A 55-year-old male presented to our emergency department at the behest of his primary care physician after being evaluated for dysarthria and left upper-extremity weakness, which had been present for the past month. His symptoms were sudden in onset. His left upper-extremity weakness had gradually resolved over the past few weeks, but he continued to have mild dysarthria.

The patient had a history of hypertension and mitral valve prolapse. Five years prior, he underwent a percutaneous balloon mitral valvuloplasty, followed by placement of an annuloplasty ring and a left atrial appendage clip.

The patient was born in New York, raised in Pittsburgh, Pennsylvania, and has lived in Philadelphia for the past 25 years. He is divorced and lives alone. He does not have pets. He works as a health advocate. He said he did not travel outside of the country. He hikes occasionally but said he had no any animal contact. He is not sexually active. He smokes cigarettes daily and drinks beer occasionally. He claimed no intravenous drug use.

On presentation, the patient was afebrile, and vitals were within normal limits. He was noted to have mild slurring of speech and a broken, decayed molar tooth. There were no stigmata of infective endocarditis. The rest of his exam was without obvious abnormalities.

Initial lab work showed no leukocytosis or renal/hepatic derangements. Blood cultures were sent and yielded no growth. An MRI showed acute ischemia in the midbrain with small chronic infarctions in the right thalamus and bilateral cerebellar hemispheres. A transesophageal echocardiogram 

 showed 2 large, mobile echo-densities attached to the mitral valve, emanating from the annuloplasty ring.

The patient underwent bioprosthetic mitral valve replacement and explantation of the annuloplasty ring. Mitral valvular tissue was sent for surgical pathology along with acid-fast bacilli, fungal, and tissue cultures. In addition, a paraffin block of mitral valve tissue was sent to an outside laboratory for 16S ribosomal RNA (rRNA) sequencing. Surgical pathology showed variably intense acute and chronic inflammation suggestive of infective endocarditis. Serial blood cultures were negative throughout the hospital stay and all surgical cultures yielded no growth. 

 species serologies were negative. 16S rRNA sequencing did not identify the culprit organism. The patient was discharged on ceftriaxone, doxycycline, and vancomycin. He was doing well on his outpatient follow-up visit after completing 6 weeks of antibiotic therapy.

The patient presented 1 year later with fevers, fatigue, dyspnea, and dry cough that had been present for 2 weeks. A CT scan of the chest showed diffuse, patchy ground-glass opacities and an 8-millimeter left lung apical nodule suspicious for malignancy. COVID-19 testing was negative. Lab work showed a white blood cell count of 4300/µL (normal range, 4-11×103/µL), platelet count of 42000/µL (normal range, 140-450×103 /µL), hemoglobin level of 9.4 g/dL (normal range, 14-18 g/dL), lactate dehydrogenase level of 1179 IU/L (normal range, 125-220 IU/L), ferritin level of 9335 ng/mL (normal range, 22-275 ng/mL), and a fibrinogen level of 73 mg/dL (normal range, 200-600 mg/dL). A transthoracic echocardiogram showed a mobile echo-density on the anterior mitral leaflet. Blood cultures were negative throughout the admission. A bone marrow biopsy was performed due to suspicion of hemophagocytic lymphohistiocytosis (HLH) and showed macrophages engulfing nucleated red cells and myeloid cells, confirming the diagnosis. Special bone marrow stains for acid-fast bacilli and fungi were negative. In light of the HLH, the patient was deemed high risk for bleeding during valvular surgery and managed with medical therapy alone. He was subsequently discharged with doxycycline for 6 weeks and a corticosteroid taper for management of the HLH.

An outpatient PET scan 1 month later again showed an apical nodule on the left lung suspicious for malignancy. Three weeks after the PET scan, the patient returned to the emergency department for fevers, chills, and drenching sweats. A transesophageal echocardiogram revealed a mobile echo-density (1.5 cm×0.9 cm large) on the anterior mitral leaflet and severe prosthetic mitral valve stenosis. Blood cultures were once again negative. Interventional radiology performed a core biopsy of the lung nodule, and the patient was diagnosed with a large cell neuroendocrine tumor. A blood sample was sent to an outside laboratory for Karius cell-free DNA sequencing, which returned positive for 

. Acid-fast bacilli blood cultures were collected, which were positive for acid-fast bacilli at 4 weeks and for 

The patient was started on azithromycin, ethambutol, rifabutin, and intravenous amikacin. He was deemed a poor candidate for repeat valve surgery due to his underlying comorbidities, started on radiation therapy for his neuroendocrine tumor, and discharged home. He returned to the hospital 2 weeks later with acute kidney injury secondary to aminoglycoside toxicity. Discussions with the patient and his family resulted in him being eventually discharged to home hospice.

