A male, aged 21 years, presented to our emergency department with gunshot wounds to the right upper back and left anterior chest. He required needle decompression of the right chest prior to arrival due to hypotension and concern for pneumothorax. Upon arrival at the trauma bay, the patient was awake and alert. An initial exam was notable for bilateral lower extremity paralysis. A chest X-ray noted a widened mediastinum, and a CT scan of the chest identified tracheal injury, vertebral body fractures of the fourth and fifth thoracic vertebrae, pneumomediastinum, and pneumopericardium. The patient required emergent surgical stabilization, including median sternotomy, tracheal repair, and innominate vein ligation. The patient was initiated intraoperatively on veno-venous extracorporeal membrane oxygenation (VV-ECMO) and was then transferred to the surgical intensive care unit, intubated, and sedated.

Notable only for mild, intermittent asthma.

The patient was born in the United States and had never lived outside of Philadelphia. He reported frequent sightings of rodents on the streets near his home, but not inside his residence. Three pet cats lived in his residence and were without signs of illness prior to the patient’s presentation. He reported an isolated incident of handling live chickens 2 months prior to presentation. He denied recent travel. He had no significant family history, except that his grandmother had died from lung cancer. He smoked 1 pack of cigarettes daily.

On presentation to our hospital, the patient was awake and alert, saturating well with a nonrebreather mask delivering 15 L of oxygen per minute. His heart rate was 105 beats per minute. Other vital signs were within normal limits. He was noted to have a small abrasion over the right eye. Breath sounds were auscultated bilaterally. He had no sensation and had 0 of 5 strength in his lower extremities bilaterally. The rest of his exam was without obvious abnormalities.

Initial labs were notable for mild anemia with a hemoglobin level of 13.5 g/dL (14.0-17.5 g/dL) with a decrease to 8.9 g/dL within several hours of presentation. His basic metabolic panel was unremarkable. His initial lactic acid level was elevated at 8.1 mmol/L (0.5-0.2 mmol/L) with decrease to 4.2 mmol/L within several hours of presentation. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 was negative.

X-ray of the chest revealed large-volume pneumomediastinum. CT scan of the chest revealed highly comminuted fractures of T4 and T5 vertebral bodies, as well as mediastinal hematoma, extensive pneumomediastinum, pneumopericardium, and suspected tracheal injury.

The patient remained hemodynamically stable and did not require further surgical intervention after hospital day 1 (HD1). The patient tolerated removal of his endotracheal tube on HD2 and removal of VV-ECMO on HD3. After removal of VV-ECMO, the patient became febrile with a temperature of 102.6°F and developed a productive cough. On HD4, blood and sputum cultures were collected and he was initiated on empiric piperacillin/tazobactam and vancomycin. On HD6, piperacillin/tazobactam was changed to meropenem due to persistent fevers. On HD7, a sputum culture that was collected on HD5 was noted to grow 

. On HD7, additionally, 1 of 2 sets of blood cultures that were collected on HD3 were noted to grow 

; sensitivities for this bacteria are not routinely performed. Infectious disease specialists were consulted at this time.

The patient was given 1 dose of intravenous tobramycin while susceptibility testing for 

was being performed. Based on available reports of 

susceptibility, meropenem was continued in order to target 

 and susceptibility testing was requested. Vancomycin was discontinued given that the patient’s cultures were without growth of a gram-positive organism. 

susceptibility testing ultimately showed susceptibility to meropenem, so this was continued as targeted treatment for 

Serial blood cultures were collected for several days after the initial growth of 

, but subsequent blood cultures remained without growth.

