcohol and has been extensively reviewed (182–189).
Hepatic cirrhosis results from an irreversible chronic injury to the hepatic parenchyma that is most often caused by alcoholism or viral hepatitis. Infection is the leading cause of death in patients with cirrhosis (4). Gram-negative enteric bacilli such as Escherichia coli, K. pneumoniae, and encapsulated respiratory pathogens such as S. pneumoniae are the most frequent cause of infection in these patients; however, severe infections with many other organisms, including V. vulnificus, Pasteurella multocida, Aeromonas hydrophila, Listeria monocytogenes, Campylobacter spp., and tuberculosis, also have been described.
Spontaneous bacterial peritonitis (SBP) is a common and potentially fatal infectious complication in patients with cirrhosis and ascites. Pathogenesis involves translocation of bacteria from the gut to mesenteric lymph nodes and is associated with deficiencies in humoral response and phagocytic function (190,191).
Diagnostic paracentesis should be performed in patients with ascites who have fever. Analysis of ascitic fluid should include Gram stain and culture for bacteria, mycobacteria, and fungi; measurement of albumin; absolute and differential white blood cell count; and cytopathology. Empiric antibiotic therapy is directed against suspected pathogens and should be refined once culture results become available. Because gram-negative enteric bacilli and S. pneumoniae are the most common cause of infection in these patients, a second-generation cephalosporin and a combination of fluoroquinolone plus clindamycin or metronidazole are common starting regimens. Data from two small studies showed that patients with SBP who develop renal failure had a survival advantage when treated with intravenous albumin; but risks and benefits have not been confirmed in large trials (192). Patients who have a low ascitic fluid protein or more advanced liver disease are at increased risk of developing SBP. Some authorities recommend the use of prophylactic antibiotics to prevent SBP in this subset of patients as well as those with a prior episode of SBP.
Tuberculous peritonitis, which is uncommon, usually is diagnosed by peritoneal biopsy and culture.
BONE AND JOINT INFECTIONS
Osteomyelitis
Most microorganisms can infect bone. Frequent pathogens include S. aureus (60%), Staphylococcus epidermidis (30%), streptococci, gram-negative bacilli, anaerobes, mycobacteria, and fungi (10%), and prevalence is related to mode of acquisition. Infection can occur by hematogenous seeding, by introduction after surgery or trauma, or by spread from a contiguous focus (193–199). In adults, hematogenous spread of bacteria frequently involves the spine because of the vascularity of the vertebrae. Vertebral osteomyelitis in IDUs usually involves the lumbosacral and cervical spine. Common pathogens include S. aureus, gram-negative bacilli (including P. aeruginosa), and fungi. Though the original source of these infections may be unknown, most are seeded hematogenously during an episode of bacterial endocarditis or locally from a contiguous soft tissue focus.
Adults may develop osteomyelitis of the hand caused by mouth flora (including Staphylococcus spp., E. corrodens, P. multocida, and oral anaerobes) associated with local trauma after bite wounds or closed-fist injury.
Patients with osteomyelitis complain of focal pain and tenderness. Fever is present in two-thirds of patients; erythema, warmth, and swelling are variably present. Lack of signs and symptoms frequently results in a delay in diagnosis.
In vertebral osteomyelitis, associated symptoms result when inflammation extends beyond the spine to cause retropharyngeal abscess, mediastinitis, subdiaphragmatic or iliopsoas abscess, meningitis, or epidural abscess with evidence of spinal cord compression (200). Spinal tuberculosis (Potts disease) is relatively indolent, and patients may have late sequelae and extensive vertebral destruction.
Diagnosis of osteomyelitis is made by biopsy and culture of bone. Computed tomography scan and magnetic resonance imaging are helpful in determining the extent of involvement but are not specific. Blood cultures often are negative, especially when the osteomyelitis resulted from hematogenous seeding during a remote bacteremic infection (such as endocarditis). Antibiotics alone may be sufficient therapy to cure acute osteomyelitis and should be chosen on the basis of isolated pathogens. Use of empiric therapy is suboptimal because of the wide range of potential pathogens. Surgical débridement generally is required for cure when the infection has been present for longer than 6 weeks (chronic osteomyelitis).
As noted earlier, establishing a regimen that is mutually acceptable to the patient and clinician is challenging because of the requirement for prolonged intravenous therapy. This challenge is compounded by the tendency for many physicians to undertreat associated bone pain symptoms; therefore, consultation with a pain management specialist may be beneficial.
