Early de-escalation of antibiotic therapy in hospitalized cellular therapy adult patients with febrile neutropenia.

Febrile neutropenia (FN) is an oncologic emergency frequently encountered in hematopoietic cell transplant (HCT) and chimeric antigen receptor (CAR) T-cell therapy patients, which requires immediate initiation of broad-spectrum antibiotics. Data regarding antibiotic de-escalation (DE) in neutropenic patients are limited, and guideline recommendations vary. A clinical protocol for antibiotic DE of broad-spectrum agents was implemented if patients were afebrile after 72 hours and had no clinical evidence of infection. The primary endpoint was the difference in the number of antibiotic therapy days between the pre-and post-DE protocol implementation group. Secondary endpoints included rates of subsequent bacteremia during index hospitalization, 30-day mortality, and hospital length of stay. Retrospective chart reviews were conducted to assess outcomes for patients who received allogeneic HCT, autologous HCT, or CAR T-cell therapy under the antibiotic de-escalation protocol (post-DE) compared to those who did not (pre-DE). The pre-DE group underwent HCT/CAR T-cell from February 2018 through September 2018 (n=64), and the post-DE group from February 2019 through September 2019 (n=67). The median duration of antibiotics was significantly lower in the post-DE group (6 days; range 3-60 days) compared to the pre-DE group (8 days; range 3-31 days) (p=0.034). There were no differences in any secondary endpoints. We conclude that antibiotic DE in neutropenic HCT or CAR T-cell therapy patients treated with broad-spectrum antibiotics for at least three days who are afebrile and without documented infection appears to be a safe and effective practice. Adopting it significantly reduces the number of days of antibiotics without compromising patient outcomes.

Implementation of routine Clostridioides difficile infection (CDI) primary prophylaxis in lung transplant recipients.

Lung transplant recipients are at an increased risk for Clostridioides difficile infection (CDI), and those who develop CDI post-transplant can have worsened outcomes including graft failure and death. We sought to describe the efficacy and safety of primary CDI prophylaxis with oral vancomycin among 86 adult lung transplant recipients. Overall, we observed a 9.3% (8/86) incidence of CDI among patients receiving prophylaxis, with the majority of infections occurring a median of 25 days after completion of prophylaxis. Furthermore, we observed a 4.7% incidence of VRE infection/colonization. Opportunities exist to optimize the duration of CDI prophylaxis to balance the benefits and risks in lung transplant recipients.

Determinants of Vancomycin Trough Concentration in Patients Receiving Continuous Veno-Venous Hemodialysis.

BACKGROUND: Vancomycin pharmacokinetics are altered in the critically ill and are further distorted by renal replacement therapy. Limited literature is available evaluating vancomycin dosing in continuous veno-venous hemodialysis (CVVHD). OBJECTIVE: The goal of this analysis was to identify factors that affect vancomycin trough concentration in patients on CVVHD and to determine an appropriate dosing strategy. METHODS: This was a single-center, retrospective cohort study of adult inpatients admitted to the Cleveland Clinic from May 2016-December 2017. Patients in the intensive care unit who received ≥ 2 doses of vancomycin during CVVHD were included. Patients with interruptions of CVVHD inappropriately timed troughs, a change in dialysate rate, and those who received different vancomycin dosages were excluded. Multivariable linear regression including age, sex, weight, Sequential Organ Failure Assessment score, albumin, 24-hour urine output (UOP), dialysate rate, filter type, and vancomycin dose was run to determine predictors of vancomycin concentration. RESULTS: A total of 160 patients were included. The median vancomycin dose was 12.6 mg/kg with a trough of 24.6 mcg/mL. Weight, 24-hour UOP, vancomycin dose (mg/kg), and dialysate rate (mL/kg/h) were all determined to be independent predictors of vancomycin trough level. Patients who received <10 mg/kg doses of vancomycin (N=18) achieved a median trough of 21.5 mcg/mL, with 83% being therapuetic. In patients who received >10 mg/kg (N=142), the median trough was 25.5 mcg/mL, with 47% being therapeutic. CONCLUSION AND RELEVANCE: Vancomycin dose, dialysate rate, UOP, and weight are independently associated with vancomycin trough concentration. In CVVHD patients, vancomycin dosed at 10 mg/kg every 24 hours may be an appropriate recommendation.