A repeat CT scan of the chest was obtained due to the patient’s persistent fevers, cough, and sputum culture results; it was notable for consolidative and ground glass opacities in the right lung apex and right lower lobe. These findings were felt to represent sequelae of pulmonary contusion.

 noted in the patient’s blood cultures, a transthoracic echocardiogram was obtained; it did not demonstrate valvular vegetations or other evidence of endocarditis. Additionally, a HIV fourth-generation assay was nonreactive, and a HIV RNA level was below the level of detection.

was requested and sent to an outside laboratory. Results were not available during the patient’s hospitalization, but ultimately demonstrated susceptibility to meropenem, which the patient had received empirically throughout his hospitalization (

The patient completed a 14-day course of meropenem at the recommendation of the infectious disease specialists. His fevers persisted for the first 5 days of antibiotic treatment, although with a progressive downtrend in his temperature curve. His fevers had completely resolved after 6 days of antibiotic treatment. Numerous subsequent blood cultures were without growth. He was discharged to a rehabilitation facility after a 19-day hospitalization.

 species are small, gram-negative coccobacilli.

, although many species are seldom encountered in clinical settings.

 The most common species to cause disease in humans is 

, which is a highly transmissible organism that causes prolonged respiratory illness. With improved molecular testing, however, identification of new species in clinical centers is occurring with increasing frequency.

 was first identified as a cause of respiratory infection in poultry and more rarely has been isolated from rodents.

The species was first reported in humans in 1994 as a cause of bacteremia in a patient with AIDS.

 Most reports of infection have occurred in immunocompromised patients and have presented as respiratory infection, cholangitis, bacteremia, and endocarditis.

 The organism’s pathogenic role, particularly in immunocompetent patients, remains poorly understood. To our knowledge, only 3 reports have described cases of symptomatic 

 infection in patients without underlying disease or immunocompromise. These cases presented as fatal bacteremia, respiratory infection, and cervical subcutaneous abscess.

In this case, the exact route of transmission of 

 was unclear, but the patient did describe regular indirect exposure to rodents as well as recent direct handling of poultry, both of which are known reservoirs. The pathogenicity of 

 in this case was also uncertain. An additional organism, 

, was isolated from the patient’s sputum and could have been the primary pathogen responsible for his respiratory symptoms. Isolation of 

 from the blood in addition to the sputum, however, suggests systemic illness. Additionally, the patient’s fevers persisted for several days despite appropriate antimicrobial therapy based on later susceptibility testing. This suggests that his fevers were likely multifactorial in etiology given his preceding trauma and extensive surgical intervention, and not entirely attributable to 

 is frequently resistant to many antibiotics.

 Prior reports have identified resistance to b-lactams, cephalosporins, macrolides, and fluoroquinolones.

was noted to be resistant to aztreonam, ciprofloxacin, and tobramycin, with intermediate susceptibility to gentamicin. The patient recovered well with a 14-day course of empiric meropenem, susceptibility to which was noted after completing treatment. This case, in addition to the in vitro sensitivity data reported in the literature,

 suggest that piperacillin/tazobactam and meropenem are reasonable empiric antibiotics in the treatment of 

In summary, manifestations and outcomes of 

 infection are variable and further reports are needed to illustrate its pathogenicity and optimal treatment. Our case serves as one of few reports of 

 in an immunocompetent patient. Although rare, 

 will likely be identified more frequently in clinical settings due to increasing access to microbial identification technology such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and it should be considered as a potential pathogen in immunocompetent patients.

Novick is a first-year infectious disease fellow at Temple University Hospital in Philadelphia. She is interested in HIV, infectious sequelae of substance use disorders, and social determinants of health.

Moon is a fourth-year medical student at the Lewis Katz School of Medicine at Temple University in Philadelphia. She plans to pursue a residency in internal medicine.

Waters V, Halperin SA. Bordetella pertussis. In: Bennett JE, Dolin R, Blaser MJ, eds. 

Mandell Douglas and Bennett’s Principles and Practice of Infectious Diseases

Hayashimoto N, Yasuda M, Goto K, Takakura A, Itoh T. Study of a Bordetella hinzii isolate from a laboratory mouse. 

Jiyipong T, Morand S, Jittapalapong S, Raoult D, Rolain J-M. Bordetella hinzii in rodents, Southeast Asia. 

Cookson BT, Vandamme P, Carlson LC, et al. Bacteremia caused by a novel Bordetella species, “B. hinzii.” 

