Impact of hydroxychloroquine on disease progression and ICU admissions in patients with SARS-CoV-2 infection.

PURPOSE: To evaluate whether use of hydroxychloroquine was associated with a reduced likelihood of intensive care unit (ICU) admission in patients with coronavirus disease 2019 (COVID-19) in the early weeks of the pandemic. METHODS: A retrospective, observational cohort study was conducted to determine selected treatment outcomes in 336 patients hospitalized with COVID-19 at an acute care community hospital in the Hudson Valley region of New York from March 20 to April 20, 2020. Eligibility included admission to the hospital, a laboratory-confirmed diagnosis of SARS-CoV-2 infection, and no need for intubation or intensive care at admission. The median (interquartile range) ages of patients who received hydroxychloroquine (n = 188) and those who did not (n = 148) were 68 (58-82) and 64 (51-73) years, respectively. In a multivariable model that included age, gender, obesity, diabetes, and hydroxychloroquine use, patients who received hydroxychloroquine were significantly more likely than those not treated with the drug to be transferred to an ICU (odds ratio, [OR], 8.1; 95% confidence interval [CI]: 3.8-17) and significantly more likely to be intubated (OR, 7.99; 95% CI, 3.76-16.91); these associations were not influenced by disease severity. In-hospital mortality did not differ significantly with disease severity between those who did and those who did not receive hydroxychloroquine. CONCLUSION: Hydroxychloroquine use was significantly associated with increased risks of ICU admission and intubation in patients with mild, moderate, and severe symptoms of COVID-19. There were no significant between-group differences in mortality with use vs nonuse of hydroxychloroquine.

Long-Term Efficacy of Oral Vancomycin Prophylaxis for the Prevention of Clostridium difficile Recurrence.

BACKGROUND: Limited evidence suggests that prophylactic oral vancomycin may be beneficial in preventing Clostridium difficile infection (CDI) recurrence, but long-term efficacy is unknown. OBJECTIVE: To evaluate the long-term efficacy of oral vancomycin prophylaxis (OVP) in preventing CDI recurrence in subjects who require subsequent antibiotic exposure. METHODS: A retrospective cohort study was conducted at a community hospital. A total of 91 subjects with a history of CDI between January 2013 and December 2015 who had a subsequent hospitalization requiring systemic antibiotics within 12 months were evaluated. Thirty-two subjects who received prophylaxis with oral vancomycin were compared to 59 subjects who did not receive prophylaxis. RESULTS: CDI recurrence within 12 months was significantly lower in subjects receiving OVP compared to those who did not receive OVP (6.3% vs 28.8%; odds ratio [OR]: 0.16; 95% confidence interval [CI]: 0.04-0.77; P = .011) including patients whose previous CDI was an initial episode (3.7% [1/27] vs 28.3% [15/53]; OR: 10.3; 95% CI: 1.28-82.6; P = .009). CONCLUSION: Use of OVP in subjects with a history of CDI up to 12 months prior to subsequent antibiotic exposure appears to reduce the risk of CDI recurrence for up to 12 months.

Opioid use in knee arthroplasty after receiving intravenous acetaminophen.

BACKGROUND: Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. METHODS: This retrospective, case-control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. RESULTS: One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). CONCLUSION: IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays.

Evaluation of bleeding rates in renal transplant patients on therapeutic intravenous heparin.

BACKGROUND: It is unknown whether coagulation properties differ between renal transplant and nontransplant patients. OBJECTIVE: To assess whether renal transplant patients on intravenous (IV) heparin, titrated to therapeutic activated partial thromboplastin times (aPPT; 56-93 seconds), experienced a higher rate of bleeding compared to nontransplant patients. METHODS: Twenty-nine renal transplant and 29 nontransplant patients receiving IV heparin for a deep vein thrombosis, pulmonary embolism, atrial fibrillation, or acute coronary syndrome were randomly identified through a retrospective chart review. RESULTS: Renal transplant patients had higher bleeding rates on IV heparin therapy compared to nontransplant patients (31% vs 6.9%, respectively; P = .041). Renal transplant patients experienced a drop in hemoglobin of at least 1 g/dL or the need for a transfusion more often then nontransplant patients (69% vs 45%, respectively; P = .111), although the difference was not statistically significant. CONCLUSIONS: Further research is necessary to identify the factors contributing to increased rates of bleeding in renal transplant patients on IV heparin and to determine the ideal aPTT to appropriately balance anticoagulation in renal transplant patients.

