Dtsch Arztebl Int. 2021 Jan 11;118(1-2):11. doi: 10.3238/arztebl.m2021.0044.

NO ABSTRACT

PMID:33750528 | DOI:10.3238/arztebl.m2021.0044

Kidney Int. 2021 Apr;99(4):1026. doi: 10.1016/j.kint.2021.01.009.

NO ABSTRACT

PMID:33745535 | DOI:10.1016/j.kint.2021.01.009

Drug Ther Bull. 2021 Mar 19:dtb-2021-000015. doi: 10.1136/dtb.2021.000015. Online ahead of print.

ABSTRACT

Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID:33741603 | DOI:10.1136/dtb.2021.000015

Drug Ther Bull. 2021 Mar 19:dtb-2021-000014. doi: 10.1136/dtb.2021.000014. Online ahead of print.

ABSTRACT

Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID:33741602 | DOI:10.1136/dtb.2021.000014

Eur J Cancer. 2021 Mar 16;148:76-91. doi: 10.1016/j.ejca.2021.01.043. Online ahead of print.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types.

METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models.

RESULTS: Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88-1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52-7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64-1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31-3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment.

CONCLUSION: The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity.

PMID:33740500 | DOI:10.1016/j.ejca.2021.01.043

Rev Prat. 2020 Nov;70(9):1035-1036.

NO ABSTRACT

PMID:33739770

Rev Prat. 2020 Oct;70(8):871.

NO ABSTRACT

PMID:33739690

Sci Rep. 2021 Mar 18;11(1):6403. doi: 10.1038/s41598-021-85708-2.

ABSTRACT

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

PMID:33737635 | DOI:10.1038/s41598-021-85708-2

Heart. 2021 Mar 18:heartjnl-2020-318869. doi: 10.1136/heartjnl-2020-318869. Online ahead of print.

ABSTRACT

AIMS: Corticosteroid-dependent and colchicine-resistant recurrent pericarditis (RP) is a challenging management problem, in which conventional anti-inflammatory therapy (nonsteroidal anti-inflammatory drugs, colchicine, corticosteroids) is unable to control the disease. Recent data suggest a potential role for anti-interleukin-1 (IL-1) agents for this condition. This study was designed to assess the safety and efficacy of anti-IL-1 agents in this setting.

METHODS: We performed a systematic review and meta-analysis of randomised controlled trials and observational studies assessing pericarditis recurrences and drug-related adverse events in patients receiving anti-IL-1 drugs for pericarditis.

RESULTS: The meta-analysis assessed 7 studies including 397 pooled patients with RP. The median age was 42 years, 60% were women and the aetiology was idiopathic in 87%. After a median follow-up of 14 months (IQR,12-39), patients receiving anti-IL-1 agents (anakinra or rilonacept) had a significantly reduction in pericarditis recurrences (incidence rate ratio 0.06, 95% CI 0.03 to 0.14), compared with placebo and/or standard medical therapy. Anti-IL-1 agents were associated with increased risk of adverse events compared with placebo (risk ratio (RR) 5.38, 95% CI 2.08 to 13.92): injection-site reactions occurred in 15/41 (36.6%) vs none (RR 14.98, 95% CI 2.09 to 107.09), infections occurred in 13/51 (25.5%) vs 3/41 (7.3%; RR 3.65, 95% CI 1.23 to 10.85). Anti-IL-1 agents were not associated with increased risk of severe adverse events.

CONCLUSIONS: In patients with RP, anti-IL-1 agents (anakinra and rilonacept) are efficacious for prevention of recurrences, without severe adverse events.

PMID:33737453 | DOI:10.1136/heartjnl-2020-318869

Int J Chron Obstruct Pulmon Dis. 2021 Mar 10;16:615-628. doi: 10.2147/COPD.S291920. eCollection 2021.

ABSTRACT

BACKGROUND: The Clinical COPD Questionnaire (CCQ) is a simple patient-reported tool to measure clinical control of chronic obstructive pulmonary disease (COPD).

OBJECTIVE: This open-label, single-arm, non-interventional study (NCT03663569) investigated changes in CCQ score during treatment with tiotropium/olodaterol in clinical practice.