Vandamme P, Hommez J, Vancanneyt J, et al. Bordetella hinzii sp. nov., isolated from poultry and humans. 

. 1995;45(1):37-45. doi: 10.1099/00207713-45-1-37

Gadea I, Cuenca-Estrella M, Benito N, et al. Bordetella hinzii, a “new” opportunistic pathogen to think about. 

Arvand M, Feldhues R, Mieth M, Kraus T, Vandamme P. Chronic cholangitis caused by Bordetella hinzii in a liver transplant recipient. 

Zohourian H, Sorokin AV, Ladna JM, Mushtaq F. Bordetella hinzii: an unexpected pathogen in native valve endocarditis. 

González MM, Romano MPC, Monge MTdGG, et al. 

 endocarditis, a clinical case not previously described. 

Kattar MM, Chavez JF, Limaye AP, et al. Application of 16S rRNA gene sequencing to identify Bordetella hinzii as the causative agent of fatal septicemia. 

Negishi T, Matsumoto T, Shinagawa J, et al. A case of cervical subcutaneous abscess due to Bordetella hinzii. 

Ruiz MPP, Martinez MAV, Calleja AIL. Respiratory infection caused by Bordetella hinzii. 

Fabre A, Dupin C, Bénézit F, et al. Opportunistic pulmonary Bordetella hinzii infection after avian exposure. 

Articles

Case Study

A Case of Pneumonia and Bacteremia in a Trauma Patient Caused by Bordetella hinzii


Professor of Medicine, Division of Infectious Diseases
University of North Carolina School of Medicine
Chapel Hill, NC


Associate Professor of Pediatric and Adult Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, MD


Professor of Medicine
University of Pennsylvania Perelman School of Medicine
Philadelphia, PA


Associate Professor of Medicine, Division of Infectious Diseases
Emory University School of Medicine
Atlanta, GA


Infectious Disease Epidemiologist
Associate Professor, Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute
Boston, MA

New antiretroviral drugs with unique mechanisms of action and delivery provide promising options for treatment and pre-exposure prophylaxis (PrEP) of HIV infection and may improve adherence in certain subgroups of individuals. However, the development of an effective vaccine remains elusive, according to experts who participated in a recent 

Fostemsavir (formerly BMS-663068/GSK3684934), a prodrug whose active metabolite (temsavir) is a first-in-class attachment inhibitor that binds directly to the viral envelope glycoprotein 120 near the CD4+ binding site,

 was approved by the FDA on July 2, 2020, for adults living with HIV who have tried multiple HIV medications and whose infection cannot be treated with other therapies because of resistance, intolerance, or safety reasons.

 This approval was based largely on results from a phase 3 trial, which showed a virologic response (HIV-1 RNA <40 copies/mL) at week 48 in 54% of patients with heavily pretreated, multidrug-resistant HIV infection who received fostemsavir plus optimized background therapy.

, said that its oral dosing is advantageous over ibalizumab, which is dosed intravenously, although he said that fostemsavir will probably be limited for patients with few or no treatment options.

, added that long-acting injectable and oral agents, capsid inhibitors, and monoclonal antibodies are also being studied in the HIV space, as are alternative delivery approaches, such as subcutaneous injections, pumps, implants, and patches. However, she pointed out that access to and the cost of these novel options will be key issues moving forward, particularly when currently available oral agents are highly effective for suppressing HIV viral load in the majority of cases.

“The discussions we’ll have to have on how and who and where are going to be very important,” said Agwu. “It doesn’t mean we shouldn’t have those discussions because for the people who are living with HIV, these are maybe life-saving, game-changing remedies for them.”

Long-Acting Injectable Therapies to Treat HIV

The panelists discussed potential uses and challenges with the long-acting injectable therapy containing cabotegravir (an HIV-1 integrase strand-transfer inhibitor) and rilpivirine (a non-nucleoside reverse-transcriptase inhibitor), which is injected in 2-mL doses in the gluteus medius every 4 weeks for the maintenance of virologic suppression in patients who are initiating or transitioning therapy. Although the FDA declined to approve the combination in December 2019 due to concerns related to chemistry manufacturing and controls, the drug manufacturer (ViiV Healthcare) stated that no related safety issues have been reported and the safety profile of the products has not changed. ViiV Healthcare submitted another new drug application that was accepted in April 2020.