Implementation of a Leeches + Antimicrobial Prophylaxis Order Panel to Optimize Medicinal Leech Use at a Tertiary Care Academic Medical Center.

Medicinal leech therapy promotes vascular flow and can be used to salvage grafts. Medicinal leeches have a symbiotic relationship with Aeromonas species and can therefore present a risk of bacterial transmission to patients. Antimicrobial prophylaxis is warranted for the duration of leech therapy, however, an institutional evaluation of 40 patients receiving medicinal leech therapy demonstrated poor adherence with recommendations. An electronic medical record order panel for antimicrobial prophylaxis with medicinal leech therapy was implemented, leading to a subsequent improvement in adherence to prophylaxis use, including significant increases in the ordering of antibiotics and the appropriate timing of initiation in the subsequent 10 patients receiving medicinal leech therapy after panel implementation. Aeromonas infections were rare before and after panel implementation, and developed only in the patient subset with non-optimized prophylaxis.

Pre-transplant vaccination compliance in adult heart and lung transplant recipients.

BACKGROUND: Vaccine preventable diseases can affect solid organ transplant recipients post-transplant. Therefore, the administration of vaccines and assessment of serologic response should be prioritized in the pre-transplant period. METHODS: This single-center, retrospective study included 349 adult heart or lung transplant candidates between December 1, 2017 and November 30, 2019. We describe vaccination or serologic status for hepatitis A, hepatitis B, tetanus, pneumococcal, influenza, and other recommended vaccinations among heart or lung transplant candidates. RESULTS: Eighty-two heart transplant candidates (91%) and 77 lung transplant candidates (30%) received an ID consult prior to transplant. More patients completed the pneumococcal series (66.7% vs. 28.6%, P = .045) in the heart transplant group that received an ID consult. In the lung transplant group, patients with an ID consult demonstrated higher rates of immunity to hepatitis A (84.4% vs. 72.9%, P = .047), hepatitis B (75.3% vs. 56.9%, P = .005), and measles (71.4% vs. 52.5%, P = .005) compared to those without. CONCLUSIONS: Our results demonstrate the value of consulting ID and administering vaccinations in the early evaluation phase, prior to transplant listing. Opportunities remain to better optimize vaccination rates prior to transplant in heart and lung transplant candidates.

Antimicrobial use in central nervous system infections.

PURPOSE OF REVIEW: Central nervous system (CNS) infections are associated with high rates of morbidity and mortality. The purpose of this review is to summarize current antimicrobial therapies, as well as, updates in the management of community-acquired meningitis and healthcare-associated meningitis and ventriculitis. RECENT FINDINGS: Due to the increasing rates of multidrug resistant and extensively-drug resistant organisms, available antimicrobials are limited. Novel treatment options include newer systemic antimicrobials and antimicrobials that have previously limited data in the management of CNS infections. Although limited by retrospective data, intrathecal (IT) and intraventricular (IVT) routes of administration offer the opportunity for antimicrobials that conventionally have minimal cerebrospinal fluid (CSF) penetration to achieve high CSF concentrations while minimizing systemic exposure. SUMMARY: Updates in the use of systemic, IT, and IVT antimicrobials offer promise as therapeutic options for CNS infections. Additional pharmacokinetic and prospective data are needed to confirm these findings.

Multicenter point prevalence evaluation of the utilization and safety of drug therapies for COVID-19 at the onset of the pandemic timeline in the United States.

