A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Treatment of Multidrug-resistant or Rifampicin-resistant Tuberculosis With an All-oral 9-month Regimen Containing Linezolid or Ethionamide in South Africa: A Retrospective Cohort Study.

BACKGROUND: In 2019, the South African tuberculosis program replaced ethionamide with linezolid as part of an all-oral 9-month regimen. We evaluated treatment outcomes for patients assigned to regimens including linezolid in 2019 and ethionamide in 2017. METHODS: This retrospective cohort study included patients treated for multidrug-resistant/rifampicin-resistant tuberculosis throughout South Africa between 1 January and 31 December 2017 and 1 January to 31 December 2019. The cohort treated with a 9-month regimen containing ethionamide for four months, was compared with a cohort treated with a 9-month regimen containing linezolid for 2 months. The regimens were otherwise identical. Inverse probability weighting of propensity scores was used to adjust for potential confounding. A log-binomial regression model was used to estimate adjusted relative risk (aRR) comparing 24-month outcomes between cohorts including treatment success, death, loss to follow up, and treatment failure. Adverse event data were available for the linezolid cohort. FINDINGS: In total, 817 patients were included in the cohort receiving ethionamide and 4244 in the cohort receiving linezolid. No evidence for a difference was observed between linezolid and ethionamide regimens for treatment success (aRR = 0.96, 95% confidence interval [CI] .91-1.01), death (aRR = 1.01, 95% CI .87-1.17) or treatment failure (aRR = 0.87, 95% CI .44-1.75). Loss to follow-up was more common in the linezolid group, although estimates were imprecise (aRR = 1.22, 95% CI .99-1.50). CONCLUSIONS: No significant differences in treatment success and survival were observed with substitution of linezolid for ethionamide as a part of an all-oral 9-month regimen. Linezolid is an acceptable alternative to ethionamide in this shorter regimen for treatment of multidrug-resistant/rifampicin-resistant tuberculosis.

Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

A real-world cost-effectiveness study of vancomycin versus linezolid for the treatment of late-onset neonatal sepsis in the NICU in China.

BACKGROUND AND OBJECTIVE: Currently, the detection rates of methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS) in the blood cultures of neonates with sepsis exceed the national average drug resistance level, and vancomycin and linezolid are the primary antibacterial drugs used for these resistant bacteria according to the results of etiological examinations. However, a comprehensive evaluation of their costs and benefits in late-onset neonatal sepsis in a neonatal intensive care unit (NICU) has not been conducted. This study aimed to compare the cost and effectiveness of vancomycin and linezolid in treating neonatal sepsis in the NICU. METHODS: A cost-effectiveness analysis of real-world data was carried out by retrospective study in our hospital, and the cost and effectiveness of vancomycin and linezolid were compared by establishing a decision tree model. The drug doses in the model were 0.6 g for linezolid and 0.5 g for vancomycin. The cost break down included cost of medical ward, NICU stay, intravenous infusion of vancomycin or linezolid, all monitoring tests, culture tests and drugs. The unit costs were sourced from hospital information systems. The effectiveness rates were obtained by cumulative probability analysis. One-way sensitivity analysis was used to analyze uncertain influencing factors. RESULTS: The effectiveness rates of vancomycin and linezolid in treating neonatal sepsis in the NICU were 89.74% and 90.14%, respectively, with no significant difference. The average cost in the vancomycin group was ¥12261.43, and the average cost in the linezolid group was ¥17227.96. The incremental cost effectiveness was ¥12416.33 cost per additional neonate with treatment success in the linezolid group compared to vancomycin group at discharge. Factors that had the greatest influence on the sensitivity of the incremental cost-effectiveness ratio were the price of linezolid and the effectiveness rates. CONCLUSIONS: The cost for treatment success of one neonate in linezolid group was ¥5449.17 more than that in vancomycin group, indicating that vancomycin was more cost-effective. Therefore, these results can provide a reference for a cost effectiveness treatment scheme for neonatal sepsis in the NICU.

Linezolid shows high safety and efficacy in the treatment of Pythium insidiosum keratitis in a rabbit model.