, said that a benefit of long-acting injectable dosing is that it may help reduce the internalized stigma for many individuals living with HIV who take a daily oral medication. “It’s a constant reminder when you have that pill bottle on your bathroom stand that says, ‘I am HIV positive,’” she noted.

However, the panelists pointed out potential drawbacks with long-acting injectables, such as the risk for drug resistance in patients who miss injections and the possible need to modify the clinic set-up to ensure availability of nursing staff when patients are receiving injections.

“Although there may be some adherence problems that get solved by the injections, I think that there are other adherence risks that get created,” said 

. “It’ll be more incumbent upon us as providers to ensure that our patients are coming in at the appropriate frequency, and we may need to modify our practices.”

Long-Acting Injectables as Pre-Exposure Prophylaxis

Long-acting injectable therapy with cabotegravir may provide a discreet option for PrEP that does not require daily dosing, according to a recent interim analysis of the phase 2b/3 HPTN 083 trial (NCT02720094).

 The interim results from the trial showed that cabotegravir injection every 8 weeks was superior to daily oral emtricitabine/tenofovir (Truvada) for preventing HIV acquisition in cisgender men who have sex with men and transgender women who have sex with men.

To have population-level effectiveness, long-acting injectable PrEP needs to cater to a population of individuals who are eligible for and interested in receiving it but are not interested in daily oral PrEP, according to 

. “If the only people who are interested in long-acting PrEP are people who are already taking daily PrEP…it’s not going to have any population-level effectiveness,” she said.

Marcus added that identifying individual barriers to receiving oral PrEP is important to assess whether long-acting injectable PrEP is appropriate for them, noting that it would be more likely to benefit an individual who forgets to take daily medications than one who has difficulty with coming into the clinic.

“If their [issue is] that they don’t want to be coming into the clinic every 3 months, long-acting injectables may not help them,” she said. “They may have to come in even more.”

Other individuals who may be good candidates for long-acting injectable PrEP include those for whom having oral medication may put them at risk for bodily or emotional harm, such as people in unequal power relationships, commercial sex work, or homeless living situations, said Eron and Marcus. Individuals who use injectable drugs or are on methadone maintenance may also be good candidates for PrEP if they come in frequently for syringe changes, said Marcus.

Agwu added that long-acting injectable PrEP could also expand the options in the armamentarium for a given patient at different times of their life.

“If a patient has to go abroad for 2 months, maybe that’s the time to get your shot,” she said. “You don’t have to worry about taking your pills to Morocco.”

She said that further work is needed to optimize system and administration issues and improve practices for delivering long-acting injectable therapy in the clinic. Eron concluded that further research to ensure the efficacy and demedicalization of PrEP is important to improve uptake, as the perception that PrEP care is more intensive than HIV care continues to persist among individuals who are eligible for PrEP.

Preventative and Therapeutic HIV Vaccines

Although the phase 2b/3 HVTN702 trial (NCT02968849), which studied the RV144 Thai vaccine regimen for the prevention of HIV infection in South Africa, was recently discontinued because of a lack of efficacy, Kelley said that this outcome does not mark the end of the journey for finding an effective vaccine, which will be the key to ending the HIV epidemic.

“There’s still more work to be done and no reason to lose hope,” she said. “We’re thinking about monoclonal antibodies and long-acting antiretrovirals in place of a traditional vaccine.”

Kelley said that researchers are getting closer to identifying what the immune system needs to do to protect itself from HIV infection. “If these neutralizing antibodies are the key, how do we make our human immune system create those neutralizing antibodies? ….That’s been extremely difficult to do,” she said. “We can make the antibodies outside the person, but we can’t make the person produce the antibodies. This is the biggest barrier right now.”