 is a member of the nontuberculous mycobacteria group found ubiquitously in nature. First described in 2004 by Tortoli et al,1 it is genetically related to the MAIS group (

) but different from all 3; hence, it is aptly named “Chimaera” after the Greek mythological hybrid creature.

 infections occurred in multiple European countries and the United States. These infections were linked to open-heart procedures, including valve replacement and aortic graft procedures, that utilized 3T heater-cooler units (HCUs)2. The most likely mechanism of infection appears to be transmission of mycobacteria via aerosolized particles from the cooler units, followed by inoculation of the surgical field.3 As of 2017, approximately 120 cases of 

 have been associated with HCUs. According to Sommerstein et al,4 the incidence rate based on the current number of reported cases likely underestimates the true incidence of 

 infections that complicate valve replacement surgery; they estimate an incidence rate of 156 to 282 cases worldwide, with 51 to 80 of those cases annually.

 has a long incubation period and tends to cause subclinical infection due to overall low virulence. In the HCU outbreak, patients presented with vague signs and symptoms including fever, fatigue, shortness of breath, cough, and weight loss, that did not develop until years after undergoing cardiac surgery; the earliest patient in the 3T HCU outbreak had undergone surgery in 2008.5 Hence, cases such as these can be particularly difficult to identify and seldom raise clinical suspicions. Our patient did not develop symptoms until 5 years after his cardiac surgery. During the same time period, 1 other case of 

 infective endocarditis was diagnosed at our hospital. Further investigation by our hospital infection-control department—with the help of the CDC and the Department of Health—led to identifying the culprit HCU used in both patients.

Diagnosis poses another challenging aspect in these cases. Even if mycobacterial blood cultures are promptly obtained, it can take a median time of 20 days for colonies to grow on acid-fast culture systems.(

 Molecular testing may be required to arrive at species-level identification, which can delay diagnosis further and may take up to 41 days.6 Failure to provide adequate antimicrobial therapy in the setting of 

 endocarditis can lead to catastrophic complications such as heart failure, in addition to the morbidity, mortality, and health care system expense associated with this diagnosis.

 is intrinsically resistant to many classes of antibiotics. Treatment involves extended courses of multiple antibiotics that may include macrolides, rifamycins, ethambutol, quinolones, and parenteral aminoglycosides.7 Our patient developed acute kidney injury 2 weeks after beginning treatment, which was attributed to intravenous amikacin. He was not a surgical candidate for valve replacement and was eventually discharged to home hospice.

 endocarditis presents a diagnostic and management challenge for clinicians. Its indolent nature and slow growth on acid-fast cultures can delay diagnosis. Infection-control consultation is recommended to identify the source and prevent further cases. When diagnosed, treatment requires extended courses of multiple antibiotics. Surgical valve replacement may be required. Even with optimal treatment, the mortality rate of 

Zoheir Khan, MD, is an infectious disease fellow at Einstein Medical Center in Philadelphia, Pennsylvania.

Jeremy L. Agostinho, MD, is an infectious disease fellow at Einstein Medical Center in Philadelphia, Pennsylvania.

Tortoli E, Rindi L, Garcia MJ, et al. Proposal to elevate the genetic variant MAC-A, included in the Mycobacterium avium complex, to species rank as Mycobacterium chimaera sp. nov. 

. 2004;54(Pt 4):1277-1285. doi:10.1099/ijs.0.02777-0

Haller S, Höller C, Jacobshagen A, et al. Contamination during production of heater-cooler units by Mycobacterium chimaera potential cause for invasive cardiovascular infections: results of an outbreak investigation in Germany, April 2015 to February 2016. 

 2016;21(17). doi:10.2807/1560-7917.ES.2016.21.17.30215

Kohler P, Kuster SP, Bloemberg G, et al. Healthcare-associated prosthetic heart valve, aortic vascular graft, and disseminated Mycobacterium chimaera infections subsequent to open heart surgery. 

 2015;36(40):2745-2753. doi:10.1093/eurheartj/ehv342

Sommerstein R, Hasse B, Marschall J, et al; Swiss Chimaera Taskforce. Global health estimate of invasive Mycobacterium chimaera infections associated with heater-cooler devices in cardiac surgery. 

. 2018;24(3):576-578. doi:10.3201/eid2403.171554

Marra AR, Diekema DJ, Edmond MB. Mycobacterium chimaera infections associated with contaminated heater-cooler devices for cardiac surgery: outbreak management. 

