Clinical manifestations and treatment outcomes for patients with Pseudomonas endocarditis.

OBJECTIVES: To investigate clinical outcomes of patients with Pseudomonas endocarditis and identify factors associated with treatment failure. METHODS: Adult patients meeting definitive Duke's criteria for Pseudomonas endocarditis at 11 hospitals were identified between May 2000 and February 2024. Failure was defined as death or microbiological failure by day 42. First-line therapy consisted of cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam alone or in combination. RESULTS: Forty-eight patients met inclusion criteria; 29% were persons who inject drugs and 13% were organ transplant recipients. Pseudomonas aeruginosa was the causative species in 98% of cases. Patients who experienced 42 day cure were more likely to be initially managed with first-line ß-lactam agents compared with those who experienced clinical failure (97% versus 62%, P = 0.004). Treatment with first-line ß-lactams was associated with shorter time to treatment initiation and a lower likelihood of infection due to MDR Pseudomonas spp. In the univariate model, patients who experienced 90 day mortality were more likely to have prosthetic valve endocarditis (57% versus 24%, P = 0.02), an intracardiac complication (36% versus 9%, P = 0.04) and a higher median (IQR) Pitt bacteraemia score [2.5 (2-3.8) versus 1 (0-2), P = 0.048]. Combination therapy did not improve clinical outcomes but did increase the rate of adverse effects resulting in drug discontinuation compared with monotherapy, (21% versus 0%, P = 0.08). CONCLUSIONS: This is the largest study of Pseudomonas endocarditis to date. We identified improved clinical outcomes when cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam were used for initial treatment. We did not identify a clinical benefit for combination treatment.

Serratia endocarditis: antimicrobial management strategies and clinical outcomes.

OBJECTIVES: The incidence of Serratia endocarditis is increasing, yet optimal treatment has not been defined. Our objective was to investigate the outcomes of patients with Serratia endocarditis by treatment strategy. METHODS: We reviewed adult patients with definitive Serratia endocarditis at two independent health systems between July 2001 and April 2023. Combination therapy was defined as receipt of ≥2 in vitro active agents for ≥72 h. RESULTS: Seventy-five patients were included; 64% (48/75) were male and 85% (64/75) were people who inject drugs. Compared with monotherapy, receipt of combination therapy was associated with lower rates of microbiological failure (0% versus 15%, P = 0.026) and 90 day all-cause mortality (11% versus 31%, P = 0.049). Antimicrobial discontinuation due to an adverse event was more common among patients receiving combination therapy compared with monotherapy (36% versus 8%, P = 0.058). CONCLUSIONS: In the largest series of Serratia endocarditis to date, combination antibiotic treatment was associated with improved outcomes. However, larger, prospective studies are warranted.

Outcomes of pregnant women exposed to Sotrovimab for the treatment of COVID-19 in the BA.1 Omicron predominant era (PRESTO).

BACKGROUND: Sotrovimab, a monoclonal antibody with efficacy against SARS-CoV-2 including certain Omicron variants, has been used in treatment of mild-moderate COVID-19. Limited data exists regarding its use in pregnant women. METHODS: Electronic medical record review of pregnant COVID-19 patients treated with sotrovimab from 12/30/21 - 1/31/22 (Yale New Haven Health Hospital System [YNHHS]) was performed. Included were pregnant individuals ≥ 12 years, weighing ≥ 40 kg, with positive SARS-CoV-2 test (within 10 days). Those receiving care outside YNHHS or receiving other SARS-CoV-2 treatment were excluded. We assessed demographics, medical history, and Monoclonal Antibody Screening Score (MASS). The primary composite clinical outcome assessed included emergency department (ED) visit < 24 h, hospitalization, intensive care unit (ICU) admission, and/or death within 29 days of sotrovimab. Secondarily, adverse feto-maternal outcomes and events for neonates were assessed at birth or through the end of the study period, which was 8/15/22. RESULTS: Among 22 subjects, median age was 32 years and body mass index was 27 kg/m2. 63% were Caucasian, 9% Hispanic, 14% African-American, and 9% Asian. 9% had diabetes and sickle cell disease. 5% had well-controlled HIV. 18%, 46%, and 36% received sotrovimab in trimester 1, 2, and 3, respectively. No infusion/allergic reactions occurred. MASS values were < 4. Only 12/22 (55%) received complete primary vaccination (46% mRNA-1273; 46% BNT162b2; 8% JNJ-78,436,735); none received a booster. CONCLUSIONS: Pregnant COVID-19 patients receiving sotrovimab at our center tolerated it well with good clinical outcomes. Pregnancy and neonatal complications did not appear sotrovimab-related. Though a limited sample, our data helps elucidate the safety and tolerability of sotrovimab in pregnant women.