Frank added that therapeutic vaccines are also being investigated as a strategy for curing HIV, with “cure” defined “in the context of doing something other than requiring people to take regular antiretroviral therapy to control the virus replication.” Specifically, the goal of a therapeutic vaccine is to improve the individual’s immune response against the infection to enable the withdrawal of antiretroviral therapy and promote an improved immune response to control virus replication, said Frank. He concluded that although therapy and prevention continue to improve, the absence of an effective vaccine and a cure are “the real vacuum” in HIV prevention and treatment, respectively.

Advice for Physicians Treating Patients with HIV

At the conclusion of the exchange, the panelists discussed tips for physicians in the screening, diagnosis, and treatment of patients living with HIV. Agwu stressed the importance of asking patients about risk factors for HIV, including sexual activity, and testing and offering PrEP for patients at high risk. Kelley added that in addition to routine discussions about sexual health, maintaining consistency in the treatment of each patient and identifying other issues that are common to those living with HIV, such as other sexually transmitted infections, is important.

Marcus added that discussing sexual health in an open-ended, nonjudgmental, patient-centered way is important for optimal communication with patients and that communicating the U = U (undetectable = untransmissible) message can be “transformative” for them.

Frank concluded that although undetectable viral load is often the primary focus of antiretroviral therapy, providers should also consider additional factors, such as comorbid conditions, when optimizing HIV therapy and managing overall care for patients.

“It’s important that we remind our patients that they may have other medical conditions, or they may develop other medical conditions, and those medical conditions may pose as great a risk, if not a bigger risk, than their HIV disease,” said Frank. “I have many patients with uncontrolled hypertension and uncontrolled diabetes and lipids that are high. I tell them that they’re going to die of a heart attack or a stroke or be on dialysis long before they ever get a complication of their HIV. Dying of a heart attack with an undetectable viral load isn’t my goal of their treatment. It’s not just about their HIV.”

1. Langley DR, Kimura SR, Sivaprakasam P, et al. Homology models of the HIV-1 attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action. 

. 2015; 83(2):331-350. doi:10.1002/prot.24726

2. FDA approves new HIV treatment for patients with limited treatment options. Press release. FDA. July 2, 2020. Accessed October 13, 2020. 

https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-treatment-patients-limited-treatment-options

3. Kozal M, Aberg J, Pialoux G, et al; BRIGHTE Trial Team. Fostemsavir in adults with multidrug-resistant HIV-1 infection. 

. 2020;382(13):1232-1243. doi:10.1056/NEJMoa1902493

4. Long-acting injectable form of HIV prevention outperforms daily pill in NIH study. News release. National Institutes of Health. July 7, 2020. Accessed October 13, 2020. 

https://www.nih.gov/news-events/news-releases/long-acting-injectable-form-hiv-prevention-outperforms-daily-pill-nih-study

Peer Exchange

An expert panel discussion around long-acting injectables' role in both preventing and treating HIV.

Emerging Options for Treatment and Prevention of HIV Infection

Biologics have traditionally been used to treat patients with cancer and various inflammatory diseases. More recently, biologics have emerged as a novel treatment modality in recurrent 

infection (CDI). Currently, the recommended first-line treatment of CDI includes oral antibiotics vancomycin and fidaxomicin.

 However, comprehensive management of CDI cannot be achieved with antibiotics alone, as they disrupt the normal gut flora and do not target 

 spores. Fidaxomicin and fecal microbiota transplant (FMT) have been favored in the management and prevention of recurrent CDI due to their theorized ability to combat microbiota dysbiosis. With mounting evidence of the correlation among antibiotic use, host microbiota dysbiosis, and recurrent CDI, biologics and novel strategies may also play a key role in CDI therapy.

Bezlotoxumab (Zinplava) is a human monoclonal antibody that was approved by the United States Food and Drug Administration (FDA) in October 2016 as adjunctive therapy for the management of patients at high risk for recurrent CDI. 

exerts its pathologic effects primarily through the production of enterotoxin (toxin A) and cytotoxin (toxin B).

