Assessment and Management of Endocarditis Among People Who Inject Drugs in the General Hospital Setting

The opioid crisis has continued to expand in the United States. In the past two decades, the number of individuals with opioid use disorder has increased dramatically, and so has the number of people who die from opioid-related overdoses. Unfortunately, despite the availability of effective pharmacologic agents such as buprenorphine and methadone, the adoption of these medications by the health care system has been slow. There are many reasons for this slow uptake, including limited education for medical students and residents regarding substance use disorders, fragmentation of addiction treatment from general medical care, stigma against substance use disorders, and a belief that medication treatment is simply “replacing one addiction for another.” Consequently, these barriers have led to a situation in which many individuals with substance use disorders go untreated. In 2017, data from the National Survey on Drug Use and Health identified that only 7.7% of Americans with substance use disorders received any formal treatment in that year (1). These data suggest that, currently, despite the recognition that we are facing an unprecedented opioid crisis, the majority of those who could benefit from treatment are not receiving it.

However, even if these individuals are not receiving formal treatment, those with substance use disorders are indeed interfacing with the health care system in significant ways. With opioid use disorders in particular, the natural history of the illness for many patients is the development of tolerance that eventually leads to the intravenous (IV) route of ingestion. The IV route provides rapid effects, requires fewer opioids to attain the same effects, and less money is spent to achieve the same high. Unfortunately, the injection route also results in numerous medical complications that result in visiting the emergency room and hospitals for treatment. Complications include viral and bacterial infections. For viral infections, hepatitis C and HIV are the most well described (2). For bacterial infections, soft tissue infections such as abscess and cellulitis, endocarditis, osteomyelitis, and septic arthritis are examples of infections that lead individuals to seek medical care (3, 4).

Indeed, individuals with drug use disorders utilize hospitals and emergency rooms at disproportionately high rates. In a 2001 study of Medicaid recipients with drug use disorders in the state of New York, almost a third of those individuals had at least one hospital stay and, on average, had over 20 inpatient days during a one-year period (5). These numbers represent an enormous amount of utilization of hospital care. Studies have shown that once individuals with drug use disorders are admitted into the hospital, these hospital encounters incur more costs and lead to higher rates of both discharge against medical advice and readmissions within 30 days of discharge (6, 7). In addition, during the hospital stay itself, behavioral disruptions may occur, including the use of illicit drugs (8).

Since 2005, there has been a steady increase in both emergency room admissions and hospitalizations due to opioid-related complications, with a near-doubling of the number of such encounters in acute care settings (9). This increase is, at least in part, driven by the number of individuals who present for treatment for infective endocarditis, with the increase concentrated in the younger white population (10, 11). Indeed, deaths from endocarditis among individuals who inject drugs have increased threefold from 1999 to 2016 (11). Among those who died from endocarditis, the proportion of those younger than 35 years of age increased by almost threefold, representing almost 35% of all deaths. Individuals with endocarditis are at risk of numerous medical complications in addition to death (e.g., sepsis, heart failure, embolic events, and stroke) and may require valve repair surgery (12).

Unfortunately, hospitalizations for endocarditis are often not utilized as opportunities to engage patients in addiction treatment (13). In fact, most hospitals offer minimal support for the underlying substance use disorder beyond managing acute issues such as withdrawal states. Studies have shown that hospitalized patients, even though they did not present seeking treatment for their substance use disorder, are nevertheless willing to start treatment and linked to addiction treatment after discharge (14, 15).

Therefore, this article provides an overview of the long-term outcomes of endocarditis among individuals who inject drugs, as well as the relevant issues that arise during the hospitalization, including the controversy over reoperation, the use of the medications for opioid use disorder, acute pain management, linkage to ongoing treatment, and the use of outpatient parenteral antimicrobial therapy.

Endocarditis Long-Term Outcomes

Endocarditis resulting from injection drug use tends to affect younger patients with fewer medical comorbidities, as opposed to endocarditis resulting from causes other than injection drug use. In a study by Kim et al. of patients undergoing surgical treatment for endocarditis, 78 individuals with a history of injection drug use were compared with 358 individuals without any history of injection drug use (16). The overall mortality was no different between those who injected drugs and those who did not. Indeed, the mortality rate during the time immediately after surgery was noted to be lower among those who injected drugs. The superior survival in this group is likely due to their overall better physical health and lack of other medical comorbidities; yet the 5- and 10-year survival rates for those who injected drugs were 79% and 70%, respectively, and 76% and 69% among those who did not, respectively. As such, endocarditis remains a severe medical illness with significant morbidity and mortality.