Septic Arthritis
Septic arthritis occurs when bacteria seed joints previously damaged by trauma, instrumentation, osteoarthritis, or chronic inflammatory conditions. Infection with S. aureus is most common, though infection with many other organisms has been reported. Arthrocentesis with culture and microscopic examination of joint fluid are required for diagnosis. Differential diagnosis includes gonorrhea, crystal arthropathy, and a variety of noninfectious etiologies.
Two particular syndromes are more common among IDUs than in the normal population and involve fibrocartilaginous joints, which are most susceptible to hematogenous seeding.
Septic arthritis of the sternoclavicular joint caused by P. aeruginosa has been reported primarily in IDUs. Most cases occur without identification of an antecedent infection. Symptoms may be present for several months before the patient seeks evaluation. Complaints include fever, tenderness and swelling over the joint, and decreased range of motion of the ipsilateral shoulder (201). Another unusual presentation is of septic arthritis of the sacroiliac joint or symphysis pubis. Symptoms include fever and various combinations of hip, groin, thigh, or lower abdominal pain that is exacerbated by walking (202–204). In such cases, infection may spread from the joint to contiguous soft tissues and bone. Treatment may require exploratory arthrotomy, with surgical débridement of infected material followed by prolonged antibiotic therapy directed at isolated organisms.
NERVOUS SYSTEM INFECTIONS
People who use drugs are prone to a variety of central nervous system manifestations that may have an infectious origin. Such manifestations are easily missed if symptoms are mistakenly attributed to intoxication or withdrawal. Delirium, acute confusional states, encephalopathy, or coma may accompany overdose, intoxication, infection, or a large number of noninfectious etiologies. Central nervous system mass lesions, seizures, hemorrhage, stroke syndromes, transverse myelitis, and peripheral neuropathies have a similarly broad differential. Clinical features should guide diagnostic strategies, with management based on results of lumbar puncture and neuroradiologic imaging (205).
Endocarditis is the most common cause of central nervous system symptoms in IDUs and can cause meningitis (aseptic or purulent), brain abscess from septic emboli, or hemorrhage from rupture of a mycotic aneurysm. Bacteremia during IE can cause vertebral osteomyelitis, which, in turn, can be complicated by epidural abscess, with evidence of cord compression (206).
Brain abscess and subdural empyema in the absence of endocarditis usually are caused by a varied group of pyogenic bacteria; however, infection with many other organisms, including Nocardia, Aspergillusspp., Cryptococcus, mucormycosis, tuberculosis, and Toxoplasma gondii, has been reported, especially in patients coinfected with HIV. Etiology often involves extension from a contiguous focus in the mastoid, ear, or paranasal sinuses; seeding of a preexisting subdural hematoma during an episode of transient bacteremia; or direct inoculation of the subdural space after a traumatic wound. A patient with brain abscess may have nonspecific symptoms such as headache or personality change, and an abscess can attain enormous size before diagnosis. Management includes antibiotics and drainage, if indicated.
In most cases, patients with HIV who have ring-enhancing mass lesions in the brain and appropriate clinical presentation are treated empirically for toxoplasmosis. Symptoms that worsen or fail to improve after 2 weeks should prompt more aggressive evaluation, including consideration of brain biopsy.
Meningovascular syphilis has been reported in a number of patients with HIV, despite presumably effective therapy for primary syphilis infection, and it should be considered in young people who present with a new stroke (207,208).
Contamination of skin ulcers with spores of Clostridium spp. can cause neurologic symptoms from elaboration of neurotoxins.
Wound botulism is caused by contamination of injection sites or skin ulcers with Clostridium botulinum that release botulinum toxin (209–212). Toxin is absorbed, disseminated, and ultimately binds to specific receptors, where it blocks acetylcholine release, resulting in a descending, symmetric, flaccid paralysis. Fewer than 100 cases were reported between 1951 and 1993. However, over the past 15 years, there has been a dramatic increase in reported cases among IDUs who injected black tar heroin, the dark, gummy substance derived from crude preparations of opium that may be contaminated by spore-containing adulterants such as dirt.
Diagnosis is established by recovering C. botulinum from the wound or by detecting toxin in serum, but negative findings do not exclude the diagnosis. Treatment with trivalent or type-specific antitoxin can limit disease progression. Involvement of motor neurons causes respiratory failure, and patients may require respiratory support for several months until synapses are regenerated. Botulism has been reported in a patient with colonization of the paranasal sinuses after intranasal cocaine use (213).