Efficacy and safety of three antibiotics (Linezolid-LZ, 0.2%; Azithromycin-AZ, 1%; Tigecycline-TG, 1%) were determined in the treatment of Pythium insidiosum keratitis in rabbits. Infection of right eye of 38 rabbits was induced by standard intracorneal injection of P. insidiosum zoospores (left eye, intracorneal saline). Corneal infection developed in all right eyes. One hourly eye drops of one of the three antibiotics was instilled in both eyes (3 groups of 12 rabbits each) except in controls. Half of the rabbits in each group received intracorneal injection of the respective antibiotic after 4 days of starting eye drops. Clinical scoring of eyes was done over next 3 weeks. The reduction in scores post-treatment was significant for each drug (LZ: p < 0.025, AZ: p < 0.025, TG: p < 0.01). Scores with LZ (median change of 3) was significantly (p = 0.013) higher than TG (median change of 2) and comparable (p = 0.06) to AZ (median change of 3). Reduction in clinical scores in eyes receiving intracorneal antibiotics was not significantly different from the eyes that did not receive intracorneal antibiotics (p = 0.73). While no adverse effect of LZ was seen in the control corneas, 66-100% of rabbits showed reaction to AZ and TG. Histopathology showed severe inflammation in all infected corneas and intraocular extension in some of the rabbits with poor response. The success rate was noted to be 16.7%, 25% and 50% in AZ, TG and LZ respectively (p = 0.45). LZ demonstrated superior efficacy and safety and can be considered for trial in human disease.

Preparation and Evaluation of a Xanthan Gum-Containing Linezolid Ophthalmic Solution for Topical Treatment of Experimental Bacterial Keratitis.

PURPOSE: To formulate a xanthan gum-containing linezolid ophthalmic solution (LZD-XG) as a new antibiotic treatment against ocular bacterial infection. METHODS: LZD-XG was prepared and evaluated for its in vitro/in vivo ocular tolerance, in vitro/in vivo antibacterial activity, and in vivo ocular penetration. RESULTS: The optimized LZD-XG exhibited good in vitro/in vivo eye tolerance. A prolonged ocular surface residence time of LZD-XG was observed after topical instillation, and the ocular permeation was significantly better for LZD-XG than fora linezolid (LZD) ophthalmic solution. The in vitro antimicrobial activity was significantly better with LZD-XG than with LZD. In vivo evaluation also confirmed a strong therapeutic treatment effect of LZD-XG, as it significantly improved the clinical symptoms, ameliorated the damage of Staphylococcus aureus to ocular tissues, lowered the colony forming unit counts in the cornea, and decreased the myeloperoxidase activity in the cornea. CONCLUSION: LZD-XG was deemed a viable ophthalmic solution against ocular bacterial infection due to its excellent in vitro and in vivo characterizations.

Prolonged infusion of linezolid is associated with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles in patients with external ventricular drains.

OBJECTIVE: We previously investigated the pharmacokinetic and pharmacodynamic (PK/PD) parameters of routine linezolid infusions (1 h) in patients with external ventricular drains (EVD). The aim of the study was to determine whether extended linezolid infusions (200 mg/h for 3 h) were more efficacious than short linezolid infusions (600 mg/h for 1 h). METHODS: We collected cerebrospinal fluid (CSF) and plasma samples from 10 patients who received linezolid infusions after cerebral hemorrhage surgery with EVDs. Linezolid concentrations were measured by high-performance liquid chromatography (HPLC). A Monte Carlo simulation was used to measure the probability of target attainments (PTA) and the PK/PD indexes at four minimum inhibitory concentrations (MIC). RESULTS: When the same dose (600 mg) was given as an extended infusion (3 h), linezolid reached its maximum concentrations in the plasma and CSF at 3.00 h and 4.40 h, respectively. The mean penetration of linezolid in CSF was 41.31%. Using the parameter of AUC0-24 h/MIC ≥ 100, the plasma PTA provided good coverage at > 90% when MIC was ≤ 1 µg/mL, while the values were 0 in CSF. Using the parameter %T (time) > MIC ≥ 85%, the PTA in both the plasma and CSF provided good coverage when MIC ≤ 2 µg/mL. Compared with routine infusions, prolonged infusion times (3 h) showed increased PTA of linezolid. CONCLUSIONS: Prolonged infusion times increased the concentration of linezolid in the plasma, leading to improved therapeutic outcomes. However, this improvement did not exist in CSF. Lastly, the PK/PD indicator AUC/MIC ≥ 100 may be used to achieve improved outcomes in patients with critical infections.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis.

PURPOSE: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. METHODS: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). RESULTS: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). DISCUSSION: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer.

Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.

Multidisciplinary management of difficult-to-treat drug resistant tuberculosis: a review of cases presented to the national consilium in Uganda.

