Bictegravir and Metformin Drug-Drug Interaction in People with Human Immunodeficiency Virus (HIV).

A drug-drug interaction (DDI) exists between bictegravir and metformin. Bictegravir inhibits renal organic cation transporter-2, leading to increased metformin plasma concentrations. The objective of this analysis was to evaluate the clinical implications of concomitant bictegravir and metformin administration. This was a retrospective, single-center, descriptive analysis evaluating people with human immunodeficiency virus (PWH) concurrently prescribed bictegravir and metformin between February 2018-June 2020. PWH lost to follow-up or non-adherent were excluded. Data collection included: hemoglobin A1C (HgbA1C), HIV RNA viral load, CD4 cell count, serum creatinine, and lactate. Adverse drug reactions (ADRs) were assessed by provider-documented, patient-reported symptoms of gastrointestinal (GI) intolerance and hypoglycemia. Metformin dose adjustments and discontinuations were recorded. Fifty-three PWH were included (116 screened; 63 excluded). GI intolerance was reported in three PWH (5.7%). There were no documented episodes of hypoglycemia or lactic acidosis. Five PWH had metformin dose reductions (N = 3 for unspecified reasons; N = 1 for GI intolerance) or discontinuation (N = 1 unrelated to ADRs). Both diabetes and HIV control improved (HgbA1C decreased by 0.7% with virologic control in 95% of PWH). Minimal ADRs were reported in PWH receiving concurrent metformin and bictegravir. Prescribers should be aware of this potential interaction; however, no empiric metformin total daily dose adjustment appears necessary.

Antimicrobial usage at a large teaching hospital in Lusaka, Zambia.

Antimicrobial resistance is a growing global health concern. Antimicrobial stewardship (AMS) curbs resistance rates by encouraging rational antimicrobial use. However, data on antimicrobial stewardship in developing countries is scarce. The objective of this study was to characterize antimicrobial use at the University Teaching Hospital (UTH) in Lusaka, Zambia as a guiding step in the development of an AMS program. This was a cross-sectional, observational study evaluating antimicrobial appropriateness and consumption in non-critically ill adult medicine patients admitted to UTH. Appropriateness was defined as a composite measure based upon daily chart review. Sixty percent (88/146) of all adult patients admitted to the general wards had at least one antimicrobial ordered and were included in this study. The most commonly treated infectious diseases were tuberculosis, pneumonia, and septicemia. Treatment of drug sensitive tuberculosis is standardized in a four-drug combination pill of rifampicin, isoniazid, pyrazinamide and ethambutol, therefore appropriateness of therapy was not further evaluated. The most common antimicrobials ordered were cefotaxime (n = 45), ceftriaxone (n = 28), and metronidazole (n = 14). Overall, 67% of antimicrobial orders were inappropriately prescribed to some extent, largely driven by incorrect dose or frequency in patients with renal dysfunction. Antimicrobial prescribing among hospitalized patients at UTH is common and there is room for optimization of a majority of antimicrobial orders. Availability of certain antimicrobials must be taken into consideration during AMS program development.

Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock.

STUDY OBJECTIVES: Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population that may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic-pharmacodynamic target requirements. DESIGN: Prospective observational pharmacokinetic study. SETTING: Large quaternary academic medical center. PATIENTS: Sixteen obese (body mass index [BMI] 30 kg/m2 or higher) adults with sepsis and either a gram-positive bacteremia or requiring vasopressor support (septic shock), who were receiving vancomycin between November 2016 and June 2018, were included. Patients were excluded if they were receiving renal replacement therapy or extracorporeal membrane oxygenation, treatment for central nervous system infections, pregnant, or receiving vancomycin for surgical prophylaxis. INTERVENTION: Four blood samples per patient were collected following a single dose of vancomycin: one peak serum vancomycin level (within 1-2 hrs of infusion completion), two random levels during the dosing interval, and one trough level (within 30-60 min of the next dose) were measured. MEASUREMENTS AND MAIN RESULTS: A population pharmacokinetic model was developed to describe vancomycin concentrations over time. Simulations to determine optimal dosing were performed using the pharmacokinetic model with different ranges of creatinine clearance (Clcr ) and different vancomycin daily doses. Median age of the patients was 62 years; median BMI was 36.1 kg/m2 , Acute Physiology and Chronic Health Evaluation II score was 26, and Sequential Organ Failure Assessment score was 11. Eleven patients (69%) had an acute kidney injury. Median initial vancomycin dose was 15 mg/kg; median vancomycin trough concentration was 17 mg/L. A one-compartment model best characterized the pharmacokinetics of vancomycin in obese patients with sepsis or septic shock. Volume of distribution was slightly increased in this population (0.8 L/kg) compared with the general population (0.7 L/kg). Only Clcr effect on drug clearance was found to be significant (decrease in the objective function value by 16.4 points), confirming that it is a strong predictor of vancomycin clearance. CONCLUSION: To our knowledge, this study provides the first population-based pharmacokinetic model in obese patients with sepsis or septic shock. The nomograms generated from this pharmacokinetic model provide a simplified approach to vancomycin dosing in this patient population.