Tetanus is caused by the release of a potent neurotoxin by Clostridium tetani at the site of a wound in a person who lacks protective antibody (214–216). Wounds contaminated by dirt, feces, or saliva provide an appropriate anaerobic milieu for these vegetative bacteria. Until the mid-1990s, approximately 100 cases of tetanus per year were reported in the United States. However, since 1995, fewer than 50 cases of tetanus per year have been reported. Most have been associated with acute injury (70%) or chronic wounds (26%). Fifteen to eighteen percent of the reported cases were in IDUs who lacked a history of an acute injury but did inject black tar heroin and presented with infected subcutaneous injection sites. Toxin travels up the axon to spinal neurons, where it blocks the release of glycine and other neurotransmitters used to inhibit afferent motor neurons. Binding results in unrestrained nerve firing with sustained muscle contractions and rigidity. Binding is irreversible, and recovery requires generation of new axon terminals. Symptoms begin 7 to 21 days after injury. Early symptoms of trismus (lockjaw) progress to dysphagia, hydrophobia, and drooling, followed by opisthotonos, with painful flexion of the arms and extension of the legs. The patient remains conscious. Very rarely, localized tetanus can cause weakness limited to a single extremity, but this weakness usually progresses to generalized tetany. Management should include antibiotics, aggressive wound débridement, tetanus immune globulin, and supportive care. Prevention requires protective antibody levels. All patients should be immunized with tetanus toxoid every 10 years after a primary series (or immediately after a high-risk wound if more than 5 years has elapsed since the last booster).
EYE INFECTIONS
IDUs have an increased incidence of bacterial and fungal endophthalmitis as a complication of IE. Many investigators have reported C. albicans endophthalmitis as part of a syndrome of disseminated candidiasis in IDUs who injected “brown heroin,” presumably related to fungal contamination of the lemon juice used to dissolve the drug (217). The most commonly reported bacterial causes include S. aureusand Bacillus cereus.
Symptoms of endophthalmitis include acute onset of blurred vision, eye pain, and decreased visual acuity, similar to the symptoms in people who do not use drugs. Diagnosis requires a high index of suspicion; aggressive evaluation and management are required to salvage vision (218).
Cytomegalovirus retinitis is the most common serious intraocular complication of AIDS and generally occurs after reactivation of latent infection in patients with CD4 cell counts of less than 50, especially those not receiving antiretroviral therapy. Disease is characterized by retinal necrosis and edema that begins peripherally in the eye and may remain asymptomatic until there has been significant retinal destruction or detachment. Symptoms of blurring or loss of vision, floaters, or flashing lights in one or both eyes should always be evaluated with dilated ophthalmoscopy. Characteristic retinal changes include yellow-white, fluffy exudates with associated hemorrhage. Therapy with oral, intravenous, or intraocular antiviral agents can reduce the risk of vision loss. However, patients may develop significant intraocular inflammation associated with immune recovery (immune recovery uveitis) and require aggressive management to prevent permanent loss of vision.
HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED IMMUNODEFICIENCY SYNDROME
Tremendous advances have been made in our understanding of the pathophysiology, diagnosis, and management of HIV infection and AIDS since the original description, in 1981, of a cluster of homosexual men with P. carinii pneumonia (PCP) and Kaposi sarcoma (219–221). Highlights include the identification of a new cytopathic retrovirus in 1983, the development of a serologic diagnostic test in 1985, and the introduction of antiretroviral therapy in 1987. Comprehensive discussions of the AIDS pandemic, including details of transmission, seroconversion, immunosuppression related to disease stage, use of antiretroviral therapy, and prophylaxis, and treatment for opportunistic infections are available (221–228).
Epidemiology and Pathogenesis
HIV infection usually is acquired through sexual intercourse, exposure to contaminated blood, or perinatal transmission; the relative frequency of each varies by country. As of December 2009, an estimated 33.3 million persons worldwide were living with HIV/AIDS, 90% in developing countries (224). As of December 2010, AIDS had been reported in 1,129,127 people in the United States, with 476,732 still alive. Among US adults with known risk factors who were diagnosed through 2010, 24% reported injection drug use, and another 7% reported sex with an IDU (223). Among children diagnosed with HIV infection through 2010, more than 90% of the cases involved transmission from an infected mother. For both men and women, the estimated number of new cases of HIV related to injection drug use has fallen slightly each year for the past several years, perhaps because of emphasis on prevention strategies.