Immunomodulatory Agents for Coronavirus Disease-2019 Pneumonia.

Morbidity and mortality from COVID-19 is due to severe inflammation and end-organ damage caused by a hyperinflammatory response. Multiple immunomodulatory agents to attenuate this response have been studied. Corticosteroids, specifically dexamethasone, have been shown to reduce mortality in hospitalized patients who require supplemental oxygen. Interleukin-6 antagonist, tocilizimab, and Janus kinase inhibitors have also been shown to reduce mortality. However, patients who have severe pulmonary end-organ damage requiring mechanical ventilation or extracorporeal membrane oxygenation appear not to benefit from immunomodulatory therapies. This highlights the importance of appropriate timing to initiate immunomodulatory therapies in the management of severe COVID-19 disease.

Dosing implications for liposomal amphotericin B in pregnancy.

Liposomal amphotericin B (LAmB) is used in the treatment of opportunistic fungal and parasitic infections, including leishmaniasis. Given its lack of known teratogenicity in pregnancy, LAmB is a preferred agent for treatment for these patients. However, significant gaps remain in determining optimal dosing regimens for LAmB in pregnancy. We describe the use of LAmB for a pregnant patient with mucocutaneous leishmaniasis (MCL) using a dosing strategy of 5 mg/kg/day for days 1-7 using ideal body weight followed by 4 mg/kg weekly using adjusted body weight. We reviewed the literature for LAmB dosing strategies, particularly dosing weight, in pregnancy. Of the 143 cases identified in 17 studies, only one reported a dosing weight, in which ideal body weight was used. Five Infectious Diseases Society of America guidelines in total discussed the use of amphotericin B in pregnancy but no guidelines included recommendations for dosing weight. This review describes our experience in using ideal body weight for dosing LAmB in pregnancy for the treatment of MCL. Use of ideal body weight may minimize risk of adverse effects to the fetus compared to the use of total body weight while maintaining efficacy for treatment of MCL in pregnancy.

Mucocutaneous Leishmaniasis in a Pregnant Immigrant.

Cutaneous leishmaniasis is a parasitic infection that causes significant maternal morbidity, and even fetal mortality, during pregnancy, yet there are limited therapeutic options. Here, we report a case of leishmaniasis in a pregnant immigrant with exuberant mucocutaneous lesions with favorable response to liposomal amphotericin B.

Collagenase Clostridium Histolyticum-aaes for Treatment of Cellulite: A Pooled Analysis of Two Phase-3 Trials.

Background: Collagen-rich fibrous septae and subcutaneous adipose protrusions play a role in cellulite pathophysiology. Collagenase clostridium histolyticum-aaes (CCH-aaes) injection causes enzymatic release of septae to resolve cellulite depressions and create a skin smoothing effect. This analysis pooled data from two identically designed, phase-3, randomized, double-blind, placebo-controlled studies to examine the efficacy and safety of CCH-aaes. Methods: Adult women with moderate/severe cellulite (3-4 on Clinician Reported Photonumeric Cellulite Severity Scale and Patient Reported Photonumeric Cellulite Severity Scale) on the buttocks received up to three treatment sessions (Days 1, 22, and 43) of subcutaneous CCH-aaes 0.84 mg or placebo per treatment area. Composite and individual component response (≥2-level or ≥1-level improvement from baseline in Patient Reported Photonumeric Cellulite Severity Scale and/or Clinician Reported Photonumeric Cellulite Severity Scale) and additional patient-reported outcomes were determined at Day 71. Results: Analysis included 424 CCH-aaes-treated and 419 placebo-treated women. CCH-aaes-treated women were 5.9 times more likely than placebo-treated women to be ≥2-level composite responders at Day 71 (odds ratio [95% confidence interval], 5.9 [2.2-15.4]; P < 0.001). A significantly greater percentage of CCH-aaes-treated women versus placebo-treated women were ≥1-level composite responders at Day 71 (39.4% versus 14.6%; P < 0.001). Subgroup analyses indicated no apparent impact of Fitzpatrick skin type category and baseline cellulite severity (moderate/severe) on CCH-aaes efficacy. An inverse relationship between age and CCH-aaes response was observed in those with a body mass index less than 32 kg per m2. The most common adverse events with CCH-aaes were injection-site bruising and injection-site pain. Conclusion: CCH-aaes treatment significantly improved moderate-to-severe buttock cellulite appearance and was generally well tolerated.