Unfortunately, despite the similar mortality rate overall, those who inject drugs experience far more reinfections that, hence, necessitate far more reoperations. In the study by Kim et al., the hazard ratio of reinfection was 6.20 (95% confidence interval [CI]=2.56–15.00) among those who inject drugs compared with those who do not. However, there are no studies that have specifically examined the effects of medication treatment for opioid use disorder after the initial episode of endocarditis. In a long-term study of medication treatment for opioid use disorder compared with drug-free treatment, the use of medication led to far fewer relapses (17). As such, it is likely that patients with endocarditis who engage in medication treatment for their opioid use disorder should experience fewer relapses compared with patients who do not. However, it remains unclear whether medication treatment at the time of the initial hospitalization indeed leads to reduced mortality or rate of reinfection and reoperation. The reality, however, is that patients with endocarditis stemming from injection drug use infrequently receive treatment for their underlying addiction.

Controversy Over the Refusal to Reoperate

One consequence of the rapid increase in the number of infective endocarditis due to injection drug use is that many hospital systems are now faced with patients who present for multiple episodes of endocarditis that may require repeat valve repair surgery. For some hospitals, the policy is to decline to operate on a patient who has previously received valve repair surgery (18, 19). The rationale for this refusal is based on the idea that reoperation is futile, because such individuals will inevitably relapse and continue to inject drugs, thus necessitating numerous reoperations in the future. Given the futility of treating the sequelae of the opioid use disorder, reoperation would be considered medically inappropriate. Some hospitals now require patients to sign a contract that states explicitly that they agree not to relapse to continued injection drug use as a condition for receiving the surgery (20).

Although there are valid arguments to be made for this position, many other medical issues arise out of chronic diseases and lifestyle choices that patients refuse to or are unable to change readily. Surgeons generally would not refuse treatment for a patient with coronary artery disease stemming from cigarette smoking, poor diet, and lack of physical exercise. Although there are differences between these behaviors and those related to opioid use disorder, they share similar issues in that they are all behaviors that result from personal choice. Indeed, lifestyle choices—including diet and exercise and the consumption of alcohol, tobacco, and drugs—account for a large proportion of morbidity and mortality that individuals face. For substance use, genetic factors account for approximately 50% of the risk of developing a substance use disorder (21, 22), and once the condition advances, the individual is less able to control the behavior. Indeed, the loss of control over the behavior is the hallmark of all substance use disorders. The altered neurobiology makes the individual susceptible to relapse, even after years of abstinence, because of the emergence of cravings and exposure to triggers and high-risk situations (23). Even a highly motivated individual, therefore, may find it difficult to remain abstinent. In fact, one of the other hallmarks of substance use disorders is the persistence of the harmful use of substances despite accumulating negative consequences, both medical and psychological.

As the understanding of substance use disorders evolves from considering it a personal choice or a moral failure to that of a chronic brain disease that requires treatment, there is a consensus building that our obligation must be not only to provide adequate treatment for the medical consequences of substance use disorders but also to treat the underlying substance use disorder itself (20). For opioid use disorders specifically, there are several medications approved by the Food and Drug Administration that are highly effective in reducing all-cause mortality and overdose risk while increasing retention in treatment and suppressing illicit opioid use (24). Unfortunately, many hospital systems at this time do not offer any specific treatment for the opioid use disorder during the hospitalization. While addiction consultation services have become more common in hospitals in recent years, most patients with infectious complications from injection drug use still do not get started on medications (25, 26). As such, there is an urgent need to adequately treat the underlying opioid use disorder during and after the hospitalization, which will help ensure that the risk of relapse and reinfection to endocarditis is minimized.

