Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review.

IMPORTANCE: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. OBSERVATIONS: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. CONCLUSIONS AND RELEVANCE: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

miR-21 mediates hematopoietic suppression in MDS by activating TGF-ß signaling.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. We observed that SMAD7, a negative regulator of transforming growth factor-beta (TGF-ß) receptor-I kinase, is markedly reduced in MDS and leads to ineffective hematopoiesis by overactivation of TGF-ß signaling. To determine the cause of SMAD7 reduction in MDS, we analyzed the 3'UTR of the gene and determined that it contains a highly conserved putative binding site for microRNA-21. We observed significantly elevated levels of miR-21 in MDS marrow samples when compared with age-matched controls. miR-21 was shown to directly bind to the 3'UTR of SMAD7 and reduce its expression in hematopoietic cells. Next, we tested the role of miR-21 in regulating TGF-ß signaling in a TGF-ß-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with a chemically modified miR-21 inhibitor led to significant increases in hematocrit and led to an increase in SMAD7 expression in vivo. Inhibition of miR-21 also led to an increase in erythroid colony formation from primary MDS bone marrow progenitors, demonstrating its ability in stimulating hematopoiesis in vitro. Taken together, these studies demonstrate the role of miR-21 in regulating overactivated TGF-ß signaling in MDS.

Medication reconciliation by a pharmacist in patients with HIV on antiretroviral therapy: the needed balance of availability and expertise.

Medication reconciliation is an important process to help reduce medication errors.1,2 Based on our experience, pharmacists enhance the medication reconciliation process in this high-risk group. However, such interventions need to be carefully implemented. Pharmacy technicians, although readily available and potentially beneficial, may lack the necessary expertise with complicated ART regimens or multiple comorbidities because they are usually unable to critically evaluate for appropriateness.5 Pharmacy residents and non-ID/HIV-specialized pharmacists could fill the gap of availability, but they need to be properly trained on the disease and medication management. Initially, they should be allowed to shadow an experienced pharmacist, provided with a structured approach, and have access to a specialist in the field if one is available. We understand that not all institutions have the resources to hire full-time ID/HIV pharmacists; in that situation, involvement of trained general pharmacists will be helpful. Furthermore, having only ID/HIV-specialized pharmacists conduct medication reconciliation may lead to substandard care if one is unavailable on weekends or holidays. A more standardized and sustained effort is clearly needed.

Nested case-control study of the emergence of tigecycline resistance in multidrug-resistant Klebsiella pneumoniae.

We performed a nested case-control study (ratio of 1:4) on the emergence of tigecycline-resistant multidrug-resistant Klebsiella pneumoniae (TR-MDRKP) isolates among patients who initially presented with a tigecycline-susceptible MDRKP isolate. Out of 260 patients, 24 (9%) had a subsequent clinical culture positive for a TR-MDRKP isolate within the 90-day follow-up period. On logistic regression analyses, receipt of tigecycline (adjusted odds ratio [OR], 5.06; 95% confidence interval [CI], 1.80 to 14.23; P = 0.002) was the only independent predictor of subsequent isolation of a TR strain.

Impact of an Educational and Laboratory Stewardship Intervention on Inpatient COVID-19 Therapeutics at a Veterans Affairs Medical Center.

Background: Accurate and timely prescriptions of COVID-19 therapeutics, laboratory testing, and antimicrobial stewardship have been a challenge throughout the pandemic as new evidence emerges. While universal consultation with infectious disease specialists on patients admitted with COVID-19 is desirable, it is not always feasible due to limited resources. Observations: In this single-center study, we implemented a combined educational and laboratory stewardship intervention geared toward hospitalist practitioners resulting in improved accuracy of remdesivir and dexamethasone prescriptions, reduced laboratory use of blood cultures, interleukin 6 assay, and Legionella sputum cultures, and a decrease in antibiotic use for patients with mild-to-moderate oxygen requirements over 6 months. These improvements were seen in tandem with decreased reliance on infectious disease consultation. Conclusions: These efforts support proof of the principle of combined educational and laboratory stewardship interventions to improve the care of COVID-19 patients, especially where infectious disease consultation may not be available or is accessed remotely.

Pasteurella multocida Bacteremia Secondary to Peritoneal Dialysis Associated Peritonitis: A Case Report and Literature Review.