Identification, pharmacologic considerations, and management of prostatitis.

BACKGROUND: Prostatitis is a collection of signs and symptoms that occur as a result of inflammation or swelling of the prostate gland. There are many different causes for prostatitis, including infection; occasionally no clear etiology for the inflammation is found. Effective treatment often depends on identification of the cause, but a microbiologic organism is not always detectable, especially in cases of chronic prostatitis. OBJECTIVE: The aim of this article was to review identification and treatment options for prostatitis, including pharmacologic and nonpharmacologic interventions. METHODS: Relevant information was identified through a search of MEDLINE (1966-June 2010), International Pharmaceutical Abstracts (1970-June 2010), and EMBASE (1947-June 2010). Randomized, controlled trials that examined prostate cancer, benign prostatic hypertrophy, or procedures related to the prostate (ie, biopsies) were excluded. RESULTS: A working classification system for prostatitis was developed in 1999, but there are few randomized controlled trials that distinguish between the various treatment options. Bacterial prostatitis can be acute or chronic but always requires some degree of antimicrobial therapy. Pharmacologic features of fluoroquinolones make them the preferred agents for most patients. These antibiotics can become trapped in a chronically inflamed prostate due to pH differences between prostatic tissue and serum. Many fluoroquinolones have penetration ratios (prostate level:serum level) of up to 4:1. A study in European men (N = 117) who received levofloxacin 500 mg/d with a diagnosis of chronic bacterial prostatitis demonstrated clinical success rates of 92% (95% CI 84.8%-96.5%), 77.4% (95% CI, 68.2-84.9%), 66.0% (95% CI, 56.2%-75.0%), and 61.9% (95% CI, 51.9%-71.2%) at 5-12 days, 1 month, 3 months, and 6 months after treatment. Additionally, there have been numerous randomized, placebo-controlled trials in patients with chronic prostatitis that have studied α-blockers, steroid inhibitors, anti-inflammatory agents, and bioflavonoids. Treatment responses to α-blockers appear to be greater with longer durations of therapy in α-blocker-naïve patients (National Institutes of Health-Chronic Prostatitis Symptom Index [NIH-CPSI] score reduction of at least 3.6 points after 6 weeks of tamsulosin therapy [P = 0.04] and up to 14.3 and 9.9 point NIH-CPSI score reductions with 14 weeks of terazosin and 24 weeks of alfuzosin therapy, respectively [P = 0.01 for both]). Combination therapy with an α-blocker, an anti-inflammatory, and a muscle relaxant does not appear to offer significant advantages over monotherapy (12.7 vs 12.4 point reduction in NIH-CPSI scores) and a stepwise approach to therapy involving antibiotics followed by bioflavonoids and then α-blockers appears to effectively reduce symptoms for up to 1 year in patients with chronic prostatitis (mean NIH-CPSI point reduction of 9.5 points compared with baseline, P < 0.0001). Patients who have had multiple unsuccessful treatment regimens may benefit from direct stimulation of the pelvic muscles through electromagnetic or electroacupuncture therapy. CONCLUSIONS: Prostatitis can resemble various other medical conditions but proper classification and an understanding of the pharmacologic features and expectations of the medications used to treat it can help identify effective treatment strategies. Fluoroquinolones are the preferred agents for treating bacterial causes of prostatitis and have demonstrated efficacy in some cases of chronic prostatitis when an organism has not been identified. However, the use of agents with anti-inflammatory or antiadrenergic properties may be necessary in combination with or after trying antimicrobial agents.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital-acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence-based pharmacotherapy. Further research with well-designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.

Aerosolized Delivery of Antifungal Agents.

Pulmonary infections caused by Aspergillus species are associated with significant morbidity and mortality in immunocompromised patients. Although the treatment of pulmonary fungal infections requires the use of systemic agents, aerosolized delivery is an attractive option in prevention because the drug can concentrate locally at the site of infection with minimal systemic exposure. Current clinical evidence for the use of aerosolized delivery in preventing fungal infections is limited to amphotericin B products, although itraconazole, voriconazole, and caspofungin are under investigation. Based on conflicting results from clinical trials that evaluated various amphotericin B formulations, the routine use of aerosolized delivery cannot be recommended. Further research with well-designed clinical trials is necessary to elucidate the therapeutic role and risks associated with aerosolized delivery of antifungal agents. This article provides an overview of aerosolized delivery systems, the intrapulmonary pharmacokinetic properties of aerosolized antifungal agents, and key findings from clinical studies.