Initiation of Medications for Opioid Use Disorder During Hospitalization

Evidence-based pharmacologic treatments for opioid use disorder include buprenorphine, methadone, and extended-release naltrexone (27). In the general hospital setting, buprenorphine and methadone can be readily utilized, whereas extended-release naltrexone poses numerous challenges (i.e., the need to be abstinent from opioids 7–10 days before initiation). As such, this section focuses largely on both buprenorphine and methadone. Both buprenorphine and methadone can be dispensed to patients who are hospitalized for medical and psychiatric reasons, as long as the primary admission diagnosis is not opioid use disorder, as outlined in the Code of Federal Regulations. The ordering clinician does not require any special license for dispensing either of these medications during the hospitalization, because the medication treatment is considered incidental to the primary reason for admission. However, there are considerable differences when considering whether to utilize buprenorphine or methadone among the hospitalized population.

Buprenorphine, because of its partial agonism and high affinity, requires an induction process of which the hospital staff may not be familiar. The need to stop full agonist opioids before the induction can also pose challenges to hospitalized patients who may be experiencing acute pain, either from the medical illness that prompted the admission or from postoperative pain. Given buprenorphine’s “ceiling effect” on analgesia, combined with its high affinity at the mu-receptor, the assumption was previously made that buprenorphine would eliminate the ability to control acute pain adequately (28). Buprenonrphine’s ceiling effect is due to its partial agonist activity at the mu-opioid receptor, producing only partial activation of the receptor. This is in contrast to full agonists, such as morphine or methadone, which can maximally activate the receptor. However, emerging evidence suggests that buprenorphine may not have a ceiling effect for analgesia and can be coadministered with full agonist opioids to adequately manage pain (29–31). However, more research is clearly needed to understand the optimal approach in managing acute pain in patients taking buprenorphine. Despite these limitations, there are considerable advantages to buprenorphine over methadone. One is the ability to attain the therapeutic dose rapidly, which will help to both eliminate withdrawal symptoms and decrease cravings for opioids. Given its partial agonism, the risk for respiratory depression is low, and the therapeutic dose (anywhere from 8 to 24 mg/day) can be attained rapidly. Another advantage of buprenorphine is the ability to discharge the patient from the hospital with a prescription to continue treatment, as long as the prescription is written by a waivered prescriber (i.e., a clinician who possesses the Drug Enforcement Administration [DEA] X license to prescribe buprenorphine formulations approved for the treatment of opioid use disorder). Previous studies have shown that discontinuation of medications leads to an increase in mortality and overdose risk (32). In a study by Liebschutz et al., hospitalized patients with opioid use disorder who were randomized to the linkage group were far more successful in continuing treatment postdischarge (15). Individuals randomized to the linkage group were started on buprenorphine in the hospital, were given a prescription to continue the treatment, and were referred to the hospital’s own buprenorphine clinic. Those in the control group were provided with a buprenorphine taper over the course of 5 days and then referred to buprenorphine treatment in the community. Those in the linkage group were significantly more likely to start outpatient treatment (72.2%) compared with those who were tapered off and referred to treatment elsewhere (11.9%). Therefore, every effort should be made not only to initiate medical treatment while patients are in the hospital but also to link those patients to ongoing outpatient treatment without any gap in treatment.

Methadone is another viable medication option to initiate in the hospital. Unlike buprenorphine, methadone can be easily coadministered with other full agonist opioids without concerns for precipitated withdrawal, eliminating any need for an induction process as is required with buprenorphine. In addition, the use of methadone has been shown to reduce the incidence of discharge against medical advice among hospitalized patients, although the specific reason for this effect remains speculative (33). Unfortunately, there are disadvantages with methadone that warrant discussion. First, because of its long half-life and the absence of a ceiling effect, titration to higher dose ranges (i.e., >80 mg/day) cannot be attained rapidly without significant risk of respiratory depression. The starting dose in the hospital is typically no more than 30 or 40 mg/day, mirroring federal guidelines on the highest permitted dose in the first 24 hours at methadone clinics. This dose may be sufficient to treat acute opioid withdrawal but may not be sufficient to suppress illicit opioid use (24). There are numerous clinically significant drug–drug interactions, as well as a dose-dependent concern for QT prolongation (34, 35). Finally, because methadone for the treatment of opioid use disorder cannot be prescribed, it must be tapered off before discharge unless arrangements can be made for a direct transfer of the patient to a methadone maintenance clinic. If no such arrangement can be made, the patient would need to seek admission at the methadone clinic after discharge from the hospital, creating a potentially dangerous disruption in their treatment. A direct admission occurs when the methadone clinic accepts the patient into their program before hospital discharge and the patient receives their methadone dose at the clinic without any gap in treatment following discharge.