 Bezlotoxumab functions by binding to and neutralizing the effects of toxin B. Bezlotoxumab received FDA approval based on the results of the MODIFY I and MODIFY II phase 3 clinical trials. Results of these trials showed significant reduction in the recurrence of CDI up to 12 weeks after initial resolution of symptoms with bezlotoxumab when compared with placebo (MODIFY I: 28% vs 17%, respectively, 

 <.001; MODIFY II: 26% vs 16%, respectively, 

 Bezlotoxumab is generally well tolerated; however, there was found to be an increased incidence of heart failure (HF) among those with underlying HF when compared with placebo.

Data support the routine use of bezlotoxumab for the management of recurrent CDI. While the 2018 Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) clinical practice guidelines do not provide guidance for incorporating its use into routine practice, bezlotoxumab may be recommended in combination with fidaxomicin in a subset of patients at high risk for recurrent disease in the next iteration of the guidelines.

 Results from a post hoc analysis of the MODIFY trials suggested patients at highest risk of recurrence included those who were aged ≥ 65 years, had compromised immunity, severe CDI, prior CDI episode(s), and infection with ribotypes 027/078/2442,6. The greatest benefit observed with bezlotoxumab was in patients with ≥ 3 risk factors.

Bezlotoxumab may help address the significant clinical and economic impacts seen by recurrent CDI. A 20% to 30% rate of recurrence has been shown among patients treated with antibiotics (primarily vancomycin and metronidazole) for CDI.

 Recurrent infection leads to increased length of hospital stay, prolonged antibiotic exposure, and increased morbidity and mortality.

 Recurrent CDI also creates significant financial costs. Approximately $8.2 billion was spent on CDI hospital stays in 2009, with a recurrent episode estimated to cost $11,146 more than an initial episode.

 On an institutional level, there is also the associated cost of infection prevention services to mitigate transmission to staff and patients. Bezlotoxumab administered as a single 10-mg/kg intravenous dose has the potential to offset these costs by preventing readmission for recurrent CDI. The average wholesale price of bezlotoxumab is estimated to be $114 per milliliter (1 gram per 40 milliliter vial).

 Not including administrative costs, insurance coverage, and unique drug pricing strategies the cost for a patient weighing 70 kg would be approximately $3192. To determine the cost-effectiveness of bezlotoxumab compared with placebo, Prabhu et al conducted a computer-based study to assess incremental cost comparisons and impact on quality-adjusted life-years (QALYs). They determined the incremental cost for receiving bezlotoxumab to be $2444 per patient.

 They also found a reduction in CDI recurrence and a 0.12 difference in QALY between the bezlotoxumab (8.45 QALY) and placebo (8.33 QALY) groups.

 Bezlotoxumab may help offset costs associated with recurrent CDI readmissions as well as enhance patients’ quality of life.

Results from additional post hoc analyses of the MODIFY trials showed no difference in recurrent CDI when bezlotoxumab was administered on days 0–2 or 3–4, or ≥ 5 days after the initiation of standard-of-care oral antibiotics (vancomycin, metronidazole, or fidaxomicin).

 Also, bezlotoxumab did not reduce the duration of diarrhea. Given the cost of the drug, and its use primarily to prevent recurrence, bezlotoxumab is often reserved for outpatient use. To truly carve out a niche for its use in CDI therapy, cost and efficacy comparisons between bezlotoxumab with other antibiotics and biologic strategies, such as FMT, are needed. Data suggest that treatment of CDI with fidaxomicin has a lower risk of second recurrence compared with vancomycin.

 The impact of using bezlotoxumab in patients treated with fidaxomicin would further help identify a definitive role for bezlotoxumab in CDI therapy.

As with bezlotoxumab, FMT and bacteriophage therapies have been introduced to further combat the microbiota disruption seen with traditional antibiotic treatment. FMT is recommended for patients with second or subsequent CDI who have failed appropriate antibiotic treatments.

 Guideline recommendations of 2 or more failed antibiotic treatments prior to FMT is largely based on expert opinion. Results from observational and randomized clinical trials showed treatment success rates between 77% and 94%.