We report the fiftieth case in the literature of Pasteurella species peritoneal dialysis (PD)-related peritonitis and the third reported case of Pasteurella multocida bacteremia associated with PD-related peritonitis. Our review provides the most up-to-date collection of all fifty reported cases of PD-related peritonitis caused by Pasteurella species. A 77-year-old Caucasian male with a past medical history significant for new-onset left-ventricular systolic heart failure, severe mitral valve regurgitation, and end-stage renal disease on PD for six months presented to the emergency department with a one-week cloudy peritoneal effluent and intermittent abdominal pain. Pasteurella multocida was isolated from blood cultures and peritoneal fluid cultures. The patient was treated with intravenous piperacillin-tazobactam and intraperitoneal cefepime. The PD catheter was not removed or exchanged. A repeat blood culture on the third hospital day was negative. His hospital course was complicated by cardiogenic shock, atrial fibrillation, and gastrointestinal bleeding, and his goals of care changed to focus on comfort measures. This case report and literature review provide a resource for healthcare providers who may encounter this infection in the future. This case also serves as a reminder of the challenges of PD in patients at risk of acquired zoonotic infections from their pets. Based on the reviewed three cases of Pasteurella multocida bacteremia associated with PD-related peritonitis, blood cultures may be a prudent option for patients presenting with peritoneal dialysis associated peritonitis to ensure that concurrent bacteremia is not overlooked.

Impact of a Rapid Blood Culture Diagnostic Panel on Time to Optimal Antimicrobial Therapy at a Veterans Affairs Medical Center.

PURPOSE: Utilization of rapid diagnostic testing alongside intensive antimicrobial stewardship interventions improves patient outcomes. We sought to determine the clinical impact of a rapid blood culture identification (BCID) panel in an established Antimicrobial Stewardship Program (ASP) with limited personnel resources. METHODS: A single center retrospective pre- and post-intervention cohort study was performed following the implementation of a BCID panel on patients admitted with at least 1 positive blood culture during the study period. The primary outcome was time to optimal therapy from blood culture collection. Secondary outcomes included days of therapy (DOT), length of stay, and 30-day mortality and readmission rates. RESULTS: 277 patients were screened with 180 patients included, with 82 patients in the pre-BCID and 98 in the post-BCID arms. Median time to optimal therapy was 73.8 hours (IQR; 1.1-79.6) in the pre-BCID arm and 34.7 hours (IQR; 10.9-71.6) in the post-BCID arm (p ≤ 0.001). Median DOT for vancomycin was 4 and 3 days (p ≤ 0.001), and for piperacillin-tazobactam was 3.5 and 2 days (p ≤ 0.007), for the pre-BCID and post-BCID arms, respectively. Median length of hospitalization was decreased from 11 to 9 days (p = 0.031). No significant change in 30-day readmission rate was noted, with a trend toward lower mortality (12% vs 5%; p = 0.086). CONCLUSION: Introduction of BCID into the daily workflow resulted in a significant reduction in time to optimal therapy for bloodstream infections and DOT for select broad-spectrum antibiotics, highlighting the potential benefits of rapid diagnostics even in settings with limited personnel resources.

The management of treatment-experienced HIV patients (including virologic failure and switches).

Significant advances in the potency and tolerability of antiretroviral therapy (ART) have led to very high rates of virologic success for most who remain adherent to therapy. As a result, the life expectancy of people living with HIV (PLWH) has increased significantly. PLWH do, however, continue to experience a significantly higher risk of noninfectious comorbidities and chronic age-related complications, including cardiovascular disease and malignancies, which are now the biggest drivers of this excess morbidity and mortality. Therefore, in addition to virologic failure, the management of the treatment-experienced patient increasingly requires optimization of ART to enhance tolerability, avoid drug-drug interactions, and mitigate non-AIDS complications and comorbid conditions. This article will present principles of the management of virologic failure, poor immunologic recovery, and strategies for optimizing ART in the setting of virologic suppression.

Emerging therapies for the treatment of Helicobacter pylori infections.