Extended-release naltrexone, an opioid antagonist that produces no opioid effect, is a third option for pharmacologic treatment during the hospitalization. However, for this medication to be administered, the patient must be opioid free for 7–10 days to avoid precipitated withdrawal, caused by the naltrexone displacing the full agonist. Because many hospitalized patients are experiencing acute pain and require the use of opioids, the need to achieve a week or more of opioid abstinence is a considerable challenge (28). However, for those patients who prefer the use of naltrexone, it is not unreasonable to help arrange for the initiation of extended-release naltrexone after discharge, especially if the patient feels confident about maintaining abstinence. Another option is to offer oral naltrexone in the hospital, as a bridge to extended-release naltrexone after discharge, for those patients who are amenable and are good candidates. Unfortunately oral naltrexone alone is unlikely to sufficiently suppress illicit opioid use or keep patients in treatment because of high rates of nonadherence (36).

Ultimately, the choice of medication is best made on an individual basis, and clinicians should be open to supporting patient and family preferences. Any medication treatment is likely to be superior to no medication at all. Nevertheless, recent data have suggested that after a nonfatal opioid overdose, both methadone and buprenorphine reduce all-cause and opioid-related mortality in the following 12 months, whereas no such associations were found with extended-release naltrexone (37).

Acute Pain Management for Patients With Endocarditis

Individuals with opioid use disorder who are hospitalized for endocarditis or other infections may experience considerable acute pain, either as a result of the infection itself or from the surgical intervention needed to remove the source of the infection. However, many factors lead to these patients receiving suboptimal pain treatment. Unlike chronic pain management, in which opioids should be the last resort when other treatments have failed, there is considerable need for timely management of the acute pain. However, it would be inappropriate to withhold opioids for patients with opioid use disorder because of several factors that make these individuals more prone to experiencing pain. Their tolerance to opioids can make their opioid requirement significantly higher than that of patients without any opioid tolerance. These patients may already be on buprenorphine or methadone, and clinicians may be reluctant to provide additional analgesia because of the erroneous assumption that no additional opioids are needed for pain management (38). If such patients are presenting with opioid withdrawal, that will also add to their experience of pain. More important, these individuals may be experiencing considerable opioid-induced hyperalgesia. In a study of volunteers with chronic pain, participants underwent a baseline test of their pain threshold and pain tolerance (39). After submerging a hand into a container of ice water, the subjects indicated the time at which they experienced pain (pain threshold) and the time at which they withdrew the hand because the pain became intolerable (pain tolerance). After the baseline measurements were taken, the subjects were instructed to take therapeutic doses of morphine to control their chronic pain. After 1 month of continued use of morphine, the subjects returned for their follow-up assessment. Even though their self-reported pain score decreased, there was a significant decrease in both the pain threshold and pain tolerance. This suggests that patients with opioid use disorder using high doses of illicit opioids for an extended period may be experiencing considerable hyperalgesia, characterized by a lower pain threshold and lower pain tolerance. Combined, these factors indeed may make individuals with opioid use disorder prone to experience more acute pain and require more analgesic medications to attain the same level of analgesia. Given that patients with opioid use disorder with comorbid chronic pain experience relapses more commonly in response to pain, adequate pain management may be critical during the hospitalization (40).