 2017;65(4):669-674. doi:10.1093/cid/cix368. Published correction appears in 

Nomura J, Rieg G, Bluestone G, et al. Rapid detection of invasive Mycobacterium chimaera disease via a novel plasma-based next-generation sequencing test. 

 2019;19(1):371. doi:10.1186/s12879-019-4001-8

Kasperbauer SH, Daley CL. Mycobacterium chimaera infections related to the heater-cooler unit outbreak: a guide to diagnosis and management. 

. 2019;68(7):1244-1250. doi:10.1093/cid/ciy789. Published correction appears in 

Articles

Case Study

Nonspecific, nondolent symptoms make this disease difficult to diagnose.

A Case of Mycobacterium Chimaera Infective Endocarditis 

Identification of patients to undergo testing for 

 infection (CDI) is largely based on a high index of suspicion, although the role of asymptomatic carriage in transmission highlights the importance of infection control in inpatient and outpatient settings, according to experts who participated in a 

, also discussed recommendations for treatment of recurrent CDI and considerations for selecting the most appropriate treatment method.

The 2017 guidelines from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) state that patients with unexplained and recent onset of at least 3 unformed stools in a 24-hour period are the “preferred target population for testing” of CDI.1 However, 

 noted that presentation of CDI can range from mild symptoms to severe sepsis, fulminating colitis, or death and that clinical judgment is the most important consideration when selecting patients for testing. She said that presence of risk factors for CDI along with fever, elevated white blood cell (WBC) count, and frequent diarrheal stools increases suspicion; however, she added that diarrhea can also be associated with antibiotics, parasites, or consumption of contaminated food or water and that testing every patient with diarrhea would likely lead to overdiagnosis because individuals may be colonized with nontoxigenic forms of 

, noted that with the increase in pay-for-performance initiatives and public reporting of CDI rates, hospitals are particularly motivated to ensure that the CDI rates are low to prevent financial penalties and that positive tests for patients who are colonized with nontoxigenic 

, added that, rather than testing for CDI in any patient with diarrhea as a “knee-jerk reaction,” clinicians should broaden the differential diagnosis and evaluate the clinical presentation, such as assessing for the presence of blood in the diarrhea or whether the diarrhea is secretory or osmotic.

He added that irritable bowel syndrome (IBS) and postinfection IBS can complicate the clinical picture and that it is important to determine whether another bout of diarrhea indicates a recurrent infection or an alternative issue in a patient with a history of CDI to direct therapy appropriately. However, Feuerstadt said that patients with inflammatory bowel disease (IBD) are an exception, so all patients with IBD who experience an exacerbation should undergo testing for CDI because of the high incidence in this population.

Feuerstadt said that in addition to the IDSA/SHEA guidelines that provide recommendations for selecting candidates for testing, factors such as WBC count, creatinine level, and recent history of antimicrobials are also helpful to consider.

“If a patient has loose stools and recently received antimicrobials, they’re in the [intensive care unit], and their white [blood cell] count is 40,000, you probably know what’s going on there,” he said. “That might be a circumstance where time is of the essence and you might send off a stool assay before starting antimicrobials, but you may also want to empirically start antimicrobials due to your suspicion that [

, also pointed out that the work-up for a patient with community-acquired diarrhea needs to be different than for a patient with health care–associated diarrhea, in which CDI is high on the list of probable causes. For example, he recommended a multiplex polymerase chain reaction platform for patients with community-associated diarrhea to rule out multiple other potential causes.

In general, tests for CDI detect the organism itself or its primary toxins (toxin A and/or B). Commonly available options include toxigenic culture, nucleic acid amplification test (NAAT), glutamate dehydrogenase (GDH) assay, cell culture cytotoxicity neutralization assay, and toxin A and B enzyme immunoassays. Gerding noted, however, that the cell culture cytotoxicity neutralization assay has become obsolete because it is time consuming and difficult to perform.1

The NAAT is among the more commonly used tests in the United States and detects several toxin gene targets in the organism, although it has a low to moderate specificity and may pick up cases of patients colonized with 

, according to Gerding. He added that specific toxin tests, typically performed using enzyme immunoassays for toxin A and/or B, identify toxigenic 

 strains but have low sensitivity and that GDH assays are commonly used but need paired with another diagnostic test because GDH is found in toxigenic and nontoxigenic strains.

The IDSA/SHEA guidelines recommend using a stool toxin test as part of a multistep algorithm for diagnosis, which may involve GDH plus toxin test, GDH plus toxin test followed by NAAT as an arbitration test, or NAAT plus toxin test.1 However, Gerding noted that the difference in diagnostic yield among the algorithms may be introducing inconsistencies with diagnosis of CDI in current practice.