An outbreak of SARS-CoV-2 on a transplant unit in the early vaccination era.

BACKGROUND: Solid organ transplant recipients are at increased risk of COVID-19-associated morbidity and mortality. AIMS: We describe a nosocomial outbreak investigation on an immunocompromised inpatient unit. METHODS: Patients positive for SARS-CoV-2 were identified. An epidemiologic investigation was assisted with whole genome sequencing of positive samples. RESULTS: Two patients were identified as potential index cases; one presented with diarrhea and was initially not isolated, and the other developed hypoxemia on hospital day 18 before testing positive. Following identification of a SARS-CoV-2 cluster, the unit was closed and all patients and staff received surveillance testing revealing eight additional positive patients and staff members. Whole genome sequencing confirmed an outbreak. Enhanced infection prevention practices mitigated further spread. Asymptomatic patients with COVID-19 were successfully treated with bamlanivimab. DISCUSSION: Preventing SARS-CoV-2 outbreaks in transplant units poses unique challenges as patients may have atypical presentations of COVID-19. Immunocompromised patients who test positive for SARS-CoV-2 while asymptomatic may benefit from monoclonal antibody therapy to prevent disease progression. All hospital staff members working with immunocompromised patients should be promptly encouraged to follow infection prevention behaviors and receive SARS-CoV-2 vaccination. CONCLUSION: SARS-CoV-2 outbreaks on immunocompromised units can be mitigated through prompt identification of cases and robust infection prevention practices.

Pharmacists leadership in a medication shortage response: Illustrative examples from a health system response to the COVID-19 crisis.

As medication experts, clinical pharmacists play an active and dynamic role in a medication shortage response. Supplementing existing guidelines with an actionable framework of discrete activities to support effective medication shortage responses can expand the scope of pharmacy practice and improve patient care. Dissemination of best practices and illustrative, networked examples from health systems can support the adoption of innovative solutions. In this descriptive report, we document the translation of published shortage mitigation guidelines into system success through broad pharmacist engagement and the adaption and implementation of targeted strategies. The profound, wide-reaching medication shortages that accompanied the coronavirus disease 2019 (COVID-19) pandemic are used to highlight coordinated but distinct practices and how they have been combined to expand the influence of the pharmacy enterprise.

Case Report: Disseminated Strongyloidiasis in a Patient with COVID-19.

The SARS-CoV-2 virus has emerged and rapidly evolved into a current global pandemic. Although bacterial and fungal coinfections have been associated with COVID-19, little is known about parasitic infection. We report a case of a COVID-19 patient who developed disseminated strongyloidiasis following treatment with high-dose corticosteroids and tocilizumab. Screening for Strongyloides infection should be pursued in individuals with COVID-19 who originate from endemic regions before initiating immunosuppressive therapy.

Repurposing antimicrobial stewardship tools in the electronic medical record for the management of COVID-19 patients.

During the COVID-19 pandemic, the antimicrobial stewardship module in our electronic medical record was reconfigured for the management of COVID-19 patients. This change allowed our subspecialist providers to review charts quickly to optimize potential therapy and management during the patient surge.

Effect of steady-state atorvastatin on the pharmacokinetics of a single dose of colchicine in healthy adults under fasted conditions.