 The highest success rates were observed with instillation of feces via the colon (80%-100%), and results from other studies suggested increased success with more than 2 FMT administrations.

 A small, randomized controlled trial comparing FMT with standard vancomycin 14-day treatment, with the primary end point of resolution of diarrhea without relapse after 10 weeks, was terminated early due to significant differences favoring resolution in the FMT arm.

 FMT is generally safe; however, there is a risk of physical complications with instillation and transmission of infection from donors. Of recent concern is the transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). COVID-19 can cause gastrointestinal symptoms, and the virus has been detected in stool.

 However, the transmission of COVID-19 infection by fecal route is unclear.

 The primary supplier of FMT, OpenBiome, suggests it is providing appropriate COVID-19 screening of all FMT donors.

Bacteriophage therapy is the use of viruses to specifically infect bacteria.

 Many bacteriophages have narrow ranges of host targets, which help prevent the dysbiosis seen with antibiotics. Furthermore, bacteriophages can potentially degrade and penetrate biofilms.

 Data for bacteriophage use is promising; however, identification of definitive targets for CDI are ongoing.

Antimicrobial stewardship can aid in identifying patients at risk for CDI recurrence, disease progression, and those who may benefit from biologic therapies. Although expensive compared with antibiotic treatment options, biologic therapy can provide cost savings in the long term by preventing recurrence leading to hospitalization. Antimicrobial stewardship programs can also help prevent the inappropriate use of agents like bezlotoxumab by redirecting their use to the outpatient setting. Administration of bezlotoxumab in the outpatient setting ensures the health care system will be reimbursed for the cost of the drug by third-party payers. Biologics are a novel and promising treatment option, particularly for patients with CDI refractory to antibiotic therapy. More data would assist in the incorporation of these agents into the CDI treatment algorithm in a way that is beneficial to the patient and cost-effective.

Helen Berhane, PharmD, is a PGY2 infectious diseases pharmacy resident at the University of California, Davis Medical Center in Sacramento.

Jennifer Curello, PharmD, BCIDP, is an infectious diseases clinical pharmacist at the University of California, Davis Medical Center in Sacramento.

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. 2018;9:1701. Published 2018 Jul 31. doi:10.3389/fmicb.2018.01701

Stewardship and Prevention

Biologics have become a novel treatment in recurrent C. difficile.

The Role of Antimicrobial Stewardship in the Treatment of C difficile

Antimicrobial-resistant (AMR) bacteria pose grave threats to global public health. In the United States, AMR organisms are estimated to cause an estimated 2.8 million infections per year, resulting in more than 35,000 deaths.

Infections caused by gram-negative bacteria (GNB), like extended-spectrum β-lactamase–producing 

 (CRE), and difficult-to-treat resistance (DTR) non-lactose fermenters, such as 

, are therapeutic challenges. Controversies and uncertainties about the roles of older, broad-spectrum agents in the treatment of ESBL-E infections persist, despite the failure of piperacillin-tazobactam to demonstrate noninferiority compared with meropenem in the landmark MERINO trial, which compared the treatments in patients with bacteremia caused by third-generation cephalosporin-resistant 

Since late 2014, 7 novel antibiotics with activity against ESBL-E, CRE, and/or DTR 

 have been approved by the United States Food and Drug Administration: ceftazidime-avibactam (Avycaz), ceftolozane-tazobactam (Zerbaxa), plazomicin (Zemdri), meropenem-vaborbactam (Vabomere), imipenem-cilastatin-relebactam (Recarbrio), cefiderocol (Fetroja), and eravacycline (Xerava).

While these agents offer advantages in effectiveness and safety over colistin or polymyxin B, and the long-standing, last-resort antibiotics against CRE or DTR 

infections, their uptake into clinical practice has been slow. Moreover, there is considerable confusion among clinicians where specific drugs fit within therapeutic hierarchies.