KEY POINTS: In a multicenter point-prevalence study, we found that the rate of supportive care was high; among those receiving COVID-19 drug therapies, adverse reactions occurred in 12% of patients. PURPOSE: There are currently no FDA-approved medications for the treatment of coronavirus disease 2019 (COVID-19). At the onset of the pandemic, off-label medication use was supported by limited or no clinical data. We sought to characterize experimental COVID-19 therapies and identify safety signals during this period. METHODS: We conducted a noninterventional, multicenter, point prevalence study of patients hospitalized with suspected/confirmed COVID-19. Clinical and treatment characteristics within a 24-hour window were evaluated in a random sample of up to 30 patients per site. The primary objective was to describe COVID-19-targeted therapies. The secondary objective was to describe adverse drug reactions (ADRs). RESULTS: A total of 352 patients treated for COVID-19 at 15 US hospitals From April 18 to May 8, 2020, were included in the study. Most patients were treated at academic medical centers (53.4%) or community hospitals (42.6%). Sixty-seven patients (19%) were receiving drug therapy in addition to supportive care. Drug therapies used included hydroxychloroquine (69%), remdesivir (10%), and interleukin-6 antagonists (9%). Five patients (7.5%) were receiving combination therapy. The rate of use of COVID-19-directed drug therapy was higher in patients with vs patients without a history of asthma (14.9% vs 7%, P = 0.037) and in patients enrolled in clinical trials (26.9% vs 3.2%, P < 0.001). Among those receiving drug therapy, 8 patients (12%) experienced an ADR, and ADRs were recognized at a higher rate in patients enrolled in clinical trials (62.5% vs 22%; odds ratio, 5.9; P = 0.028). CONCLUSION: While we observed high rates of supportive care for patients with COVID-19, we also found that ADRs were common among patients receiving drug therapy, including those enrolled in clinical trials. Comprehensive systems are needed to identify and mitigate ADRs associated with experimental COVID-19 treatments.

Multicenter point-prevalence evaluation of the utilization and safety of drug therapies for COVID-19.

BACKGROUND: There are currently no FDA-approved medications for the treatment of COVID-19. At the onset of the pandemic, off-label medication use was supported by limited or no clinical data. We sought to characterize experimental COVID-19 therapies and identify safety signals during this period. METHODS: We conducted a non-interventional, multicenter, point prevalence study of patients hospitalized with suspected/confirmed COVID-19. Clinical and treatment characteristics within a 24-hour window were evaluated in a random sample of up to 30 patients per site. The primary objective was to describe COVID-19 targeted therapies. The secondary objective was to describe adverse drug reactions (ADRs). RESULTS: A total of 352 patients from 15 US hospitals were included. Most patients were treated at academic medical centers (53.4%) or community hospitals (42.6%). Sixty-seven patients (19%) were receiving drug therapy in addition to supportive care. Drug therapies included hydroxychloroquine (69%), remdesivir (10%), and interleukin-6 inhibitors (9%). Five patients (7.5%) were receiving combination therapy. Patients with a history of asthma (14.9% vs. 7%, p=0.037) and those enrolled in clinical trials (26.9% vs. 3.2%, p<0.001) were more likely to receive therapy. Among those receiving COVID-19 therapy, eight patients (12%) experienced an ADR, and ADRs were more commonly recognized in patients enrolled in clinical trials (62.5% vs 22%, OR=5.9, p=0.028). CONCLUSIONS: While we observed high rates of supportive care for patients with COVID-19, we also found that ADRs were common among patients receiving drug therapy including in clinical trials. Comprehensive systems are needed to identify and mitigate ADRs associated with experimental COVID-19 therapies.

Tocilizumab therapy in 5 solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2.