Etravirine: a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) active against NNRTI-resistant strains of HIV.

BACKGROUND: Since 1981, the AIDs epidemic has continued to expand and, at the end of 2007, there were ~33 million people worldwide living with HIV, including 1.2 million in North America. OBJECTIVE: This article provides a comprehensive overview of the nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine when used in treatment-experienced adult patients with multidrug-resistant HIV infections. METHODS: Relevant information was gathered through a search of MEDLINE (1966-December 2008) and International Pharmaceutical Abstracts (1970-December 2008) databases, as well as abstracts of the Conference on Retroviruses and Opportunistic Infections (2006-2008) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2002-2008). Clinical trial data were limited to human studies that were Phase IIa or higher. The search terms used were etravirine and TMC125. References were also identified through screening of citations in the articles gathered. RESULTS: Etravirine is an NNRTI that is able to adapt its binding orientation and overcome common NNRTI resistance associated mutations (RAMs) such as K103N. It was originally formulated in polyethylene glycol (PEG), but pharmacokinetic studies using an updated tablet formulation identified a more favorable absorption profile that has allowed the study of lower doses (200 mg instead of 900 mg BID). Phase IIa studies using the PEG formulation of etravirine found that viral loads were reduced in both treatment-naive and treatment-experienced patients with HIV (-1.99 vs -0.86 log10 copies/mL; P < 0.001). Phase IIb studies expanded on this finding by using various doses of the reformulated tablet to evaluate virologic efficacy in highly treatment-experienced patients with triple-class (protease inhibitor, nucleoside/nucleotide reverse transcriptase inhibitors [NRTI], and NNRTI) resistance. Patients in an open-label, partially blinded, Phase IIb study (N = 199) were randomized to receive an optimized background regimen alone or in combination with either 400 or 800 mg of etravirine BID. Regardless of the dose, patients in the etravirine arms had a greater decrease in viral load from baseline (-1.04 and -1.18 log10 copies/mL, respectively) compared with patients in the placebo arm (-0.19 log10 copies/mL; P = 0.005 and P < 0.001, respectively). The DUET studies (DUET-1, N = 612; DUET-2, N = 593) are 2 ongoing, international, randomized, double-blind, placebo-controlled, Phase III trials in which patients with preexisting RAMs are treated with darunavir/ ritonavir and an optimized NRTI background in combination with etravirine or placebo and the optional use of enfuvirtide. According to pooled, 48-week data from these studies, significantly more patients who received etravirine achieved an HIV RNA <50 copies/ mL (61% vs 40%; P < 0.001) and had greater virologic (-2.25 vs -1.49 log10 copies/mL reduction in HIV RNA from baseline; P < 0.001) and immuno-logic (98 vs 73 cells/mm(3) CD4 cell count change from baseline; P < 0.001) responses compared with placebo. Additionally, the incidence of adverse events, including diarrhea, nausea, and headache, was similar between treatment groups in the DUET studies; rash, however, was significantly more common in the etravirine group (17% vs 9%; P < 0.001). CONCLUSION: Etravirine is an NNRTI that was reported to be effective when used as part of an optimized, highly active antiretroviral therapy regimen in NNRTI treatment-experienced adult patients with HIV.

Posaconazole: an extended-spectrum triazole antifungal agent.

BACKGROUND: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent. OBJECTIVE: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592. Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site. RESULTS: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). CONCLUSIONS: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.

Pegaptanib sodium for the treatment of neovascular age-related macular degeneration: a review.