According to Chopra, asymptomatic carriage is an important consideration because carriers can act as reservoirs of transmission and probable vehicles of transmission to other patients. She added that the rate of asymptomatic carriage varies, with rates as high as 50% among older adults and approximately 5% to 10% among healthy adults.

“It’s important that we understand and realize that...these asymptomatic carriers don’t have diarrhea, but we are detecting [

 and they can transmit it,” she said, emphasizing the importance of infection control with hand hygiene and contact precautions in outpatient care settings and dialysis units and in inpatient care settings.

However, Chopra added that testing asymptomatic patients for carriage in the hospital setting is not routinely performed and would be a poor use of resources, and even hospitalized patients with risk factors for asymptomatic carriage are only put in contact isolation to prevent transmission if the hospital is facing an outbreak. Gerding noted that the data are currently insufficient to recommend universal screening for CDI, in part, because testing is invasive and isolation of positive patients would use a large number of isolation rooms. “I think we need more data before we jump on the colonization bandwagon, even in hospitals,” he said.

 Clinical Practice Guidelines and Treatment Options

According to the 2018 IDSA/SHEA guidelines, the recommendations for management of the first recurrence of CDI are a prolonged tapered and pulsed vancomycin regimen or fidaxomicin (if a standard vancomycin regimen was used previously) or a standard vancomycin regimen (if metronidazole was used for the previous infection).1 However, 

, noted that metronidazole has largely fallen out of favor for CDI infection because it has a broad spectrum of coverage (likely eliminating gut bacteria that are protective against CDI) and has been shown to have lower rates of efficacy than vancomycin. The inferior response rate of metronidazole to vancomycin was demonstrated in a pooled analysis of 2 multinational trials designed to compare clinical success of tolevamer, a nonantibiotic toxin-binding polymer, with vancomycin and metronidazole, respectively, in patients with CDI.2 Tolevamer was found to be inferior to both antibiotics, and rates of clinical success were higher with vancomycin than with metronidazole (81.1% vs 72.7%).2

“That’s what built up this concept on the clinical side [that] metronidazole is less targeted and alters the gut microbiota, which leads to higher risk for recurrence,” Feuerstadt said.

For second or subsequent recurrences, regimens recommended by the 2018 IDSA/SHEA guidelines include tapered and pulsed regimen of vancomycin, standard vancomycin regimen followed by rifaximin, fidaxomicin (if not used for prior infections), and microbiota replacement therapy or fecal microbiota transplantation (although the expert panel recommended appropriate antibiotic regimens for at least 3 episodes of CDI prior to trying this strategy).1

Feuerstadt noted that these recommendations in the 2018 guidelines have changed substantially from 2010, as metronidazole was largely removed from 2018 guidelines in favor of vancomycin or fidaxomicin in the first-line setting and fidaxomicin was introduced as an option for treatment of first recurrence.

Reilly concluded that assessing likelihood of patient compliance with the regimens, particularly the 8-week pulsed tapered vancomycin regimen, is important when selecting a treatment plan. He said in his experience, compliance tends to drop off after getting past the twice-per-day portion of the regimen. Salgo added that compliance is particularly difficult when dosing frequency drops to once every 2 to 3 days.

“We have to think about the patients we see who have [

 infection],” Reilly said. “Are they going to be compliant with this, taking vancomycin 4 times per day for possibly 2 weeks, then another 2 times per day for a week, once per day for another week, and every 2 to 3 days for up to 8 weeks? That’s a demanding regimen that we have to put a patient on. I understand the efficacy behind it, but we shouldn’t approach it and say, ‘Oh, I’ll just use that’ when there’s an alternative available that might be easier [and] that the patient might be more compliant with.”

McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). 

. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085

Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. 

. 2014;59(3):345-354. doi:10.1093/cid/ciu313

Peer Exchange

Investigators apply guidelines into practical management strategies.

Clostridioides difficile Infection: Diagnosis, Testing, Screening, and Treatment

Antimicrobial use data are essential for informing and assessing the progress of a stewardship program, but there are multiple challenges to collecting and analyzing the data in a meaningful, useful way. Data can be obtained from electronic health records, internal pharmacy documentation, or, most tediously, manual chart review.

Regulatory bodies such as the Centers for Medicare & Medicaid Services (CMS), Centers for Disease Control and Prevention (CDC), and the Joint Commission have developed several standards to guide the development and implementation of antimicrobial stewardship programs (ASPs). These standards define what elements of a stewardship program, including the tracking and reporting of metrics, must be met for reimbursement. Although antibiotic use data must be collected by each facility to receive CMS funding, reporting of facility-specific data to the CDC’s National Healthcare Safety Network (NHSN) remains optional, in contrast to hospital-acquired infection data, for which reporting is mandatory.