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotics of Last Resort in Treating Gram-Negative Infections in Adult Critically Ill Patients.

PURPOSE OF REVIEW: We provide an overview of antimicrobials that are considered last resort for the treatment of resistant gram-negative infections in adult critically ill patients. The role in therapy, pharmacodynamic (PD) goals, and pharmacokinetic (PK) changes in critical illness for aminoglycosides, polymyxins, tigecycline, fosfomycin, and fluoroquinolones are summarized. RECENT FINDINGS: Altered PK in septic patients in the intensive care unit (ICU) is observed with many of our agents of last resort. Based on the available literature, dosage adjustments may be required to optimize PK parameters and meet PD targets for most effective bacterial killing. Data is limited, studies are conducted in heterogeneous patient populations, and conclusions are frequently conflicting. Strategic dosing regimens such as high-dose extended interval dosing of aminoglycosides or loading doses with colistin and polymyxin B are examples of ways to optimize antibiotic PK in critically ill patients. Benefits of these strategies must be balanced with risks of increased toxicity. Patients with resistant gram-negative infections may present with septic shock in the ICU. Sepsis can significantly alter the PK of antibiotics and require dosage adjustments to attain optimal drug levels. An understanding of PK and PD properties of these agents of last resort will help to maximize therapeutic efficacy while minimizing toxic effects.

Pharmacokinetic/Pharmacodynamic Considerations of Beta-Lactam Antibiotics in Adult Critically Ill Patients.

PURPOSE OF REVIEW: Beta-lactam antibiotics are commonly prescribed in critically ill patients for a variety of infectious conditions. Our understanding of how critical illness alters beta-lactam pharmacokinetics/pharmacodynamics (PK/PD) is rapidly evolving. RECENT FINDINGS: There is a growing body of literature in adult patients demonstrating that physiological alterations occurring in critically ill patients may limit our ability to optimally dose beta-lactam antibiotics to reach these PK/PD targets. These alterations include changes in volume of distribution and renal clearance with multiple, often overlapping causative pathways, including hypoalbuminemia, renal replacement therapy, and extracorporeal membrane oxygenation. Strategies to overcome these PK alterations include extended infusions and therapeutic drug monitoring. Combined data has demonstrated a possible survival benefit associated with extending beta-lactam infusions in critically ill adult patients. This review highlights research on physiological derangements affecting beta-lactam concentrations and strategies to optimize beta-lactam PK/PD in critically ill adults.

Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus-infected patients.

An analysis of the interaction between dolutegravir and metformin was conducted in the HIV ambulatory clinic setting. This was a multicenter, retrospective case series evaluating adult, HIV-infected patients concurrently prescribed dolutegravir and metformin. Historical electronic medical records were utilized to collect case-specific data. Laboratory parameters including serum creatinine (SCr), hemoglobin A1c (HgbA1c), plasma HIV RNA, CD4 cell count, and lactate were reviewed. Adverse drug reactions were assessed using patient-reported gastrointestinal intolerance and hypoglycemic symptoms. Metformin dose reduction or discontinuation was also recorded. Nineteen patients identified as concurrently taking metformin and dolutegravir were included. Eighteen patients were on metformin prior to dolutegravir initiation, with 13 having received metformin for at least six months prior to dolutegravir. At the time of dolutegravir initiation, one patient had a preemptive metformin dose reduction. Seven patients were initiated on dolutegravir with a metformin dose greater than 1000 mg daily. Eleven patients had baseline and three- to six-month follow-up HgbA1c. Of those 11 patients, eight had stable or decreased values. Thirteen of the 19 patients had an increase in SCr, with a median increase of 0.3 mg/dl (0.03-0.43). Gastrointestinal distress (N = 3) and hypoglycemic symptoms (N = 3) were reported in a total of five patients. Adverse drug reactions resulted in metformin dose reduction (N = 2) and/or discontinuation (N = 2). There were no reported cases of lactic acidosis. Providers concurrently prescribing dolutegravir and metformin should be aware of potential consequences with this combination and may consider an empiric metformin dose reduction to prevent intolerable adverse drug reactions.