BACKGROUND: Patients with drug resistant tuberculosis (DR-TB) with comorbidities and drug toxicities are difficult to treat. Guidelines recommend such patients to be managed in consultation with a multidisciplinary team of experts (the "TB consilium") to optimise treatment regimens. We describe characteristics and treatment outcomes of DR-TB cases presented to the national DR-TB consilium in Uganda between 2013 and 2019. METHODS: We performed a secondary analysis of data from a nation-wide retrospective cohort of DR-TB patients with poor prognostic indicators in Uganda. Patients had a treatment outcome documented between 2013 and 2019. Characteristics and treatment outcomes were compared between cases reviewed by the consilium with those that were not reviewed. RESULTS: Of 1,122 DR-TB cases, 189 (16.8%) cases from 16 treatment sites were reviewed by the consilium, of whom 86 (45.5%) were reviewed more than once. The most frequent inquiries (N = 308) from DR-TB treatment sites were construction of a treatment regimen (38.6%) and management of side effects (24.0%) while the most frequent consilium recommendations (N = 408) were a DR-TB regimen (21.7%) and "observation while on current regimen" (16.6%). Among the cases reviewed, 152 (80.4%) were from facilities other than the national referral hospital, 113 (61.1%) were aged ≥ 35 years, 72 (40.9%) were unemployed, and 26 (31.0%) had defaulted antiretroviral therapy. Additionally, 141 (90.4%) had hepatic injury, 55 (91.7%) had bilateral hearing loss, 20 (4.8%) had psychiatric symptoms and 14 (17.7%) had abnormal baseline systolic blood pressure. Resistance to second-line drugs (SLDs) was observed among 9 (4.8%) cases while 13 (6.9%) cases had previous exposure to SLDs. Bedaquiline (13.2%, n = 25), clofazimine (28.6%, n = 54), high-dose isoniazid (22.8%, n = 43) and linezolid (6.7%, n = 13) were more frequently prescribed among cases reviewed by the consilium than those not reviewed. Treatment success was observed among 126 (66.7%) cases reviewed. CONCLUSION: Cases reviewed by the consilium had several comorbidities, drug toxicities and a low treatment success rate. Consilia are important "gatekeepers" for new and repurposed drugs. There is need to build capacity of lower health facilities to construct DR-TB regimens and manage adverse effects.

Hospital-acquired Skin and Skin-structure Infection in COVID-19 Infected Patient with Prolonged Hospitalization.

Acute bacterial skin and skin-structure infections (ABSSSI) is defined in 2013 by the US Food and Drug Administration as a bacterial cellulitis/erysipelas, major skin abscesses, and wound infections. The Infectious Diseases Society of America (IDSA) in 2014 classifies skin and soft-tissue infection (SSTI) as either non-purulent (which includes cellulitis, erysipelas, and necrotizing infection) or purulent (including furuncle, carbuncle, and abscess). Among hospitalized patients with SSTI, healthcare-associated infections account for 73.5% of all cases. Notably, skin and skin-structure infections caused by Pseudomonas aeruginosa, a common hospital pathogen, was reported to cause higher total cost and longer hospital length of stay compared to non-P. aeruginosa cases, despite causing only approximately 5.7% of all healthcare-associated SSTIs. Infection with P. aeruginosa should always be considered in non-healing skin infections in patients with prolonged hospitalization and antibiotic exposure. Tissue culture, preferably taken by surgical debridement, should be promptly performed; and when hospital-infection is suspected, appropriate antibiotics should be started along with removal of all devitalized tissue and to promote skin and soft tissue healing. Expedited discharge should be considered when possible, with adequate antibiotic treatment and follow up for definitive wound treatment.

Pharmacokinetics and Pharmacodynamics of Linezolid in Patients With Sepsis Receiving Continuous Venovenous Hemofiltration and Extended Daily Hemofiltration.

BACKGROUND: This prospective study compared pharmacokinetics (PK) and pharmacodynamics (PD) of linezolid in patients with sepsis receiving continuous venovenous hemofiltration (CVVH) with patients receiving extended daily hemofiltration (EDH). METHODS: Patients with sepsis treated with linezolid and CVVH or EDH were included. Serial blood samples were collected and linezolid concentrations measured. PKs were analyzed using Pmetrics. Monte Carlo simulations were used to evaluate PD target achievement. RESULTS: From 20 patients, 320 blood samples were collected for PK and PD analysis. PK profiles of linezolid were best described by a 2-compartment model. PK parameters were not significantly different between EDH and CVVH groups and were associated with body weight, renal replacement therapy (RRT) duration, and sequential organ failure assessment score. Monte Carlo simulations showed poor fractional target attainment for a minimum inhibitory concentration (MIC) of 2 mg/L with standard 600 mg intravenous administration every 12 hours. CONCLUSIONS: Patients with sepsis receiving RRT exhibited variability in PK/PD parameters for linezolid. PK parameters were not significantly different between CVVH- and EDH-treated patients. Higher probability of target attainment would be achievable at a MIC of 2 mg/L in EDH patients. Higher linezolid doses should be considered for patients on RRT to achieve adequate blood levels.