The potential consequence of undertreated pain is that patients may then choose to use illicit opioids to attain adequate pain relief or leave the hospital against medical advice. Patients may also be reluctant to request pain relief, because asking for more opioids may be interpreted to be “drug-seeking behavior.” Distinguishing between these two opposites—undertreated pain requiring more analgesia as opposed to patients seeking the nonmedical use of opioids—is a challenging clinical dilemma. Although no consensus exists on how to approach this situation, a possible approach is to utilize a similar risk-stratification approach used for patients with chronic pain. In chronic pain management, aberrant drug-taking behaviors are indications that the patient may be using the opioids for nonmedical reasons (i.e., to get high, to self-medicate moods, or to sell for profit) (41). However, those aberrant behaviors relevant to chronic pain are unhelpful in the acute-care setting. Although preliminary, a set of objective signs was proposed in a study as a way to risk-stratify hospitalized patients with opioid use disorder (42). The objective sign includes such items as follows: evidence of tampering with the IV lines, attempts to steal needles (e.g., from the sharps box), attempts to cheek or hoard dispensed medications, and drug paraphernalia or drug use noted in the hospital room. These are examples of more egregious examples, but other items are red flags that warrant closer scrutiny: discordance between self-reported pain score and objective behavior, leaving the room without permission or for extended periods of time, appearing intoxicated after administration of the opioid, receiving visitors who appear to be intoxicated, and excessive focus given to the use of opioids. The presence of such evidence for the nonmedical use of opioids may warrant implementing strategies to minimize the ability to engage in those behaviors (e.g., securing IV line access, giving multiple oral medications to make it harder to cheek specific medications) and a frank discussion with the patient and family about how to safely manage pain. Additionally, the presence of such behaviors may also lead to a discussion about whether buprenorphine or methadone needs to be initiated as a condition for receiving short-acting opioid analgesics. Every effort should be made to maximize nonopioid strategies for pain management and recognize that prolonged hospitalization is a challenge even for physically healthy individuals. Conversely, the absence of any of the aberrant behaviors or objective signs may be an indication that the use of opioids is appropriate and warrants continuation if the underlying medical problem is best managed using opioid analgesics. Ongoing monitoring and reassessment are clearly needed for all high-risk patients, but the withholding of pain medications solely for the suspicion that the patient is “lying” about their pain may be inappropriate because of the aforementioned factors.

Linkage to Treatment

Although the use of medication treatment for opioid use disorder may be critically important during the hospitalization, equally important may be to ensure adequate linkage to treatment after discharge. Without ongoing treatment, the risk of relapse to illicit opioids remains very high shortly after discharge. With the disruption and new symptoms caused by the medical hospitalization, the period immediately after the hospital stay is fraught with challenges, especially for those with endocarditis. Given the challenges that patients face in accessing medication treatment for opioid use disorder, ensuring that patients can access addiction treatment without any delay is critical. This can be achieved by making sure that appointments at treatment programs are made before discharge from the hospital and that a prescription for buprenorphine, if used, is provided to bridge the patient until the appointment. If methadone was initiated in the hospital, a direct admission to the methadone program ideally is arranged to avoid any delays. If such an arrangement cannot be made, then every effort should be made to arrange an intake at a methadone program soon after discharge.

Previous studies suggest that linking patients to treatment after discharge is a challenge even if medications are started in the hospital. Even after making efforts to link patients, studies show that around 50% of the patients may not successfully be linked to treatment at 30 or 60 days after discharge (25, 26, 28). Referring patients to the hospital’s own program may be the most effective approach, as demonstrated in some studies (15, 38). In a study by Liebschutz et al., in which hospitalized patients were referred to their own hospital’s addiction clinic, over 70% of the patients successfully continued treatment postdischarge (15). In a study by D’Onofrio et al. (43), patients with opioid use disorder who presented to their emergency room and were initiated onto buprenorphine were referred to their own hospital’s addiction clinic, and an intake was guaranteed within 72 hours post-discharge. Among those individuals, around 80% of patients successfully linked to treatment. These data may suggest that linkage to ongoing treatment may be far more successful if patients are referred to programs in their own system.

A novel strategy to accomplish this linkage is the use of a “bridge clinic” to allow patients to be seen immediately after discharge until the patient can be transitioned to longer term treatment. The goal is that all patients will be immediately seen, but the aim is to transition patients to other programs as soon as feasible. With this approach, patients being discharged from the hospital may be seen without any delay for medication treatment or treatment initiation if it had not been started in the hospital. This approach may be particularly helpful if there is a substantial delay in the ability to transition patients to longer term addiction treatment. For others, there may not be an addiction program within their own system to provide ongoing treatment, and patients may need to be referred to various community programs.