Current metrics are typically categorized broadly as either a process-of-care measure or an outcome measure. Process measures such as duration of therapy or proportion of patients compliant with facility-based guidelines are used to assess the impact of ASP interventions on antimicrobial use, whereas outcome measures like hospital length of stay are centered around the end effect on patients (or hospitals).

The 2016 Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), and Pediatric Infectious Diseases Society (PIDS) ASP implementation guidelines suggest measurement of antibiotic use as the best overall reflection of ASP impact versus antimicrobial cost 

 ASP interventions may incidentally lead to cost savings (eg, by decreasing unnecessary antimicrobial use) and help garner administrative support for the program, but antibiotic costs are not always congruent with patient outcomes or antibiotic appropriateness. In fact, appropriate ASP interventions can sometimes increase antimicrobial costs.

Antimicrobial consumption data are available to hospitals and allow for internal (at the same institution over time) and external (across institutions) comparison. External comparison is limited, however, by the variation in reported metrics.

 Defined daily doses (DDDs) is a consumption metric determined by dividing the amount of each antimicrobial used by its corresponding World Health Organization (WHO) standard daily dose; the sum of these amounts is then typically normalized by dividing by a volume measure such as 1000 patient-days. Although measurement of DDDs is recommended by the WHO and widely used outside the United States, it is heavily reliant on the WHO definition of standard daily dose.

 This can lead to contrasting results when indication-specific, weight-based, or renally adjusted doses are used.

Days of therapy (DOT) is the preferred metric in the United States and endorsed by the IDSA/SHEA/PIDS ASP guidelines.

 It is a count of the number of individual antimicrobial agents given to a patient on each calendar day multiplied by the total number of days of therapy, which is then standardized to account for volume by dividing by 1000 patient-days. Length of therapy (LOT) is a similar metric but considers the duration of overall antimicrobial therapy without accounting for the number of antimicrobials administered each day.

 DOT can be considered to account for the total burden of antimicrobial use while LOT accounts for the days of antimicrobial exposure. Both metrics are most useful as a tool for comparing an ASP’s performance against its own historical performance, but comparison to other facilities is limited because DOT and LOT do not account for differences in patient populations. Notably, measures of consumption should be used cautiously to avoid confusing the goal of therapy optimization with unjustified antimicrobial reduction. Although quantitative measures such as DOT and antimicrobial costs are commonly utilized performance metrics, they are only peripherally related to the impact of ASP interventions on patient quality of care and outcomes.

The most recently developed ASP metric is the NHSN SAAR, or standardized antimicrobial administration ratio. This is a standardized risk–adjusted metric of antimicrobial use that compares observed to predicted days of antimicrobial use and is useful for comparing an ASP’s performance to its expected performance based on the given patient population. The predicted number of antimicrobial days are calculated using statistical models based on nationally aggregated data from the CDC. A SAAR ratio less than 1 indicates antimicrobial use was less than predicted, a SAAR of 1 indicates use was equivalent to predicted use, and a SAAR of more than 1 indicates use was greater than expected.

In 2017, SAAR baselines were established for 13 adult and pediatric medical, surgical, medical-surgical intensive care units (ICUs), wards, step-down units, and oncology units, and there are 15 antimicrobial categories for which an institution could receive SAAR information back from the NHSN. For example, one could choose to see how their gram-positive–targeted antimicrobial use (eg, vancomycin, daptomycin, linezolid, etc) compared with the expected use for a certain unit type such as a medical ICU. NHSN allows for reporting of 89 specific antimicrobials and includes new drugs as they become FDA approved. However, because the system does not allow for manual data input, significant information technology infrastructure and investment are required to submit reportable data to NHSN. In addition, certain specialized unit types such as burn ICUs are not yet validated by NHSN and do not have a SAAR baseline to provide predicted antimicrobial days.

The CDC also provides guidance on suggested metrics for non–hospital-based stewardship programs (

). Irrespective of site, recommendations emphasize that even though savings in drug costs after implementation of a stewardship program may be used to justify the cost of the ASP, antimicrobial expenditures should not be used to track the effectiveness of stewardship efforts.

Certain settings allow for unique metrics. For example, informing outpatient clinicians that they prescribe more antimicrobials than 80% of their peers or comparing them to peers who perform in the top 10% on quality measures can result in overall reductions in antimicrobial prescribing.

 Smaller settings may be better able to track prescribing at the clinician level; however, they may also make tracking the complications of antimicrobial use (eg, 

 infection, drug interactions, and adverse drug reactions) less reliable or useful due to small sample sizes.