BACKGROUND AND OBJECTIVE: Colchicine is commonly prescribed for gout. While minimally metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme, colchicine is a substrate for P-glycoprotein (P-gp). Atorvastatin is metabolized primarily by CYP3A4 and is a P-gp inhibitor. Patients with gout often have dyslipidemia; therefore, the potential for co-administration of atorvastatin and colchicine exists. The objective of this study was to determine the effect of oral atorvastatin on the pharmacokinetics of a single, oral dose of colchicine. METHODS: Twenty-four healthy adult subjects were enrolled in this single-center, open-label, non-randomized, one-sequence, two-period drug-drug interaction study. On day 1, subjects received a single oral dose of colchicine 0.6 mg. After a 14-day washout, subjects received atorvastatin 40 mg once daily for 14 days followed by a single dose of colchicine 0.6 mg co-administered with atorvastatin 40 mg on day 28. Main outcome measures were colchicine maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC last), and AUC from time zero to infinity (AUC∞), which were compared with and without concurrent atorvastatin. RESULTS: Colchicine AUC last, AUC∞, and C max increased by 27, 24, and 31 %, respectively, when co-administered with atorvastatin. Corresponding 90 % confidence intervals around the ratios were outside the established no-effect 80-125 % interval. CONCLUSION: Increased colchicine exposure was observed after a single dose of colchicine was administered with steady-state atorvastatin. Additional studies with multiple dosing of both drugs are needed to further determine the clinical implications of these results.

Colchicine-antimicrobial drug interactions: what pharmacists need to know in treating gout.

OBJECTIVE: Review the magnitude and clinical relevance of drug-drug interactions between a new formulation of colchicine, used to treat gout, and antibiotics. SETTING AND PRACTICE DESCRIPTION: Relevant to community and institutional pharmacists servicing patients with gout. PRACTICE INNOVATION: Pharmacists have clear roles for the identification of drug-drug interactions, providing recommendations for alternative therapy or dose adjustments/modifications, and monitoring for interactionrelated adverse events. MAIN OUTCOME MEASURES: Colchicine is metabolized via cytochrome P450 3A4 (CYP3A4); therefore, coadministration with agents that inhibit this isoenzyme can produce elevated colchicine plasma concentrations, resulting in severe and sometimes fatal adverse events. Knowledge of the potential for drug-drug interactions involving antibiotics (e.g., macrolide antibiotics, azole antifungals) allows pharmacists to help patients avoid serious adverse events. RESULTS: Pharmacokinetic studies have demonstrated that the maximum plasma concentration (C(max)) and drug exposure (as assessed by area under the plasma concentration time curve [AUC]) of colchicine are increased by 277% and 282%, respectively, after coadministration with clarithromycin. Similarly, coadministration with ketoconazole increases colchicine C(max) and AUC by 102% and 212%, respectively. Other antibiotics that are strong CYP3A4 inhibitors include itraconazole and telithromycin, whereas erythromycin and fluconazole are moderate inhibitors of the isoenzyme CYP3A4. Coadministration of CYP3A4 inhibitors (particularly clarithromycin) and colchicine has resulted in acute colchicine toxicity manifested by severe gastrointestional toxicity, bone marrow suppression, multiorgan failure, and death. CONCLUSION: Pharmacist awareness of potentially clinically significant interactions between colchicine and antibiotics that inhibit CYP3A4 can help to ensure the efficacy of colchicine is realized while mitigating serious toxicities and minimizing the risk of adverse events.

Effects of grapefruit and Seville orange juices on the pharmacokinetic properties of colchicine in healthy subjects.

BACKGROUND: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug-drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported. OBJECTIVE: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers. METHODS: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mg dose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes. RESULTS: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered with Seville orange juice, a moderate inhibitor, C(max) and AUC were decreased by ∼24% and ∼20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in T(max). Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events. CONCLUSIONS: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased T(max), but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials.gov identifiers: NCT00960193 and NCT00984009.

Effect of cyclosporine on the pharmacokinetics of colchicine in healthy subjects.