There are emerging data depicting the clinical presentation of coronavirus disease 19 (COVID-19) in solid organ transplant recipients but negligible data-driven guidance on clinical management. A biphasic course has been described in some infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), beginning with a flu-like illness followed by an intense inflammatory response characterized by elevated c-reactive protein (CRP), interleukin 6 (IL-6), and acute respiratory distress syndrome (ARDS) associated with high mortality. The exuberant and possibly dysregulated immune response has prompted interest in therapeutic agents that target the cytokines involved, particularly IL-6. Tocilizumab is an IL-6 receptor antagonist with a record of use for a variety of rheumatologic conditions and cytokine release syndrome due to chimeric antigen receptor T-cell therapy but experience in solid organ and composite tissue transplant recipients (SOT/CTTRs) with SARS-CoV-2-related ARDS has not been previously reported in detail. We present the clinical course of 5 SOT/CTTRs with SARS-CoV-2-related ARDS that received tocilizumab with favorable short-term outcomes in 4. Responses were characterized by reductions in CRP, discontinuation of vasopressors, improved oxygenation and respiratory mechanics, and variable duration of ventilator support. Four bacterial infections occurred within 2 weeks of tocilizumab administration. We discuss safety concerns and the need for randomized comparative trials to delineate tocilizumab's clinical utility in this population.

Antivirals for COVID-19.

Drugs targeting RNA respiratory viruses have resulted in few effective therapies, highlighting challenges for antivirals to treat COVID-19. Several antivirals are being investigated for symptomatic COVID-19 but no definitive data support their clinical use. Remdesivir appears to result in favorable outcomes with shortened time to recovery and a modest decrease in mortality for hospitalized patients in compassionate use series and some randomized controlled trials. Currently, remdesivir is available only from the US government via an emergency use authorization process. A randomized controlled trial of lopinavir/ritonavir demonstrated no apparent clinical or virologic benefit and drug-drug interactions and side effects further limit its utility. Antivirals to treat influenza (oseltamivir) have limited activity against SARS-CoV-2, but favipiravir and umifenovir, two influenza antivirals available internationally, may have distinct viral targets and require further investigation. Antivirals with evidence of clinical activity must be studied as treatment and prophylaxis for those at high risk for severe COVID-19.

Comparison of Single-Dose and Extended-Duration Empiric Aminoglycoside Combination Therapy in Patients With Septic Shock.

BACKGROUND: Empiric combination antimicrobial therapy is often used in patients with decompensating septic shock. However, the optimal duration of combination therapy is unknown. STUDY QUESTION: The goal of this study was to compare the clinical effects of a single dose of an aminoglycoside to an extended duration of aminoglycosides for combination therapy in patients with septic shock without renal dysfunction. STUDY DESIGN: Retrospective, single-center evaluation of patients with septic shock who received empiric combination therapy with an aminoglycoside. MEASURES AND OUTCOMES: Two patient cohorts were evaluated: those who received a single dose of an aminoglycoside and those who received more than 1 dose of an aminoglycoside. The primary outcome was shock-free days at day 14. Secondary outcomes included mortality, length of stay, clinical cure, and nephrotoxicity. A post hoc subgroup analysis including only patients who received more than 2 doses of an aminoglycoside compared with a single dose was conducted. RESULTS: One hundred fifty-one patients were included in this evaluation, 94 in the single-dose aminoglycoside group and 57 in the extended duration group. There was no difference in shock-free days at day 14 between patients who received a single dose of an aminoglycoside or those who received an extended duration (12.0 vs. 11.6 days; P = 0.56). There were no differences in mortality, length of stay, clinical cure rates, or rates of nephrotoxicity between groups (28% for single dose vs. 26% for extended duration; P = 0.86). No differences in outcomes were detected when evaluating patients who received more than 2 doses of an aminoglycoside compared with a single dose. CONCLUSIONS: Patients with septic shock and normal renal function who received a single dose of an aminoglycoside for combination antimicrobial therapy had no differences detected in shock duration or nephrotoxicity development compared with those who received an extended duration of aminoglycoside combination therapy.