 Nursing homes or long-term care (LTC) facilities may choose to do point prevalence surveys of antimicrobial use, which track the proportion of residents receiving antimicrobials during a given period, to get a snapshot of the burden of antimicrobial use in the facility.

 A unique challenge for nursing homes is that antimicrobials are often provided by LTC pharmacy vendors, which may create an additional layer of complexity when trying to assess antimicrobial use and limit the reporting of antimicrobial use available to a facility (eg, antimicrobial start dates or indications).

The ideal benchmark would be centered around the primary goal(s) of ASPs: to improve patient outcomes via appropriate use of antimicrobials and to optimize antimicrobial regimens, including dosing, duration of therapy, and route of administration.

Although CMS and the Joint Commission similarly call for evidence-based antimicrobial use as well as minimization of adverse events, resistance, and hospital-acquired infections, it is difficult to measure these outcomes, and little data connect them to our most commonly collected metrics.

Key stakeholders also want metrics that correlate more with patient care. A survey of physicians and pharmacists identified that they favored patient-centered outcomes such as infection-related mortality and considered these disparate from the metrics reportedly used at their institution.

There is no perfect metric by which to judge the success of one’s stewardship program. More and more facilities are, however, opting to share their antimicrobial use data with the CDC NHSN. In turn, this provides better, higher quality data for future SAAR baseline validations and a way for stewardship programs to benchmark their institutions against others with a similar patient population.

Jason Chao, PharmD, is a postgraduate year 2 infectious diseases pharmacy resident at the University of California Davis Medical Center in Sacramento.

Nicola Clayton, PharmD, BCIDP, is an infectious diseases clinical pharmacist and the pharmacy leader of the Antimicrobial Stewardship Program at the University of California Davis Medical Center.

Bennett N, Schulz L, Boyd S, Newland JG. Understanding inpatient antimicrobial stewardship metrics. 

. 2018;75(4):230-238. doi:10.2146/ajhp160335

Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. 

. 2016;62(10):e51-e77. doi:10.1093/cid/ciw118

Ibrahim OM, Polk RE. Antimicrobial use metrics and benchmarking to improve stewardship outcomes: methodology, opportunities, and challenges. 

. 2014;28(2):195-214. doi:10.1016/j.idc.2014.01.006

Al-Hasan MN, Winders HR, Bookstaver PB, Justo JA. Direct measurement of performance: a new era in antimicrobial stewardship. 

. 2019;8(3):127. doi:10.3390/antibiotics8030127

Keys to Success with the SAAR. Centers for Disease Control and Prevention. Published March 2020. Accessed April 12, 2021. https://www.cdc.gov/nhsn/pdfs/ps-analysis-resources/aur/keys-success-saar-h.pdf

Centers for Disease Control and Prevention (CDC). Implementation of antibiotic stewardship core elements at small and critical access hospitals. Accessed April 2, 2021. https://www.cdc.gov/antibiotic-use/healthcare/pdfs/core-elements-small-critical.pdf

CDC. Core elements of outpatient antibiotic stewardship. Accessed April 2, 2021. https://www.cdc.gov/antibiotic-use/community/pdfs/16_268900-A_CoreElementsOutpatient_508.pdf

Centers for Disease Control and Prevention. Core Elements of Antibiotic Stewardship for Nursing Homes: APPENDIX B: Measures of Antibiotic Prescribing, Use and Outcome. Centers for Disease Control and Prevention. Accessed April 2, 2021. https://www.cdc.gov/longtermcare/pdfs/core-elements-antibiotic-stewardship-appendix-b.pdf

Bumpass JB, McDaneld PM, DePestel DD, et al. Outcomes and metrics for antimicrobial stewardship: survey of physicians and pharmacists. 

. 2014;59(suppl 3):S108-S111. doi:10.1093/cid/ciu545

Stewardship and Prevention

The challenging search for a metric that effectively evaluates an ASP’s direct impact on appropriate antimicrobial use and improved patient outcomes.

How Do You Measure the Success of Your Stewardship Program?

In January, the FDA approved cabotegravir/rilpivirine(Cabenuva®), the first long-acting medication used for treating HIV infection. Several long-acting modalities are currently under investigation for both 

 treatment and prophylaxis, including oral, injectable, implant, antibody therapy, and vaginal ring.

Long-acting formulations are being developed to overcome barriers—primarily, adherence—presented by daily oral therapy. Encouraging results regarding adherence comes from the phase IIb LATTE-2 study (NCT02120352) evaluating long-acting cabotegravir-rilpivirine for HIV treatment where 99% of participants preferred to continue with injectable therapy compared with 78% on oral treatment.