METHODS: Data were included from consenting COPD patients, enrolled in Bulgaria, Czech Republic, Hungary, Israel, Lithuania, Poland, Romania, Russia, Slovenia, Switzerland and Ukraine, who were receiving a new prescription for tiotropium/olodaterol according to the treating physician in a real-world environment. The primary endpoint was the occurrence of therapeutic success, defined as a 0.4-point decrease in CCQ score after treatment with tiotropium/olodaterol for approximately 6 weeks.

RESULTS: Overall, 4819 patients were treated; baseline and Week 6 CCQ scores were available for 4700 patients, mostly classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) B (51.6%) or D (42.7%). After 6 weeks' treatment, 81.4% (95% confidence interval [95% CI] 80.24-82.49) of patients achieved therapeutic success; mean improvement in overall CCQ score was 1.02 points (95% CI 1.00-1.05). Improved CCQ score was seen in 92.2% of patients (95% CI 91.43-92.98), 2.5% had no change and 5.3% showed a worsening. When stratified by prior treatment, the greatest benefit was seen in treatment-naïve patients, with 85.7% achieving therapeutic success, compared with 79.5% of those pretreated with long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) and 74.2% of those pretreated with LABA or long-acting muscarinic antagonist (LAMA) monotherapy. Overall, rescue medication decreased by 1.25 puffs/day (95% CI 1.19-1.31) versus baseline. In total, 29 patients (0.6%) reported drug-related adverse events and 7 patients reported serious adverse events (0.15%).

CONCLUSION: In 4700 COPD patients, 6 weeks' treatment with tiotropium/olodaterol, as initial treatment or follow-up to LAMA or LABA monotherapy or LABA/ICS, improved CCQ and decreased rescue medication use. The adverse event profile was consistent with the known safety profile of tiotropium/olodaterol.

PMID:33731991 | PMC:PMC7956863 | DOI:10.2147/COPD.S291920

Medicine (Baltimore). 2021 Mar 19;100(11):e24423. doi: 10.1097/MD.0000000000024423.

ABSTRACT

The association between Glutathione S-transferase Pi 1(GSTP1) genetic polymorphism (rs1695, 313A>G) and cyclophosphamide-induced toxicities has been widely investigated in previous studies, however, the results were inconsistent. This study was performed to further elucidate the association.A comprehensive search was conducted in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Wan Fang database up to January 5, 2020. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were used to estimate the association between GSTP1 rs1695 polymorphism and cyclophosphamide-induced hemotoxicity, gastrointestinal toxicity, infection, and neurotoxicity.A total of 13 studies were eventually included. Compared with the GSTP1 rs1695 AA genotype carriers, patients with AG and GG genotypes had an increased risk of cyclophosphamide-induced gastrointestinal toxicity (RR, 1.61; 95% CI, 1.18-2.19; P = .003) and infection (RR, 1.57; 95% CI, 1.00-2.48; P = .05) in the overall population. In the subgroup analyses, there were significant associations between GSTP1 rs1695 polymorphism and the risk of cyclophosphamide-induced myelosuppression (RR, 2.10; 95% CI, 1.60-2.76; P < .00001), gastrointestinal toxicity (RR, 1.77; 95%CI, 1.25-2.53; P = .001), and infection (RR, 2.01; 95% CI, 1.14-3.54; P = .02) in systemic lupus erythematosus (SLE) or lupus nephritis syndrome patients, but not in cancer patients.Our results confirmed an essential role for the GSTP1 rs1695 polymorphism in the prediction of cyclophosphamide-induced myelosuppression, gastrointestinal toxicity, and infection in SLE or lupus nephritis syndrome patients. More studies are necessary to validate our findings in the future.

PMID:33725933 | DOI:10.1097/MD.0000000000024423

Ther Innov Regul Sci. 2021 Mar 17. doi: 10.1007/s43441-021-00268-x. Online ahead of print.

ABSTRACT

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).

PMID:33730364 | DOI:10.1007/s43441-021-00268-x

J Mol Med (Berl). 2021 Mar 16. doi: 10.1007/s00109-021-02048-4. Online ahead of print.