In contrast, evidence from around the world suggests that certain behavioral and social factors are increasing the number of cases associated with unsafe sexual practices. Examples of these factors include little or no condom use, a high prevalence of multiple partners, and women’s economic dependence on marriage or prostitution. In these groups, transmission is further enhanced by a high rate of concurrent sexually transmitted infections, especially those causing genital ulcers, and a high level of viremia (viral load) when the patient first is infected (before diagnosis) and again in the late stages of illness (229).
In the past, identification of populations with high risk of exposure to HIV was based on the demographic and geographic distribution of reported AIDS cases. However, as states have implemented laboratory-initiated reporting of positive HIV viral load tests, more and more patients are being identified with a new diagnosis of HIV or AIDS without an obvious behavioral risk or exposure. This incidence reflects the increasing proportion of patients infected by a partner with unrecognized or unreported behavioral risks (230). In response, the Centers for Disease Control and Prevention (CDC) has recommended routine voluntary HIV testing for all patients aged 13 to 64 years (223,231); however, many barriers to testing remain (232,233). Testing can be postponed during acute mental health and addiction exacerbations but should be done, with appropriate communication of results, implications, and treatment options, as soon as patients are prepared to hear the results of testing even if other health problems (including addictions) are not entirely resolved.
In the United States, decreases in AIDS incidence and death began in 1996, in association with the use of potent combinations of drugs known as highly active antiretroviral therapy (HAART). However, to achieve further decreases in AIDS incidence and death, persons infected with HIV must seek testing earlier, agree to take and adhere to therapy, and actively follow risk reduction strategies to prevent further transmission (231).
Classification
Stages of HIV infection range from asymptomatic (latent) through early symptomatic infection (B symptoms) to AIDS. Classification follows CDC criteria and stratifies disease according to the CD4 cell count and the presence of various other criteria (234,235).
Primary HIV infection causes symptoms in 50% to 90% of cases, which occur 2 to 4 weeks after exposure. Symptoms of fever, adenopathy, pharyngitis, rash, and myalgias are reported by more than 50% of patients and last 1 to 4 weeks. Other nonspecific symptoms that have been reported include arthralgias, diarrhea, headache, nausea and vomiting, hepatosplenomegaly, thrush, mucocutaneous ulcers, meningoencephalitis, peripheral neuropathy, cranial nerve palsy, Guillain-Barré syndrome, radiculopathy, cognitive impairment, and psychosis (236–240).
Diagnosis
Primary HIV infection should be considered in any patient with a history of potential exposure and compatible symptoms. After performing a careful history and physical examination, the diagnosis is best established by demonstrating the presence of p24 antigen, quantitative HIV RNA (viral load), or qualitative HIV RNA in association with negative or indeterminate HIV serology. High-level viremia during the acute illness permits dissemination of virus to the central nervous system and lymphatic tissue. During this period, the patient may have no physical findings except for persistent generalized lymphadenopathy. The lymphatics are a major reservoir of HIV infection, and replication continues during the clinically latent disease stage (241,242). Plasma levels of HIV decline dramatically during the resolution of the symptomatic phase of primary HIV, presumably because of the development of humoral and cellular immune responses, and reach a nadir at 120 days (243). Seroconversion generally occurs at 6 to 12 weeks.
By 6 months after transmission, 95% of patients have developed positive HIV serology and stabilization of viral load, with levels correlating with prognosis (244–246). As the disease progresses, lymph node architecture is disrupted, releasing more HIV, with an accompanying slow but progressive decline in CD4 counts in most patients. The average life expectancy in the absence of treatment is approximately 10 years, and rates of progression appear similar by gender, race, and risk category when adjusted for quality of medical care (247–258).
However, investigators have identified a subset of asymptomatic patients (“long-term nonprogressors”) with sustained high levels of CD4 (more than 500 cells/mm3) for 7 to 10 years in the absence of antiretroviral therapy (259). Correlates of delayed progression include low viral load, preservation of lymph node architecture, increased CD8 cytolytic activity, and a vigorous HIV-specific CD+ T-cell response (260,261). One explanation for delayed disease progression involves the surface chemokine receptor CCR5, which facilitates entry of HIV into macrophages (16,262). Patients with polymorphisms in this receptor appear to progress to AIDS more slowly (10.4 vs. 6.6 years), though transmission of the virus is not affected. Homozygotes are relatively resistant to infection (263,264). Studies with agents that block viral binding to the chemokine receptors are in progress and show promise for future use as antiviral agents.