OBJECTIVE: This article reviews available information on the new selective vascular endothelial growth factor aptamer pegaptanib in the treatment of neovascular age-related macular degeneration (ARMD). The pharmacology, pharmacokinetics, pharmacodynamics, contraindications, and drug-interaction potential of pegaptanib are discussed, and the results of clinical trials evaluating its efficacy and tolerability are summarized. METHODS: Relevant articles were identified through searches of MEDLINE (1966-June 2005) and International Pharmaceutical Abstracts (1970-June 2005). The search terms included pegaptanib sodium, Macugen, age-related macular degeneration, and choroidal neovascularization. The reference lists of identified articles were reviewed for additional publications, and further information was obtained from the manufacturer of pegaptanib. Included studies were review articles and Phase II, III, and IV clinical trials, with preference given to available Phase III studies. RESULTS: Only 1 research group has evaluated the tolerability and efficacy of pegaptanib in patients with neovascular ARMD. The VEGF Inhibition Study in Ocular Neovascularization involved 2 concurrent randomized trials of intravitreous injections of pegaptanib 0.3 mg (n = 294), 1 mg (n = 300), and 3 mg (n = 296) compared with sham injections (n = 296) every 6 weeks for 54 weeks in patients with neovascular ARMD. Assessments were conducted at 6, 12, 18, 24, 30, 42, 48, and 54 weeks. The primary end point was the proportion of patients losing <15 letters on the study eye chart at 54 weeks. This end point was achieved in 70%, 71%, and 65% of patients who received pegaptanib 0.3 (P < 0.001), 1 (P < 0.001), and 3 mg (P = 0.03), respectively, compared with 55% of those receiving the sham injections. Significant improvements in visual acuity with pegaptanib compared with the sham-injection group were seen at all time points (0.3 and 1 mg: P < 0.002; 3 mg: P < 0.05). The sham-injection group was twice as likely to have severe vision loss (loss of > or =30 letters or 6 lines on the eye chart) compared with those receiving pegaptanib 0.3 or 1 mg (P < 0.001). Adverse events reported significantly more often in the pegaptanib group compared with the sham-injection group included vitreous floaters (33% vs 28%, respectively; P < 0.001), vitreous opacities (18% vs 10%; P < 0.001), and anterior-chamber inflammation (14% vs 6%; P = 0.001). Injection-related adverse events during the first year of pegaptanib treatment included endophthalmitis in 12 (1.3%) patients, retinal detachment in 6 (0.7%) patients, and traumatic injury to the lens in 5 (0.6%) patients. CONCLUSIONS: There are few published clinical data on pegaptanib. In 2 clinical comparisons with sham injections, pegaptanib was well tolerated and effective in slowing the decline in visual acuity in patients with neovascular ARMD. This agent may be considered an option for the treatment of neovascular ARMD.

Identification, management, and prevention of adverse effects associated with highly active antiretroviral therapy.

PURPOSE: The adverse effects associated with highly active antiretroviral therapy (HAART), as well as potential options available for management of these complications, are summarized. SUMMARY: Effective treatment of human immunodeficiency virus (HIV) infection requires three or four drug regimens that are complicated and commonly associated with adverse effects. This makes compliance difficult and can result in treatment failures, development of resistance, and loss of future treatment options. In addition, some adverse effects may lead to an increase in morbidity and represent additional risk factors for future complications. Serious adverse events after the initiation of HAART are related to both patient and treatment characteristics. Most organ systems can be affected, depending on the drug or class of drugs being used; therefore, proper identification of adverse effects can be difficult. The most common adverse effects are gastrointestinal, neurologic, metabolic, and cardiovascular, although renal, dermatological, and hematologic events may also be encountered. Adverse-effect management has included treatment interruptions and therapeutic drug monitoring but most commonly involves switching to another drug or class of drugs. This requires a complete understanding of HAART regimens and their associated complications. HIV clinics that have employed clinical pharmacists have been able to successfully prevent or identify adverse effects through suggestions for effective treatment alternatives, medication counseling, and compliance education. CONCLUSION: The identification, management, and prevention of adverse events associated with HAART can be difficult but are integral components of effective treatment. Proper interventions are cost-effective and have resulted in improved quality of life for patients infected with HIV.

Safety and immunogenicity of ALVAC vCP1452 and recombinant gp160 in newly human immunodeficiency virus type 1-infected patients treated with prolonged highly active antiretroviral therapy.

In order to boost immune responses in persons in whom highly active antiretroviral therapy (HAART) was initiated within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection, we administered vaccines containing a canarypox virus vector, vCP1452, with HIV-1 genes encoding multiple HIV-1 proteins, and recombinant gp160. Fifteen HIV-1-infected subjects who achieved sustained suppression of plasma viremia for at least 2 years were enrolled. While continuing antiretroviral therapy, each subject received at least four intramuscular injections of the vaccines on days 0, 30, 90, and 180. Adverse events were mild, with the most common being transient tenderness at the vCP1452 injection site. Of the 14 patients who completed vaccination, 13 had significant increases in anti-gp120 or anti-p24 antibody titers, and 9 had transient augmentation of their T-cell proliferation responses to gp160 and/or p24. HIV-1-specific CD8(+) T cells were quantified using an intracellular gamma interferon staining assay. Among 11 patients who had increased CD8(+) T-cell responses, seven had responses to more than one HIV-1 antigen. In summary, vaccination with vCP1452 and recombinant gp160 appears safe and immunogenic in newly HIV-1-infected patients on HAART.