Outpatient Parenteral Antimicrobial Therapy (OPAT)

Patients who are being treated for endocarditis will likely require treatment with long-term IV antibiotics. To accomplish this, a placement of an in-dwelling catheter is required to provide daily IV treatment, typically in the form of a peripherally inserted central catheter (PICC) line. Patients with endocarditis due to reasons other than injection drug use will usually be considered good candidates for outpatient parenteral antimicrobial therapy (OPAT), where the IV medications are delivered in the patient’s home or at an infusion center (44, 45). In many centers, OPAT is the standard of care, outcomes are excellent, and patient satisfaction is high (45). However, most practice guidelines and hospital systems have chosen to exclude patients with any history of injection drug use from OPAT (44). The reason for this exclusion is based on numerous factors. Individuals who inject drugs may use the PICC line to inject drugs and compromise the integrity of the catheter. Adherence to the antibiotic treatment may be poor. There may be safety issues for the visiting nurses. Indeed, most infectious-disease clinicians feel uncomfortable offering OPAT to patients who inject drugs (46).

However, a recent literature review examined the published literature on the use of OPAT among individuals who inject drugs, which showed that overall outcomes for these individuals may be comparable with those for individuals without a history of injection drug use (47). The study included 10 studies comprising 800 individuals with a history of injection drug use receiving OPAT in the United States, Canada, Australia, and Singapore. The most common infections were bone/joint infections (38%), endocarditis (21%), and skin/soft tissue infections (16%). Most patients were actively or recently injecting drugs, including heroin, prescription opioids, methamphetamine, cocaine, and benzodiazepines. The OPAT completion rate ranged from 72.0% to 100%. The mortality rate was 0% in seven studies, whereas three studies showed rates of 1.9%, 5.0%, and 10.3%. Four studies reported complication rates ranging from 2.7% to 9.4%. Misuse of PICC lines was reported in four studies, with two showing no instances of PICC misuse and the other two studies showing rates of 2% and 11.3%. However, most studies did not report on the substance use outcomes or the specific addiction treatment offered, if offered at all. Nevertheless, the review indicated that OPAT outcomes may not inevitably be poor when offered to patients who have an active or recent history of injecting drugs. The overall minimal rate of PICC line misuse reported in these studies are reassuring, despite the absence of intensive addiction treatment. Currently, there are no reports of OPAT in combination with medication treatment for opioid use disorder to examine whether this improves outcomes further.

Prolonged hospitalization can be quite stressful, especially for individuals who may have a history of previous psychological trauma and poor distress tolerance. As such, consideration for OPAT should be given to all patients who require long-term antibiotics, and a history of injection drug use may not need to be an absolute contraindication for OPAT. The high rates of discharge against medical advice, the behavioral issues that can arise during the hospitalization, and the cost associated with prolonged inpatient stay are all potential disadvantages to excluding patients who inject drugs from OPAT. Indeed, studies estimate that each episode of OPAT might translate to $15,000–$25,000 in savings (47). However, more research is clearly needed to identify the appropriate use of OPAT among this population.

Conclusions

In the context of the expanding opioid crisis in the Unites States, rates of hospitalization and emergency room visits for opioid-related complications have nearly doubled in the past decade. Among those individuals who inject drugs, the rate of hospitalization for endocarditis has also increased dramatically, notably among the younger white population. Especially among those who inject drugs, endocarditis is a severe and life-threatening illness, with high rates of mortality as well as reinfection to repeat episodes of endocarditis. Once in the hospital, individuals with a history of injection drug use are much more likely to be discharged against medical advice and cause behavioral disruptions, likely as a result of the limited availability of medication treatment for the underlying opioid use disorder and the potential for inadequate pain control. As such, there is a critical need to expand the availability of addiction treatment in the hospital setting. Furthermore, initiation of medication treatment needs to be paired with robust efforts to link patients to ongoing treatment in the community. Although OPAT is the standard of care for endocarditis among those who do not inject drugs, there is a growing body of evidence suggesting that individuals who inject drugs may still be appropriate candidates for OPAT. More research is clearly needed to identify optimal strategies to treat individuals who inject drugs both during and after hospitalization for endocarditis.