Most patients are diagnosed months or years after HIV infection. Verification of infection requires that a repeatedly positive enzyme immunoassay screening assay be confirmed by a Western blot that demonstrates at least two characteristic antigens (p24, gp41, or gp120/160).
Once the diagnosis of HIV has been established, all patients should have routine screening tests such as a rapid plasma reagin test for syphilis, tuberculin skin test, cytomegalovirus and toxoplasma immunoglobulin G serology, liver function tests, hepatitis serology, and Papanicolaou tests, in addition to tests such as chest radiograph or ophthalmologic examination as clinically indicated (265).
Treatment
The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV. Algorithms outline appropriate laboratory monitoring, including measurement of plasma HIV RNA, CD4 cell counts, and HIV genotypic drug resistance testing. Guidelines describe when to begin antiretroviral therapy (based on CD4 count and viral load), what drugs to initiate, when and how to change therapy, and special recommendations for pregnant women (226). All pregnant women should be offered counseling and testing for HIV and other sexually transmitted diseases, and women infected with HIV should be treated to maximize their health status and minimize risk to the fetus. Management of patients with HIV/HCV coinfection is particularly challenging (266,267). When simultaneously initiating HAART and treatment for an opportunistic infection such as tuberculosis or hepatitis, patients with advanced disease must be monitored for the development of the immune reconstitution inflammatory syndrome (225,268,269).
Additional guidelines provide disease-specific recommendations for the use of primary or secondary prophylactic antibiotics for the prevention of the most common, serious opportunistic infections, including PCP, toxoplasmic encephalitis, disseminated Mycobacterium avium–intracellulare complex, and tuberculosis (227). Immunizations for hepatitis A and B, influenza, and pneumococcus should be administered as needed (270). Therapeutic decisions require a discussion about the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, and carry serious potential consequences from the development of viral resistance associated with nonadherence to the drug regimen or suboptimal levels of antiretroviral agents.
Patient education and involvement in therapeutic decisions are especially critical for effective HIV treatment. Past and current high-risk behaviors and exposures that may have resulted in HIV infection should be reviewed and mitigation plans designed to prevent further transmission. Behaviors such as high-risk sexual activity or injection drug use not only increase the risk of HIV transmission to others but can expose the HIV-infected patient to opportunistic pathogens such as herpes simplex virus, cytomegalovirus, Cryptosporidium, human papillomavirus (HPV), human herpesvirus type 8, and hepatitis viruses. Ongoing high-risk sexual behavior should prompt discussions about risk reduction and be reviewed at each encounter. Continuing addictive behavior should prompt the offer of referral to addiction treatment services; a history of addictive disorder warrants review of relapse prevention efforts. Intensive follow-up may be required to assess adherence to treatment and to continue patient counseling to prevent transmission of HIV through unprotected sexual behavior and continued injection of drugs (271). In addition, the patient should receive education and counseling on how to reduce the risk of exposure to opportunistic pathogens associated with food, pets, water, travel, or the environment. It is strongly recommended that care be comanaged with an expert in HIV treatment.
The optimal chance for a prolonged response occurs when an adherent patient initiates combination antiretroviral therapy. Once the decision has been made to initiate treatment, the goals should be maximal and durable suppression of viral load, restoration or preservation of immunologic function, improvement in the quality of life, and reduction of HIV-related morbidity and mortality. Efficacy of therapy is evaluated by monitoring viral load, which should decrease 10-fold by the 8th week and become undetectable (<50 copies per mL) by 6 months after initiation of treatment.
Evidence is promising for at least the short-term efficacy of aggressive therapy on viral load and CD+ T-cell counts in patients treated at the time of acute HIV seroconversion; however, clinical trials completed to date have been limited by small sample sizes, short duration of follow-up, and the use of suboptimal treatment regimens. Ongoing clinical trials are addressing the question of the long-term clinical benefit of more potent treatment regimens for this group of patients.