Subtherapeutic Linezolid Concentration in a Patient With Bullous Pemphigoid Complicated by Methicillin-Resistant Staphylococcus aureus Infection: A Case Study.

We presented a case of subtherapeutic linezolid concentration in a patient with bullous pemphigoid characterized by large area skin anabrosis complicated by methicillin-resistant Staphylococcus aureus infections.

Therapeutic Drug Monitoring Can Improve Linezolid Dosing Regimens in Current Clinical Practice: A Review of Linezolid Pharmacokinetics and Pharmacodynamics.

Linezolid is an antibiotic used to treat infections caused by drug-resistant gram-positive organisms, including vancomycin-resistant Enterococcus faecium, multi-drug resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus. The adverse effects of linezolid can include thrombocytopenia and neuropathy, which are more prevalent with higher exposures and longer treatment durations. Although linezolid is traditionally administered at a standard 600 mg dose every 12 hours, the resulting exposure can vary greatly between patients and can lead to treatment failure or toxicity. The efficacy and toxicity of linezolid are determined by the exposure achieved in the patient; numerous clinical and population pharmacokinetics (popPK) studies have identified threshold measurements for both parameters. Several special populations with an increased need for linezolid dose adjustments have also been identified. Therapeutic Drug Monitoring (TDM) is a clinical strategy that assesses the response of an individual patient and helps adjust the dosing regimen to maximize efficacy while minimizing toxicity. Adaptive feedback control and model-informed precision dosing are additional strategies that use Bayesian algorithms and PK models to predict patient-specific drug exposure. TDM is a very useful tool for patient populations with sparse clinical data or known alterations in pharmacokinetics, including children, patients with renal insufficiency or those receiving renal replacement therapy, and patients taking co-medications known to interact with linezolid. As part of the clinical workflow, clinicians can use TDM with the thresholds summarized from the current literature to improve linezolid dosing for patients and maximize the probability of treatment success.

Comparative Effectiveness of Vancomycin Versus Linezolid for the Treatment of Acute Pulmonary Exacerbations of Cystic Fibrosis.

Background: Data are limited regarding the preferred antibiotics for treatment of acute pulmonary exacerbations (APEs) of cystic fibrosis (CF), when methicillin-resistant Staphylococcus aureus (MRSA) is suspected. Objective: To compare the rate of return to baseline lung function among individuals with APEs of CF treated with either vancomycin or linezolid. Methods: This retrospective study included individuals hospitalized for APEs of CF from May 1, 2015, to April 30, 2017 who were infected with MRSA and treated with vancomycin or linezolid. The primary outcome was the return to baseline lung function, as measured by forced expiratory volume in 1 s (FEV1). Descriptive and inferential statistics were used. All tests were 2-tailed with α set at 0.05. Results: A total of 122 encounters were included (vancomycin: n = 66; linezolid: n = 66). No difference existed in return to baseline FEV1 between vancomycin (53 [80.3%]) and linezolid (50 [75.8%]; P = 0.53); nor was there a difference in median percentage change in FEV1 from admission to follow-up between vancomycin (24.7%) and linezolid (20.7%; P = 0.61). Adverse drug events occurred more frequently in patient encounters treated with vancomycin (10 [15.2%]) compared with linezolid (2 [3%]; P = 0.002). Conclusion and Relevance: Our study observed no difference in the effectiveness of vancomycin compared with linezolid in terms of change in lung function for APEs of CF. The rate of adverse drug events was low. In individuals with CF infected with MRSA who are experiencing an APE, either vancomycin or linezolid appear to be viable treatment options.

Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study.

BACKGROUND: Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. METHODS: Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. RESULTS: The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. CONCLUSIONS: ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

Linezolid-induced rare triad of hypoglycaemia, bone marrow suppression and hyponatraemia in elderly.