Pharmacist-led Penicillin Allergy Assessment in the Emergency Department Reduced Empiric Fluoroquinolone Use.

In a retrospective, quasi-experimental study of 380 adult patients with a reported penicillin allergy who received antibiotics at a community hospital emergency department, a pharmacist-led penicillin allergy assessment via medical records review and patient interview improved guideline-preferred antibiotic use by 13% (P = .018) and reduced fluoroquinolone use by 11% (P = .035).

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms.

Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many ß-lactamases, including extended spectrum ß-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactose-fermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

Evaluation of 3 Months of Once-Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection.

Background: Centers for Disease Control and Prevention recommends 3 months of once-weekly rifapentine/isoniazid (3HP) for latent tuberculosis infection (LTBI) treatment given by directly observed therapy (DOT) or self-administered therapy (SAT) in patients ≥2 years old. 3HP has been associated with increased incidence of hepatic, gastrointestinal, flu-like, and cutaneous adverse drug reactions (ADRs) compared with isoniazid monotherapy. Objective: This study evaluated 3HP completion rates and tolerability for LTBI treatment in a real-world setting. Methods: A single-center retrospective cohort with a nested case-control study, comparing patients experiencing ADRs with those who did not, evaluated patients ≥18 years old receiving 3HP by DOT or SAT for LTBI at Cleveland Clinic from October 2011 through July 2018. Information on baseline characteristics, 3HP administrations, and ADRs were collected. Results: Of 199 patients screened, 144 were included (111 DOT, 33 SAT). 3HP completion rates were high at 82.6% and similar between DOT and SAT groups. During treatment, 92/144 (63.9%) patients experienced any ADR. The most common ADR included flu-like symptoms (38.2%) and gastrointestinal (31.9%) and hepatic (2.1%) reactions. Despite high rate of overall ADRs, rates of significant ADRs (grade 2 or higher) were 4.2%. Overall, 9% of patients discontinued 3HP because of ADRs. After adjusting for other factors associated with ADRs at baseline, SAT was not associated with increased incidence of ADRs, but female sex was a significant predictor (odds ratio = 2.61 [95% CI, 1.23 to 5.56]). Conclusion and Relevance: This study observed high 3HP treatment completion rates, low incidence of significant ADRs, and low discontinuation rates resulting from ADRs.

Penicillin allergy skin testing as an antibiotic stewardship intervention reduces alternative antibiotic exposures in hematopoietic stem cell transplant recipients.

BACKGROUND: Antibiotic allergy de-labeling using penicillin allergy skin testing (PAST) can reduce the use and cost of alternative, non-ß-lactam antibiotics in general inpatient populations. This strategy's role in hematopoietic stem cell transplant (HSCT) recipients is unclear. METHODS: This study aimed to determine the effect of a pre-transplant PAST protocol on antibiotic use, days of therapy (DOT), and cost in an immunocompromised population at a single center from 7/1/2010-2/1/2019. Patients who received chimeric antigen receptor (CAR) T-cell therapy and those who underwent transplantation in the outpatient setting were excluded. RESULTS: Of 1560 patients who underwent inpatient HSCT during the study period, 208 reported ß-lactam allergy (136/844 [16%] pre- and 72/716 [10%] post-implementation; P < .001). PAST was performed on 7% and 54% of HSCT recipients pre- and post-implementation, respectively. Only two positive PAST were noted. There were no adverse reactions to PAST. There were no significant differences in the disease and transplant characteristics between the two groups. Days of therapy and cost of alternative antibiotics significantly decreased post-implementation (mean 788 vs 627 days, P = .01; mean $24 425 vs $17 518, P = .009). CONCLUSION: Penicillin allergy skin testing adjudicates reported ß-lactam allergy in HSCT recipients, lowering use, DOT, and cost of alternative antibiotics and promoting effective formulary agents to treat immunocompromised HSCT recipients.