The proportion of patients with each of the various AIDS-defining conditions, the rate of disease progression, the rate of AIDS deaths, and the average life expectancy have changed dramatically coincident with the widespread use of HAART and prophylaxis against opportunistic infections (272,273). In the past, patients with advanced HIV disease (defined as CD4 cell count <50 cells/mm3) had a median survival of 12 to 18 months. However, many of these patients had received no antiretroviral therapy or received nucleoside analogues only. Treatment strategies now known to prolong survival include use of HAART, use of primary and secondary prophylaxis for PCP and Mycobacterium avium– intracellulare complex, and care by a physician knowledgeable about both HIV and primary care (265,274–276). This is particularly important for older individuals in whom management of other comorbidities can complicate HIV therapy. The effect of HAART became apparent in 1996, as the need for inpatient hospitalizations declined and the incidence of AIDS-defining illnesses decreased. Nevertheless, CD4 counts and viral load remain the most important determinants of the rate of progression (277). One important new challenge is to recognize atypical presentations of opportunistic infections during HAART (272,273).
Failure of therapy at 4 to 6 months can be ascribed to nonadherence (including inability to comply with complex dosing schedules), suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Drug–drug or drug–food interactions can profoundly affect the absorption and efficacy of certain medications. For example, methadone levels can be significantly decreased when given with certain protease inhibitors (ritonavir, nelfinavir, or lopinavir) and nonnucleoside reverse transcriptase inhibitors (nevirapine or efavirenz) and often require an increase in methadone maintenance dosage. Conversely, use of maintenance methadone can significantly decrease the level of some nucleoside reverse transcriptase inhibitors (stavudine or didanosine), requiring an increase in antiretroviral dosage. Atazanavir may cause an increase in buprenorphine levels and result in sedation or mental status changes. In contrast, limited data suggest that buprenorphine needs no dosage adjustment and is less likely to be associated with adverse events when given with HAART regimens that include efavirenz (278,279). As noted previously, antiretroviral drug selection often is complicated by the development of side effects. Patients with HIV appear to have a higher incidence of drug-associated toxicity than the general population, especially when renal or hepatic dysfunction is present.
Interactions between the protease inhibitor class and other drugs and foods are extensive and often require dose modification or drug substitution. For example, concurrent therapy with rifampin can decrease the concentration of protease inhibitor by as much as 80%, so its use should be avoided to prevent development of antiretroviral resistance and treatment failure. The combination of a protease inhibitor with terfenadine, astemizole, or cisapride can result in serious cardiotoxicity; these drugs are no longer available in the United States. Overdose due to interactions between methylenedioxymethamphetamine (MDMA, ecstasy) or gamma hydroxybutyrate (GHB) and protease inhibitors has been reported. The development and severity of these adverse effects often are unpredictable; thus, assessment of toxicity should be performed frequently as part of routine follow-up care. To avoid toxic combinations, a careful review of all medications should be performed by the pharmacist whenever a new agent is added to the patient’s regimen. In addition, when side effects occur and acute intervention is required, all drugs should be discontinued simultaneously to minimize development of resistance. Patients whose therapy fails despite apparent adherence should have their regimen changed; this change should be guided by a careful review of past and current medication use and the results of drug resistance testing.
As the epidemiology of AIDS changed, investigators have studied the risks, benefits, and costs of discontinuing chemoprophylaxis against opportunistic infections (280–286). Primary prophylaxis for PCP and toxoplasmosis can be discontinued once the CD4 lymphocyte count has increased to at least 200 cells/μL for more than 3 months in response to treatment with HAART (228). Secondary prophylaxis for PCP, cryptococcosis, and toxoplasmosis can be discontinued once the CD4 lymphocyte count has increased to at least 200 cells/μL for more than 6 months in response to treatment with HAART as long as the patient has completed appropriate therapy and has no symptoms or signs attributable to these pathogens (228). Although patients who respond to aggressive antiretroviral therapy may have prolonged suppression of plasma viremia to below detectable levels, persistent viral reservoirs have been identified in peripheral blood mononuclear cells, particularly CD4 cells (287–294). This reservoir of latent virus must be considered when decisions are made about possible termination of antiretroviral therapy, as viral rebound occurs within 1 to 3 weeks in nearly all patients, is associated with an increased risk of opportunistic infection and death (295) and is generally not recommended. In addition, development of drug resistance, with possible cross-resistance to other drugs, is possible if a sustained reduction in viral load is not maintained.
