Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation
SOURCE: Holmgaard FB, Guglielmetti L, Lillebaek T, et al. Efficacy and tolerability of concomitant use of bedaquiline and delamanid for multidrug- and extensively drug-resistant tuberculosis: A systematic review and meta-analysis. Clin Infect Dis 2023;76:1328-1337.
These authors at the Center for Global Health in Aarhus, Denmark, and the Sorbonne in Paris performed a systematic review of 13 studies examining the tolerability and success of bedaquiline (BDQ) and delamanid (DLM) in the treatment of 1,031 individuals with multidrug (MDR)- and extensively drug-resistant (XDR) tuberculosis. More than 1,700 publications were reviewed, and this meta-analysis focused on those publications strictly involving the treatment of adults with MDR/XDR tuberculosis who concurrently received both agents, who did not also receive clofazimine or moxifloxacin (both of which can prolong QTc), and in whom microbiologic data at six months of treatment was available.
Treatment of MDR/XDR is particularly challenging, often involving multiple agents with a large pill burden and limiting side effects. Both BDQ and DLM have raised hopes of improved treatment outcomes in this group of patients, although the concurrent use of these two drugs has raised concerns about their combined effect on prolongation of QTc and the risk of cardiac arrhythmias.
At the time of this publication, a Phase III randomized clinical trial of BDQ was in progress, and many of the patients included in the 13 studies were treated on a compassionate use basis or with salvage regimens. The study size ranged from 28 to 472 individuals, with a median age of 24 years to 50 years. Human immunodeficiency virus (HIV)-infected patients were included in some of these studies. Ten of the studies provided data on QTc intervals, although only one was a randomized controlled treatment trial specifically designed to examine the effect of these agents on QT interval. A prolonged QTc was defined as > 500 msec or an increase in QTc ≥ 60 msec on treatment compared with baseline during active treatment (Fridericia’s formula was used to calculate corrected QT in 9/10 studies). Pooled efficacy estimates from the 13 studies showed a favorable treatment outcome of 73% (confidence interval [CI], 64.3% to 81.8%) (favorable outcome as defined by the World Health Organization [WHO]), with a range of 46.4% to 90.8%. Sputum conversion by six months of treatment ranged from 61% to 95%. Two studies observed no difference in favorable outcomes when comparing the combined use of BDQ/DLM to BDQ or DLM alone, whereas one study found BDQ was associated with better outcomes than the use of both drugs.
The pooled data estimated a risk of QTc prolongation of 7.8% (range, 1.3% to 33.33%). Serious cardiac events occurred in 6/798 patients (0.8%), five of which were unrelated to prolongation of QTc, including three myocardial infarctions and two patients with heart failure. Only one patient developed an arrhythmia (bigeminy). The single randomized clinical trial that focused on cardiac effects found no evidence of clinically significant QTc prolongation and no serious cardiac events or deaths. At least one serious adverse effect occurred in 19.7% of the patients during treatment, including respiratory and gastrointestinal side effects, abnormal liver tests, and peripheral neuropathy. BDQ and DLM were permanently discontinued in 3.9% and 4.5% of patients, respectively.
Overall, this meta-analysis shows that concurrent treatment with BDQ and DLM was fairly well tolerated, with a minimal risk of clinically significant prolongation of QTc or cardiac events. The success of treatment was better than anticipated, especially when considering many of these patients were quite ill and receiving salvage therapy as well as other medical therapies.
SOURCE: Bhukhan A, Dunn C, Nathoo R. Case report of leprosy in Central Florida, USA, 2022. Emerg Infect Dis 2023;29:1698-1700.
A case of lepromatous leprosy was diagnosed in a 54-year-old man presenting for care to HCA Osceola Hospital in Central Florida (just south of Orlando) in 2022. He had lived in the United States his entire life, and he worked outdoors in landscaping. Because he was not an immigrant and had no recognized contacts or exposures, and he denied any significant travel or contact with armadillos in the area, concerns were raised about his apparent lack of risk factors for leprosy. And the media immediately chanced on this information, raising alarms that leprosy had become “endemic” in Central Florida and perhaps even endemic in the Southeastern United States.