ABSTRACT

The common phenomenon expected from any anti-cancer drug in use is to kill the cancer cells without any side effects to non-malignant cells. Doxorubicin is an anthracycline derivative anti-cancer drug active over different types of cancers with anti-cancer activity but attributed to unintended cytotoxicity and genotoxicity triggering mitogenic signals inducing apoptosis. Administration of doxorubicin tends to both acute and chronic toxicity resulting in cardiomyopathy (left ventricular dysfunction) and congestive heart failure (CHF). Cardiotoxicity is prevented through administration of different cardioprotectants along with the drug. This review elaborates on mechanism of drug-mediated cardiotoxicity and attenuation principle by different cardioprotectants, with a focus on Hsp27 as cardioprotectant by prevention of drug-induced oxidative stress, cell survival pathways with suppression of intrinsic cell death. In conclusion, Hsp27 may offer an exciting/alternating cardioprotectant, with a wider study being need of the hour, specifically on primary cell line and animal models in conforming its cardioprotectant behaviour.

PMID:33728476 | DOI:10.1007/s00109-021-02048-4

Drug Des Devel Ther. 2021 Mar 9;15:1101-1110. doi: 10.2147/DDDT.S296197. eCollection 2021.

ABSTRACT

PURPOSE: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials.

METHODS: Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10.

RESULTS: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.

CONCLUSION: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.

PMID:33727798 | PMC:PMC7955752 | DOI:10.2147/DDDT.S296197

Cancer Res. 2021 Mar 16:canres.2435.2020. doi: 10.1158/0008-5472.CAN-20-2435. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR tyrosine kinase inhibitors (TKIs) has been a paradigm shift. Osimertinib and rociletinib are third-generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard of care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here we characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs, comprising the most comprehensive proteomic dataset resource to date to investigate third-generation EGFR TKI resistance in lung adenocarcinoma. Unbiased global quantitative mass spectrometry uncovered alterations in signaling pathways, revealed a proteomic signature of epithelial mesenchymal transition, and identified kinases and phosphatases with altered expression and phosphorylation in TKI-resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition, resulting in subsequent inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Anticorrelation analyses of this phosphoproteomic dataset with published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures program predicted drugs with the potential to overcome EGFR TKI resistance. The PI3K/MTOR inhibitor dactolisib in combination with osimertinib overcame resistance both in vitro and in vivo. Taken together, this study reveals global proteomic alterations upon third-generation EGFR TKI resistance and highlights potential novel approaches to overcome resistance.

PMID:33727228 | DOI:10.1158/0008-5472.CAN-20-2435

Cochrane Database Syst Rev. 2021 Mar 8;3:CD003427. doi: 10.1002/14651858.CD003427.pub5.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors, contribute to persons with SCD being particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person-years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review which was first published in 2002, and previously updated, most recently in 2017. OBJECTIVES: To compare the effects of antibiotic prophylaxis against pneumococcus in children with SCD receiving antibiotic prophylaxis compared to those without in relation to: 1. incidence of Streptococcus pneumoniae infection; 2. mortality (as reported in the included studies); 3. drug-related adverse events (as reported in the included studies) to the individual and the community; 4. the impact of discontinuing at various ages on incidence of infection and mortality.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform (not in 2020 given access issues relating to Covid-19 pandemic). Additionally, we carried out hand searching of relevant journals and abstract books of conference proceedings. Date of the most recent search: 25 January 2021.

SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug.

DATA COLLECTION AND ANALYSIS: The standard methodological procedures expected by Cochrane were used. Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the certainty of the evidence.

MAIN RESULTS: Six trials were identified by the searches, of which three trials were eligible for inclusion. A total of 880 children, who were between three months to five years of age at randomization were included. The included studies were conducted in centres in the USA and in Kingston, Jamaica. In trials that investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-certainty evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-certainty evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five years. Overall, the certainty of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias).

AUTHORS' CONCLUSIONS: The evidence examined was determined to be of low certainty and suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.

PMID:33724440 | DOI:10.1002/14651858.CD003427.pub5

Otolaryngol Pol. 2021 Feb 16;75(2):1-5.