OBJECTIVE: Colchicine and cyclosporine are often administered together, particularly in patients who have undergone solid-organ transplantation. However, the potential for drug-drug interactions between these agents resulting in colchicine toxicity is high. METHODS: This study sought to determine the effect of cyclosporine (100-mg capsule) on the pharmacokinetics of the US Food and Drug Administration-approved formulation of colchicine (0.6-mg tablet) after single oral-dose administration in 24 healthy subjects under fasted conditions in a phase 1, single-sequence, 2-period drug-drug interaction trial. RESULTS: Coadministration of cyclosporine increased colchicine maximum observed plasma concentration, area under the plasma concentration-time curve to the last measurable time point, and area under the plasma concentration-time curve to time infinity on average by 224%, 216%, and 215% (ie, almost doubled), respectively, and decreased colchicine oral clearance on average by 72% (from 48.24 to 13.42 L/h), indicating substantially higher colchicine exposures when combined with cyclosporine, compared with colchicine alone. CONCLUSION: The dose of colchicine should be reduced by ≥ 50% when colchicine and cyclosporine are administered concurrently for treatment and prophylaxis of gout flares or treatment of patients with familial Mediterranean fever. Health care professionals should be vigilant for potential adverse events during colchicine/cyclosporine coadministration, notably in patients who have undergone solid-organ transplantation. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00983931 (http://clinicaltrials.gov/ct2/show/NCT00983931).

Are dosing adjustments required for colchicine in the elderly compared with younger patients?

INTRODUCTION: The objective of this study was to compare the relative bioavailability of the US Food and Drug Administration-approved formulation of colchicine after a single 0.6 mg dose in young (18-30 years of age) and elderly (≥60 years of age) healthy subjects to determine whether dosing adjustments are required in elderly patients. METHODS: A single-dose, single-drug, parallel-group study was performed in 20 young subjects with normal renal function (defined as creatinine clearance [CrCl] ≥80 mL/min) and 18 elderly subjects with normal or mild renal impairment (CrCl ≥50 mL/min) in otherwise good health. Blood samples were collected for up to 72 hours postdose and analyzed for colchicine using a validated liquid chromatography/tandem mass spectrometry method. Noncompartmental pharmacokinetic parameters were compared using analysis of variance methods. RESULTS: There were no statistically significant (P < 0.05) differences in mean colchicine pharmacokinetic parameters between young and elderly subjects, including peak plasma concentration (C(max)) (2.53 vs. 2.56 ng/mL), time to C(max) (1.25 vs. 1.25 hours), area under the plasma concentration-time curve to infinity (22.29 vs. 25.01 ng/h/mL), elimination half-life (25.4 vs. 30.1 hours), oral clearance (0.40 vs. 0.35 L/h/kg), and apparent volume of distribution (14.3 vs. 14.8 L/kg), respectively. CONCLUSION: The lack of any significant differences in colchicine pharmacokinetic parameters between young and elderly healthy subjects, with some of the latter including mild renal impairment, suggests that dose modification of colchicine may not be necessary in healthy elderly patients. However, when evaluating the use of colchicine dosing in an elderly patient, the confounding effect on overall exposure and safety from comorbid conditions, the use of concomitant medications, and the administration of multiple doses should be considered.

Unapproved drugs in the United States and the Food and Drug Administration.

Despite more than a century of evolving federal legislation, there remain many unapproved drugs on the United States (US) market. This article reviews the history of drug approval in the US, beginning with the landmark Pure Food and Drug Act of 1906, through to the development of the US Food and Drug Administration (FDA). The Pure Food and Drug Act of 1906 was the first comprehensive federal legislation covering drug regulation. Intervening legislation, such as the Federal Food, Drug, and Cosmetic Act of 1938 and Kefauver-Harris Amendments in 1962, was later instituted. In June 2006, a century after the development of the FDA as an enforcement body, an initiative was undertaken to remove unapproved drugs from the marketplace. The Marketed Unapproved Drugs-Compliance Policy Guide outlines enforcement policies aimed at efficiently and rationally bringing all unapproved and illegally marketed drugs into the approval process, or discontinuing their manufacture, distribution, and sale. The FDA has been actively pursuing control of unapproved drugs in recent years, with an approach concentrating on drug safety to ensure optimal public health and consumer protection.