In parallel with the development of new antibiotics, there have been advances in defining AMR GNB epidemiology. Widespread implementation of rapid and/or molecular diagnostics allow clinicians to identify AMR organisms and characterize resistance mechanisms in real time. Clinical application of molecular platforms and laboratory-based genomic data (such as those generated in the CRACKLE project)

 have demonstrated that CRE in the US is not synonymous with 

carbapenemase (KPC) production. Indeed, it is clear that CRE are due to a variety of non-KPC mechanisms, including production of metallo-β-lactamases (such as New Delhi metallo-β-lactamase) or porin mutations combined with non-carbapenemase β-lactamase production.

Molecular data are not simply of academic interest, as many new antibiotics are active against strains expressing particular resistance determinants. Therefore, optimal treatment decisions against CRE and other AMR GNB infections require clinicians to be familiar with local epidemiology and resistance mechanisms.

The Infectious Diseases Society of America (IDSA) identified the development and dissemination of timely practice recommendations as a top initiative in its 2019 Strategic Plan.

 The just-released IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections offers practical recommendations for antibiotic management of ESBL-E, CRE, and DTR 

 In the Strategic Plan, IDSA acknowledged that traditional timelines used to generate new or updated clinical practice guidelines limited the ability to address rapidly evolving topics like antimicrobial resistance. IDSA endorsed developing more narrowly focused guidance documents for the treatment of specific, complex infectious processes based on critical review of published data and expert opinion, rather than formal GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. A panel of 5 physicians and 1 pharmacist with clinical and research expertise in the treatment of patients with AMR GNB infections was assembled and given the latitude to identify key problem areas that are addressed in the initial document.

The panel held an initial meeting in March 2020, at which time the 3 pathogen groups above were chosen. Other pathogens were discussed, including AmpC-producing Enterobacterales

, but were left to subsequent iterations to facilitate timely completion of the initial publication of the first guideline. The panel was split into 3 groups of 2 members each to draft guidance for each of the 3 pathogen groups; recommendations made in the final document were discussed among the entire group over a series of subsequent meetings.

As with any guidance document, opinions differed; however, the panel came to a consensus over each recommendation. The final document addresses 18 important clinical questions and includes 4 summary tables, one of which includes recommended antimicrobial dosing for each recommended agent. As the guidance was intended to be an easily accessible summary, an extensive review of the evidence and detailed rationale were not included for each recommendation. Rather, the panelists intend to provide this additional information as complementary published reviews.

There are several key recommendations in the guidance that should be specifically mentioned. First and foremost, the polymyxins (colistin and polymyxin B) are not recommended for treating any infections by the various pathogens (with one exception) as long as one of the novel β-lactam/β-lactamase inhibitor combinations remains active. Simply put, nearly any alternative is preferred. The sole exception to this is DTR 

 infections in which cefiderocol is the only active β-lactam. Results from the recently published CREDIBLE-CR trial

 demonstrated an unexplained mortality imbalance favoring primarily polymyxin-based combination therapy over cefiderocol among patients treated for CR GNB infections, including those caused by DTR 

. For CRE infections, including those caused by metallo-β-lactamase–producing Enterobacterales, other new agents almost invariably are available and preferred over polymyxin-based therapy.

Since late 2004, 7 novel antibiotics with activity against ESBL-E, CRE, and/or DTR P aeruginosa have been approved.

Contagion, December 2020 (Vol. 05 No. 06)

A Case of Pneumonia and Bacteremia in a Trauma Patient Caused by Bordetella hinzii

Emerging Options for Treatment and Prevention of HIV Infection

The Role of Antimicrobial Stewardship in the Treatment of C difficile

IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections

Novel Salvage Therapy for Multidrug-Resistant HIV Infection

C. Difficile: Are We Making Progress?

Fostemsavir for Multidrug Resistant HIV-1: It’s Time for HIV to Overcome Attachment Issues With CD4 Cells

Entering the Phase of Phage: A Closer Look at Bacteriophage Therapy

Emergency Use Authorizations for COVID-19 Therapeutics: The Good, the Bad, and the Data-Deficient

Holiday Guest List—When the Uninvited Arrive: COVID-19 and Coinfections

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