Prevention
A great deal of emphasis has been placed on identification of impediments to successful adherence to chemoprophylaxis. Patients with depression, poor social support, and active addictive disorder are less likely to adhere to clinical regimens (296). Recommendations to improve adherence are discussed elsewhere (297,298). Similarly, patients with HIV who engage in sexual or substance use risk behaviors not only place others at risk of HIV infection but may place themselves at risk of acquisition of opportunistic pathogens. As noted earlier, there should be a formal, ongoing review of risk behaviors. Prevention messages should encourage sexual abstinence or the practice of the correct and consistent use of latex condoms (299–303). Patients should be encouraged to avoid sexual practices that might result in oral exposure to feces (e.g., oral–anal contact) to reduce the risk of intestinal infections (e.g., cryptosporidiosis, shigellosis, campylobacteriosis, amebiasis, giardiasis, and hepatitis A and B). Patients who inject drugs should be encouraged to stop using injection drugs and to enter and addiction treatment. Use of an opioid receptor antagonist such as naltrexone appears to be safe in patients with mild to moderate liver disease (304), and some data suggest that it may inhibit alcohol-mediated HIV entry into cells (305,306). If the patient continues to inject drugs, the importance of using a sterile syringe for every injection and the avoidance of sharing any injection-related drug paraphernalia with another person should be emphasized. Such patients should be encouraged to use a needle-exchange program or to safely discard syringes after one use. In areas where needle exchange is illegal, IDUs should be taught to clean their injection equipment with household bleach before use. Patients who are exposed to blood-borne pathogens may be eligible for postexposure prophylaxis (307–309). Similarly, health care workers who have an unprotected exposure to the blood of these patients should follow CDC guidelines for postexposure prophylaxis, including pretest and post-test counseling (310).
SEXUALLY TRANSMITTED DISEASES
The epidemiology, clinical features, diagnosis, and treatment of sexually transmitted diseases other than HIV/AIDS have been reviewed extensively (311). Though the prevalence is higher in people who use drugs, the presentation, diagnosis, and management of most sexually transmitted diseases are not profoundly influenced by drug use. One exception is that the diagnosis and treatment of syphilis in IDUs may be confounded by an increased prevalence of biologic false-positive nontreponemal screening tests such as venereal disease research laboratory or rapid plasma reagin tests for syphilis.
Recent studies suggest that an increasing number of persons, especially men who have sex with men, are participating in high-risk sexual behaviors (often while intoxicated) that place them at risk of acquiring syphilis, gonorrhea, herpes, chlamydia, HIV, and other sexually transmitted diseases (311–314). Related studies have shown that patients who report heavy drug or alcohol use are most likely to report high-risk sexual behavior and to have HIV infection or syphilis (315–321). The most common high-risk behaviors include multiple recent sexual partners and inconsistent use of condoms (322).
As noted earlier, the clinician and patient should conduct a formal, ongoing review of risk behavior (323). Prevention messages should encourage safe sex, including the correct and consistent use of latex condoms. In selected patients, use of postexposure prophylaxis may be warranted (307– 309). There are a number of potential complications from sexually transmitted diseases and other infectious diseases that can affect the pregnant woman or her fetus. Pregnant women who use drugs should be screened according to standard protocols and aggressively treated to minimize disastrous maternal or fetal outcomes (324).
Because of the synergistic effect of cigarette smoke in the development of HPV-associated cancers, patients with diagnosed HPV should be strongly encouraged to consider smoking cessation.
Type I human T-cell lymphotropic virus (HTLV-I) infection is present in widely scattered populations throughout the world and is the etiologic agent in adult T-cell leukemia/ lymphoma and HTLV-associated myelopathy. HTLV-II has been reported in IDUs and their sexual contacts, appears to be endemic in IDUs in the United States, and has not been definitively linked to a specific disorder. Patients with HTLV-II infection may be at increased risk of a variety of infections, suggesting an underlying immunologic impairment. Both retroviruses appear to be transmitted by sexual intercourse, administration of blood products, and mother-to-child transmission. No effective therapy exists, and prevention of exposure is the only known method of limiting spread (325).
CONCLUSIONS
Infectious complications in people who use drugs are more frequent, are more difficult to diagnose, and are more challenging to treat than similar infections in people who do not use drugs. Effective management requires attention to both medical and social issues. An improved outcome can be achieved by emphasizing risk reduction strategies in the context of a strong, ongoing therapeutic alliance.
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