Implementation of a Stewardship Initiative on Respiratory Viral PCR-based Antibiotic Deescalation.

OBJECTIVE: Respiratory viral polymerase chain reaction (RV PCR) tests assist in rapidly identifying viral pathogens and differentiating viral versus bacterial causes of pneumonia. Studies evaluating the use of RV PCR tests on antibiotic use in adults have demonstrated mixed results. We implemented an antimicrobial stewardship (ASP) intervention for patients with a positive RV PCR test result who were receiving broad-spectrum antibiotics and aimed to assess the impact on antibiotic usage. METHODS: Retrospective quasi-experimental study of adult hospitalized patients comparing time to antibiotic deescalation, duration of antibiotic therapy, and antiviral use preintervention (January-March 2016) and postintervention (January-March 2017). RESULTS: Of 172 ASP alerts reviewed, 55 (32%) were considered actionable. Of these, 47% of interventions were accepted. No significant difference was observed in median time to antibiotic deescalation (pre: 2.7 days vs post: 2.3 days, p=0.88). Time to discontinuation of antimicrobial therapy pre- and postintervention was reduced from 4 to 1.9 days (p=0.057) for piperacillin-tazobactam, from 2.7 to 1.8 days (p=0.75) for ceftriaxone, and from 3.6 to 2 days (p=0.4) for levofloxacin, respectively. Time to initiation of oseltamivir for influenza was significantly shorter in the postintervention group (pre: 11.3 hrs vs post: 3.6 hrs, p=0.02). CONCLUSION: A third of patients receiving broad-spectrum antibiotics with a positive RV PCR had an opportunity for antimicrobial optimization, although this did not translate into a significant impact on the time to antibiotic deescalation or overall antibiotic use. Combination of RV PCR results with biomarkers to rule out bacterial coinfections and chest radiographic findings may help enhance the likelihood of accepted antibiotic deescalation recommendations and represents an area of future research.

Evaluation of an electronic antimicrobial time-out on antimicrobial utilization at a large health system.

We evaluated the impact of an electronic health record based 72-hour antimicrobial time-out (ATO) on antimicrobial utilization. We observed that 6 hours after the ATO, 21% of empiric antimicrobials were discontinued or de-escalated. There was a significant reduction in the duration of antimicrobial therapy but no impact on overall antimicrobial usage metrics.

Detection of colistin heteroresistance in Acinetobacter baumannii from blood and respiratory isolates.

Polymyxins are one of the last-line antibiotics for multidrug-resistant Acinetobacter baumannii. Reports have demonstrated the emergence of colistin heteroresistance in A. baumannii, which can complicate assessment of minimum inhibitory concentrations and promote resistance to colistin. We aimed to determine the presence of colistin heteroresistance in A. baumannii isolates and correlate the results with clinical and microbiological outcomes via a retrospective study of 24 adult patients: 12 blood and 12 invasive respiratory cultures positive for colistin-susceptible A. baumannii between 1 January 2013 and 31 July 2015. Heteroresistance testing was performed by plating a 100-µL bacterial cell suspension on Mueller-Hinton agar plates containing 0, 1, 2, and 4 µg/mL colistin, and assessing for growth at 24 and 48 h. Colistin heteroresistance was exhibited in 83% of isolates. Median age was 56 [43-65] years, 10 (42%) patients resided at a facility prior to admission, 5 (21%) had a chronic tracheostomy, 18 (75%) were in the intensive care unit at the time of culture collection, and median infection-related length of stay was 12 [7-15] days. Clinical and microbiological cures were achieved in 75% of patients. Overall infection-related mortality was 21%. Our study demonstrated a high rate of colistin heteroresistance in clinical isolates of colistin-susceptible A. baumannii, although this was not associated with suboptimal clinical outcomes due to the use of aggressive colistin dosing and combination therapy. Further studies are needed to establish the association between in vitro colistin heteroresistance and clinical and microbiological outcomes.