 The purpose of this article is to provide an overview of the various ART therapies being studied and are available for prevention and treatment of HIV.

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), were approved and co-packaged as the first injectable treatment option for adults with HIV-1 

 Following an oral lead-in therapy, the cabotegravir/rilpivirine long-acting extended-release injectable suspensions are currently administered once monthly and are expected to replace the current regimen for those who are infected, have no history of treatment failure, and are virologically suppressed (HIV-1 RNA < 50 copies/mL). This long-acting injectable was approved based on the results of the phase III FLAIR (NCT02938520) and ATLAS (NCT02951052) studies, which evaluated virologic suppression in antiretroviral (ART)-naive and ART-experienced individuals, respectively.

In addition to the previously mentioned clinical trials (ATLAS, FLAIR) examining long-acting cabotegravir in the treatment of HIV, injectable cabotegravir is also being studied for pre-exposure prophylaxis (PrEP) in the HPTN 083 (NCT02720094) and HPTN 084 (NCT03164564) studies.

Promising results emerged using injectable cabotegravir every two months for PrEP in the HPTN 083 study, which enrolled cisgender men and transgender women who have sex with men.

 As with the ATLAS and FLAIR studies, an oral lead-in therapy was utilized. The study was halted early due to the superiority of injectable cabotegravir versus oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).

 Of the 52 HIV infections seen in HPTN 083, 13 infections were in the cabotegravir arm (0.41% incidence rate) compared to 39 infections in the TDF/FTC arm (1.22% incidence rate).

The interim analysis for the phase III HPTN 084 study, which enrolled HIV-uninfected women at increases risk for HIV, showed that women in the cabotegravir arm had an 89% lower risk of HIV infection compared with those receiving TDF/FTC.

 In addition, HPTN 084 showed superior efficacy for long-acting injectable cabotegravir in an interim review meeting, with the HIV incidence rate in those receiving cabotegravir at 0.21% compared with 1.79% in those receiving oral TDF/FTC. Because of the positive study outcomes at that point, it was recommended to stop the blinded phase and offer subjects in both arms of the study long-acting cabotegravir once available.

A dapivirine intravaginal ring (IVR) for HIV-1 prevention is currently on the World Health Organization’s prequalification list following the positive opinion from the European Medicines Agency in July 2020.

 The dapivirine intravaginal silicone ring is designed to slowly release dapivirine over the course of one month to reduce the risk of HIV acquisition.

In two phase III studies, the dapivirine IVR was shown to be well tolerated and reduced HIV-1 acquisition risk by 30% compared with placebo.

 The HOPE study (NCT02858037), an open-label extension of the ASPIRE study (NCT01617096), aimed to assess the uptake and use of the IVR in women who had participated in the ASPIRE study and remained HIV-1 negative. Acceptance of the dapivirine IVR was high; 92.2% of women accepted the ring at enrollment, and 97.9% of follow-up visits were completed. Adherence was also measured by testing residual dapivirine amounts in the rings; overall, 89.3% of the returned rings had more than 0.9 mg of dapivirine released, which indicated use.

Due to its cost effectiveness, acceptability, and feasibility, the IVR will provide benefit to sexually active at-risk women.

 Studies that include IVRs with both contraceptive and HIV preventative medications are underway.

One of the most promising long-acting oral antiretrovirals is islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI).

 Islatravir’s long intracellular half-life in peripheral blood mononuclear cells (PBMCs) allows for extended dosing intervals.

Interim results from a phase IIa study (NCT04003103) comparing once-monthly islatravir 60 mg tablets, 120 mg tablets, and placebo for PrEP showed no serious adverse events or deaths; in addition, the drug was well-tolerated. Tissue kinetics showed rapid and sustained distribution to cervical, rectal, and vaginal tissues, with both tested doses achieving trough concentrations above the prespecified threshold (0.05 pmol/106 cells).

Based on the favorable results from this phase II study, two phase III studies will compare islatravir once monthly at the 60 mg dose to current PrEP therapy: TDF/FTC in cisgender women (IMPOWER-022) (NCT04644029) and TDF/FTC or tenofovir alafenamide (TAF)/FTC in men who have sex with men (MSM) and in transgender women who have sex with men (IMPOWER-024) (NCT04652700).

 Additionally, islatravir is being investigated as part of a combination regimen with doravirine for once daily treatment in the ILLUMINATE study (NCT04223778).

Islatravir’s high binding affinity to reverse transcriptase combined with its long half-life (~ 190 hours in PBMCs) makes it suitable for implant formulations. A stent using a drug-eluting polymeric matrix was tested in preclinical and clinical studies. Importantly, few adverse effects were seen aside from implant site pain, tenderness, and erythema.