OBJECTIVE: To describe emerging therapies, such as levofloxacin, moxifloxacin, rifabutin, rifaximin, tinidazole, doxycycline, minocycline, lactoferrin, and plaunotol for the eradication of Helicobacter pylori infection. DATA SOURCES: Relevant information was identified through a search of MEDLINE (1966-July 2008), PubMed (1955-July 2008), American Search Premier (1975-July 2008), International Pharmaceutical Abstracts (1960-2008), Science Citation Index Expanded (1996-2008), Cochrane Databases (publications archived until July 2008), and various tertiary sources using the terms Helicobacter pylori, fluoroquinolones, levofloxacin, moxifloxacin, rifabutin, rifaximin, lactoferrin, plaunotol, tinidazole, doxycycline, minocycline, faropenem, new treatments, refractory, and salvage alone or in combination. STUDY SELECTION AND DATA EXTRACTION: Relevant information was identified and selected based on clinical relevance and value of information. In vitro and in vivo data were included if available. DATA SYNTHESIS: Data exist supporting the use of levofloxacin or rifabutin as salvage therapies for H. pylori infection. Levofloxacin triple therapy has been recommended in the current treatment guideline, but more data are needed, especially from studies conducted in the US. A rifabutin-based regimen is better tolerated than conventional quadruple therapy, but its use is limited due to cost, hematologic adverse effects, drug interactions, and predicted development of resistance. Tinidazole appears to be an option, particularly as sequential therapy when combined with other agents; however, its use is limited by the high prevalence of nitroimidazole-resistant H. pylori strains in the US. Moxifloxacin data are limited. Data supporting the use of rifaximin, doxycycline, and minocycline are lacking or do not show benefit of these drugs over standard treatments. CONCLUSIONS: H. pylori infection remains one of the most significant infections worldwide, and treatment failure rate with the current standard therapy continues to rise. Other treatment options should be explored to meet the emerging challenge.

Linezolid for the treatment of Nocardia spp. infections.

OBJECTIVE: To review the available evidence regarding the use of linezolid for the treatment of Nocardia spp. infections. DATA SOURCES: Data were identified through a search of MEDLINE (1966-May 2007), American Search Premier (1975-May 2007), International Pharmaceutical Abstracts (1960-2007), Science Citation Index Expanded (1996-2007), and Cochrane Databases (publications archived until May 2007) using the terms linezolid and Nocardia. STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies, case reports, case series, and in vitro studies were eligible for inclusion if they used linezolid for nocardiosis regardless of site of infection and outcome. DATA SYNTHESIS: We identified 11 published cases of linezolid use for Nocardia spp. infections. The predominant species isolated were N. asteroides (n = 4; 36%) and N. farcinica (n = 3; 27%). Nocardiosis with central nervous system involvement (n = 7; 64%) or disseminated disease (n = 4; 36%) were most common. The main reason for discontinuation of previous antimicrobials was most often related to adverse effects (n = 5; 45%), followed by clinical failure (n = 3; 27%). Linezolid was associated with cure or improvement in all cases (n = 11; 100%). However, the majority of patients developed serious complications that may have led to premature discontinuation of therapy with linezolid, including myelosuppression (n = 5; 45%) or possible/confirmed peripheral neuropathy (n = 2; 18%). CONCLUSIONS: The limited published data suggest that linezolid appears to be an effective alternative to trimethoprim/sulfamethoxazole for the treatment of nocardiosis. Unfortunately, the high cost and potentially serious long-term toxicities of linezolid appear to limit its use and relegate it to salvage therapy alone or in combination with other antimicrobials.

Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection.

OBJECTIVE: To report on a patient with a symptomatic, polymicrobial Escherichia coli and multidrug-resistant (MDR), extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae urinary tract infection (UTI) who was successfully treated with oral doxycycline hyclate. CASE SUMMARY: A 70-year-old white male inpatient with a history of recurrent UTI, type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with UTI and empirically treated with oral ciprofloxacin. Symptoms persisted 2 days later, and the patient was transitioned to amoxicillin/clavulanate by a different provider. The next day, upon receipt of the urine culture and susceptibility panel revealing E coli and MDR, ESBL-positive K pneumoniae infection, treatment was switched to doxycycline hyclate, which resulted in clinical improvement. DISCUSSION: Complicated UTI involving multiple pathogens requires careful clinical judgment to select the appropriate antimicrobial agent, improve clinical outcomes, and prevent resistance. Treatment with doxycycline was based on the susceptibility panel and local resistance patterns. Advantages of doxycycline for UTI include its oral formulation, wide spectrum of activity, ability to achieve high concentration in the urine, and low toxicity. CONCLUSION: Doxycycline hyclate may be an effective treatment option for patients with susceptible MDR UTI.