Leprosy still is relatively rare in the United States, with about 150 cases reported annually. Reported cases of leprosy in the United States peaked in 1983 with 456 cases and since have diminished, although there is evidence of a slight uptick in cases in certain areas. Many of the patients are foreign-born, although cases commonly report no known contacts or recognized exposures, and at least one-third of patients have no identifiable risk factors. There always has been a predominance of cases in the Southwestern and Southeastern United States and in states with larger immigrant populations. For example, in 2015, 178 cases of leprosy were reported in the United States from 32 different jurisdictions, including Puerto Rico. Three-fourths of these cases were from Arkansas, California, Florida, Hawaii, Louisiana, New York, and Texas. Even though many cases are reported in foreign-born individuals, six of the cases occurring in California between 2017 and 2020 all were born in the United States, all were males, and none had identified risk factors. In our smaller infectious disease practice in Mountain View, CA, I believe we have seen 14 cases of leprosy in 20 years, most often from India. However, one case was a locally born Caucasian woman who loved to travel internationally. None of our patients had an identified exposure, and none of the cases resulted in spread to family members or colleagues.
Concerns have been raised because of an observed uptick in cases in Florida from 10 cases in 2014 to 27 cases in 2020, most of which occurred in Central Florida. However, only 14 cases were reported from Florida the following year (2021). Five of these 2021 Florida cases occurred in Brevard County, while one case was reported from each of nine other counties (extending from Jacksonville to Palm Beach).1 This does not seem to constitute an outbreak.
Transmission of leprosy remains somewhat of a mystery. The main mode of transmission is believed to be through respiratory secretions and droplets, although it generally is held that prolonged close contact is necessary, and many people may be naturally resistant. Zoonotic transmission may play a role in some areas, and both the nine-banded armadillo and the Eurasian red squirrel are known carriers of M. leprae. Soil contact may be a risk in rare cases, although it is unproven. Whole genomic sequencing has found a similar genotypic strain in 25/39 affected patients in the United States to those found in 28/33 armadillos, although that does not necessarily implicate armadillos as the direct source for infection. In contrast, genetic studies of red squirrels in Great Britain suggest they carry an “ancestral” strain of leprosy with little apparent risk of exposure to humans.
REFERENCE
- Florida Department of Health, Division of Public Statistics and Performance Management. Hansen’s Disease (Leprosy). https://www.flhealthcharts.gov/ChartsDashboards/rdPage.aspx?rdReport=NonVitalIndNoGrpCounts.TenYrsRpt&cid=174
SOURCE: Pai MP, Cojutti PG, Gerussi V, et al. Linezolid population pharmacokinetics to improve dosing in cardiosurgical patients: Factoring a new drug-drug interaction pathway. Clin Infect Dis 2023;76:1173-1179.
There always is a concern with linezolid dosing in critical care patients — hoping to achieve sufficient concentrations of drug to treat aggressive infections, such as methicillin-resistant hospital-acquired pneumonias (HAP), but wishing to avoid complicating toxicities, such as drug interactions and acute anemia and thrombocytopenia. These authors examined the optimal dosing of linezolid in a group of 150 cardiac surgery patients (i.e., valvular replacement, coronary artery bypass graft [CABG], aortic surgery, and cardiac transplant) using therapeutic drug monitoring (TDM) and a population pharmacokinetic model of drug interactions. The median age of the group was 66 years, the median weight was 76 kg, and the median creatinine clearance was 47 mL/min. Linezolid was used either empirically or for targeted treatment, and 72% of the patients received it for either sepsis or HAP. The goal was to achieve trough concentrations of 2 mg/L to 8 mg/L.
All of the patients initially received the standard dose of linezolid 600 mg every 12 hours by mouth or parenterally. With this, more than half of the patients’ blood levels were outside the goal range (54.7%), including 14/150 patients (9.3%) whose Ctrough levels were < 2 mg/L and 68/150 patients (45.3%) with Ctroughs > 8 mg/L. Cyclosporine was the most likely culprit on lowering the elimination rate, leading to a prolonged terminal half-life. Dose reductions were required in 77% of the subjects, including dose reduction to 450 mg every 12 hours in 52% and 300 mg every 12 hours in 25%. Subsequent TDM measurements were improved with a median Ctrough of 5.35 (range 3.35-7.73) mg/L, and interpatient variability was reduced. TDM was a useful tool for monitoring linezolid dosing in this critically ill population, and 77% of these cardiac surgery patients benefitted from lower linezolid dosing, with a reduced risk of toxicity.