 In pharmacokinetic simulation studies, the 62 mg implant projects a concentration above the aforementioned target threshold (0.05 pmol/106 cells) at 12 months, with concentrations not falling below the threshold until approximately 16 months.

 Other implants being studied include tenofovir alafenamide and cabotegravir.

Lenacapavir acts as a capsid inhibitor, with additional in vitrodata showing disruption of multiple stages in HIV’s life cycle; thus, lenacapavir has the potential to work against HIV strains that have developed resistance to multiple other classes.

 In the phase II/III CAPELLA study (NCT04150068), 36 adults with multidrug resistant HIV received either placebo or daily lenacapavir for 14 days as an add-on to a failing regimen. At the end of 14 days, the lenacapavir cohort met the primary endpoint (0.5 log10 copies/mL decrease in viral load; 88%) compared with the placebo group (17%).

The aforementioned subcutaneous injectable formulation of lenacapavir displays a long half-life and is being investigated as a twice-yearly injectable for PrEP. A phase Ib study showed sustained therapeutic concentrations following a single 900 mg dose administered in three 1 mL injections (also studied were two 1.5 mL injections).

For treatment purposes, interim efficacy results from the CAPELLA study showed high rates of viral suppression through 26 weeks in study participants receiving lenacapavir injection (following the 2-week oral lead-in) in combination with an optimized background regimen in treatment-experienced people living with HIV (PLWH).

 Nineteen of the 26 subjects followed through the 26 weeks achieved viral suppression, with an average CD4 count increase of 72 cells/mm

. Gilead Sciences, Inc and Merck have announced plans to co-develop lenacapavir and islatravir as a combination injectable regimen; a coformulated oral regimen is also being studied.

Broadly neutralizing monoclonal antibodies (bNAbs) are potential agents for long-acting HIV prevention due to their ability to decrease viral load by neutralizing many strains of the pathogen and possibly reducing the viral reservoir. VRCO1 was discovered in the blood of a PLWH and is directed at the HIV-1 envelope protein CD4-binding site. This bNAb was manufactured for the Antibody Mediated Prevention (AMP) studies (NCT04801758, NCT04860323) to assess its ability to prevent HIV-1 acquisition.

The two double-blind, placebo-controlled phase IIb AMP studies enrolled more than 4000 patients collectively. HPTN 081 (NCT02568215) enrolled cisgender women, and HPTN 085 (NCT02716675) enrolled MSM and transgender persons who have sex with men.

HVTN 703/HPTN 081 (NCT04860323) included heterosexual women from sub-Saharan Africa, and HVTN 704/HPTN 085 (NCT04801758) included men and transgender persons from the Americas and Europe who have sex with men.

In each study, subjects were randomized to receive VRC01 by intravenous infusion at a dose of 10 mg/kg or 30 mg/kg every eight weeks or a control infusion every eight weeks. The outcome of both studies was to compare documented HIV-1 infection by week 80. Overall, acquisition of HIV-1 was not significantly lower with VRC01 compared with placebo in either study.

Unfortunately, viruses in persons receiving the bNAb showed greater resistance. Furthermore, as compared to other potential long-acting modalities, cost—as well as the necessity of intravenous infusions—may preclude the use of bNAbs for the immediate future. Instead, bNAbs may have a place in vaccine design and development.

 Future studies will examine combinations of bNAbs and bNAb-based vaccines.

The modalities currently under study, once realized, will allow a wide variety of options for both treatment and prophylaxis (

). Adherence, which is especially challenging for at-risk populations, could improve dramatically. Daily adherence to an oral regimen would be replaced by longer intervals between clinic visits—reducing dosing frequency, pill fatigue, and oral absorption issues (eg, drug-drug interactions, short bowel syndrome) as well as the potential avoidance of HIV-related stigma.

However, the potential impact that delayed clinic visits could have on resistance to long-acting formulations in a real-world setting requires further study. Other barriers also will need to be overcome for long-acting formulations to reach their full potential, such as cost effectiveness, co-treating comorbidities (eg, hepatitis B, substance abuse), and ensuring overall availability to at-risk populations.

Eric F. Egelund is a clinical assistant professor at the University of Florida College of Pharmacy in Jacksonville. His research interests include infectious disease pharmacokinetics, specifically those used for the treatment of tuberculosis, nontuberculous mycobacteria, and HIV.

Jessica Huston is a clinical assistant professor at the University of Florida College of Pharmacy in Jacksonville. Huston’s experience in clinical research and the pharmaceutical industry includes having served as a subinvestigator on numerous clinical trials.

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More treatment options and modalities are now available for patients.

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