Emerging therapies in the treatment of Clostridium difficile-associated disease.

OBJECTIVE: To describe emergent therapies, such as rifaximin, nitazoxanide, intravenous immunoglobulin (IVIG), tinidazole, tolevamer, and the possible use of a vaccine, in Clostridium difficile-associated disease (CDAD), one of the most common causes of diarrhea in hospitalized adults in North America. DATA SOURCES: A literature search was performed using MEDLINE (1996-October 2006), PubMed (1996-October 2006), abstracts from Infectious Diseases Society of America (September 2006) and International Conference on Antimicrobial Agents and Chemotherapy (September 2006), Internet (October 2006), Genzyme product Web site (October 2006), and Romark Laboratories Web site (October 2006) using the terms Clostridium difficile, rifaximin, nitazoxanide, intravenous immunoglobulin, tolevamer, vaccine, and tinidazole. STUDY SELECTION AND DATA EXTRACTION: Data presented in this article were selected based on clinical relevance and power of the studies. In vivo and in vitro studies supporting the use of drugs available for treatment of refractory CDAD were reviewed. Some of the information on new and emerging modalities was also included, although there were limited published data available. DATA SYNTHESIS: Clinical trials evaluating the use of nitazoxanide and tolevamer for the treatment of CDAD have been published. Tinidazole use is based on structural similarities to metronidazole; however, clinical trials have not been conducted and the cost of this agent may be a limiting factor. The use of rifaximin and IVIG will require randomized clinical trials to establish their place in therapy. Limited information in the literature suggests that a vaccine may be effective for CDAD prevention. CONCLUSIONS: CDAD is a debilitating disease with increasing treatment failure rates and recurrences using standard therapies. Clinicians need to look at other options to expand the available treatment arsenal in addition to placing a greater emphasis on prevention.

A Survey of Pharmacists in Academia on the Current Practice of Estimation of Kidney Function for Antimicrobial Dosing in Adults.

PURPOSE: To determine the methods used by pharmacists in academia to estimate kidney function for antimicrobial dosing. METHODS: Stratified by region, a random sample of Accreditation Council for Pharmacy Education recognized Colleges of Pharmacy was selected for a total of 40 programs. Identified college Web sites were reviewed for eligible participants using the predefined inclusion/exclusion criteria. This was used to create a sampling frame from which 30% and 20% of faculty were randomly chosen and invited to participate via e-mail and mail-administered surveys, respectively. RESULTS: Of the responders, 86% (31 of 36) who routinely estimate kidney function utilized the Cockcroft-Gault (CG) equation. In obese patients, 75% utilized the CG equation with or without adjustments. In patients ≥65 years, 42% adjusted serum creatinine to 1 mg/dL and 25% did not make any modifications. The majority of the responders accounted for patients with quadripalegia or bed-bound patients when estimating kidney function. In scenario examples, 51% (18 of 35) dosed an elderly female and 51% (18 of 35) a morbidly obese female as creatinine clearance ≥50 mL/min; however, 49% (17 of 35) did not. CONCLUSION: The majority of responders utilized the CG equation for estimating kidney function with or without adjustments. Although a number of consistencies were noted, discrepancies existed, especially with elderly and obese patients.

Fluoroquinolone- and ceftriaxone-based therapy of community-acquired pneumonia in hospitalized patients: the risk of subsequent isolation of multidrug-resistant organisms.

A retrospective cohort study was performed on 175 adult patients treated for community-acquired pneumonia with moxifloxacin or ceftriaxone/azithromycin in a nonintensive care unit. Both cohorts were very similar with regard to a wide range of characteristics including age, severity of disease, comorbidities, length of stay, and mortality. Multidrug-resistant organisms were subsequently isolated from 6 (15%) moxifloxacin-treated patients and 5 (4%) ceftriaxone/azithromycin-treated patients within 90 days after beginning of therapy (P = .026 on logistic regression analysis).