WHAT IS KNOWN AND OBJECTIVE: Linezolid, a member of the oxazolidinone class of antibacterial drugs, is approved by the US Food and Drug Administration (FDA) for the treatment of vancomycin-resistant Enterococcus faecium infections, nosocomial and community-acquired pneumonia, as a part of anti tubercular regimen and complicated and uncomplicated skin and soft tissue infections, including diabetic foot infections. Linezolid has potential adverse effects like bone marrow suppression, peripheral neuropathy and hyponatremia. One of the extremely rare reported adverse effects of the drug is hypoglycaemia. We present a case of Linezolid toxicity presenting as resistant hypoglycemia, bone marrow suppression and severe hyponatremia all together in a single patient. CASE DESCRIPTION: We present a case of an 82 years old gentleman with no known chronic co-morbidities. He was started on Linezolid 600 mg twice a day for 10 days by a local doctor possibly for some minor infection post hip surgery. He was in respiratory distress on arrival. Blood sugars showed severe hypoglycemia of 36 mg/dL (2.0 mmol/L). He was admitted in intensive care unit and started on injectable antibiotics and 5% dextrose infusion and sugars were strictly monitored. His blood tests revealed severe hyponatremia with sodium level of 119 mEq/L and haemoglobin (Hb) of 8.8 gm/dL, leucocytes of 6500/µL, platelets of 82 000/µL. The infection markers were normal throughout. The platelet count went progressively down from 82 000/µL on admission to 20 000/µL 2 days later; before it started rising back. Similarly there was drop in Hemoglobin and white cell counts. He required vasopressors to maintain mean arterial pressures. The blood sugar levels stabilized after the same. However patient had suffered acute lung injury secondary to aspiration and became NIV dependent and eventually passed away. WHAT IS NEW AND CONCLUSION: Our case was unique in a way that our patient had adverse effects of linezolid like myelosuppression as well as the rare side effects of hypoglycemia at the same time. This combination of adverse events has never been described in the past to our knowledge. All the adverse effects responded to antibiotic de-challenge in our case. We had ruled out the possibility of other causes of Hypoglycemia such as sepsis, insulinoma, alcohol excess, malnutrition or hypoadrenalism. We searched the PubMed database and found four case reports out of which two were diabetics and other two were non diabetics. Out of 15 cases described by Vishwanathan et al only three cases were non diabetics. Our patient was non diabetic as well. Therefore our case is only the sixth reported case of hypoglycemia in non diabetic receiving Linezolid to our knowledge.

Linezolid and the risk of lactic acidosis: Data mining and analysis of the FDA Adverse Event Reporting System.

WHAT IS KNOWN AND OBJECTIVE: Lactic acidosis (LA) is a rare but potentially lethal side effect of linezolid (LZD). However, limited by the study population, the number of patients with LA is insufficient to summarize all the clinical characteristics and risk factors. METHODS: We evaluated the association between LZD and LA using the reporting odd ratio (ROR) for mining the adverse event report signals in the FDA Adverse Event Reporting System database from January 2013 to December 2019. RESULTS AND DISCUSSION: There were 6218 reports of LZD as the primary suspected drug or secondary suspected drug, of which 275 (4.42%) reports were of LA. The ROR of LA with the use of LZD was 39.976 (95% CI 35.365-45.189). In the age composition of patients, elderly individuals (aged ≥60 years) accounted for the higher proportion, 42.54% (n = 117). LA usually occurred two weeks after LZD administration (n = 33). LZD was the unique suspected drug, accounting for 37.45% (n = 103) of all reports of LA. The drug with the most frequent occurrence of combination with LZD was 'meropenem' and 'warfarin'. WHAT IS NEW AND CONCLUSIONS: The ROR of LA caused by LZD was very high, and the number of reports about LA caused by other antibiotics was significantly different from that of LA caused by LZD. The drug combined with LZD did not seem to affect the occurrence of LA, and the high occurrence of warfarin in the reports deserves the attention of doctors.

Over 870 days of successful antibiotic suppression therapy for VRE-infected left ventricular assist device.

Left ventricular assist devices (LVADs) are used in patients with advanced heart failure. Infections are common complications following device placement; however, the efficacy of chronic antimicrobial suppression therapy for deep-seated infections is not well characterized. We report the case of a 49-year-old male with a HeartMate II LVAD who presented with a methicillin-sensitive Staphylococcus aureus pump pocket infection that was subsequently treated with antibiotics and HeartMate III pump exchange. A vancomycin-resistant Enterococcus faecium (VRE) pump pocket infection then developed and responded to surgical drainage followed by long-term suppression with daptomycin then linezolid for over 870 days. A second pump exchange was not required. To our knowledge, this represents the longest reported use of daptomycin (341 days) without symptomatic adverse events. Managing infections caused by multidrug-resistant pathogens presents a clinical challenge. This case demonstrates the potential for antimicrobial suppression therapy to allow for successful retention of a VRE-infected LVAD.