ABSTRACT

&lt;b&gt;Introduction:&lt;/b&gt; In the daily practice of an otolaryngologist, we encounter cases where the symptoms are not the result of disease but result from pharmacotherapy. In the case of symptoms such as hearing loss, tinnitus, or dizziness, polytherapy may be used as the basis for their occurrence, which, due to the lack of rationality in combining drugs, leads to symptoms that the patient and the doctor very often interpret as a new disease syndrome. &lt;br&gt;&lt;b&gt;Aim:&lt;/b&gt; The aim of the study is to show and to raise awareness of the fact that the symptoms of hearing organ impairment are frequently drug-related and only a modification of the currently used pharmacotherapy is a rational procedure in such cases. &lt;br&gt;&lt;b&gt;Material:&lt;/b&gt; This paper describes 30 cases who developed side effects of polypharmacy in the form of hearing disorders, dizziness, and tinnitus. The causes of drug-related complications were discussed, as well as effective methods of their prevention.

PMID:33724230

Ter Arkh. 2020 Dec 26;92(11):122-131. doi: 10.26442/00403660.2020.11.000870.

ABSTRACT

AIM: Baloxavir marboxil (baloxavir) is the first cap-dependent endonuclease inhibitor being studied for the treatment of influenza in single oral dosing regimen. This network meta-analysis (NMA) evaluated the efficacy and safety of baloxavir compared to other antivirals for influenza in otherwise healthy patients.

METHODS: A systematic literature review was performed on 14 November 2016 in Medline, Embase, CENTRAL, and ICHUSHI to identify randomized controlled trials assessing antivirals for influenza. A NMA including 22 trials was performed to compare the efficacy and safety of baloxavir with other antivirals.

RESULTS: The time to alleviation of all symptoms was significantly shorter for baloxavir compared to zanamivir (difference in median time 19.96 h; 95% CrI [3.23, 39.07]). The time to cessation of viral shedding was significantly shorter for baloxavir than zanamivir and oseltamivir (47.00 h; 95% CrI [28.18, 73.86] and 56.03 h [33.74, 87.86], respectively). The mean decline in virus titer from baseline to 24 h was significantly greater for baloxavir than for the other drugs. Other differences in efficacy outcomes were not significant. No significant differences were found between baloxavir and the other antivirals for safety, except total drug-related adverse events where baloxavir demonstrated a decrease compared to oseltamivir and laninamivir.

CONCLUSION: The NMA suggests that baloxavir demonstrated better or similar efficacy results compared to other antivirals with a comparable safety profile. Baloxavir led to a significant decrease in viral titer versus zanamivir, oseltamivir and peramivir and decreased viral shedding versus zanamivir and oseltamivir.

PMID:33720617 | DOI:10.26442/00403660.2020.11.000870

Clin Infect Dis. 2021 Mar 15:ciab032. doi: 10.1093/cid/ciab032. Online ahead of print.

ABSTRACT

BACKGROUND: Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP.

METHODS: In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population.

RESULTS: Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, -1.8%; 95% confidence interval [CI]: -8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, -7.6%; 97.5% CI: -15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively.

CONCLUSIONS: Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated.

CLINICAL TRIALS REGISTRATION: NCT02019420.

PMID:33720350 | DOI:10.1093/cid/ciab032

Eur J Ophthalmol. 2021 Mar 15:11206721211001268. doi: 10.1177/11206721211001268. Online ahead of print.

ABSTRACT

INTRODUCTION: Ibrutinib is a small-molecule drug approved for the treatment of haematological disorders and is known to be associated with visual disturbances, but uveitis has not yet been reported as an adverse effect of this medication. We present two cases of ibrutinib-associated severe uveitis in patients with chronic lymphocytic leukaemia.

CASE DESCRIPTION: Our first case is a 65-year-old woman who presented with acute onset of bilateral fibrinous anterior uveitis 1 day after starting ibrutinib. Her vision was hand movements in the right eye and 20/120 in the left with hyperaemic discs and subretinal fluid. Ibrutinib was stopped and she experienced a significant improvement under local and oral steroid treatment. The second case is a 64-year-old male with subacute onset of bilateral hypertensive anterior uveitis with pupillary seclusion and right eye hyphaema. He was on ibrutinib for the past 9 months. His vision at presentation was 20/80 and 20/60 for the right and left eye, respectively. He responded poorly to local steroid treatment until ibrutinib was stopped due to cardiac side-effects, after which his uveitis resolved and treatment was stopped.

CONCLUSION: The temporal association between changes in ibrutinib treatment and our patients' ocular inflammation suggests a causative link. Ibrutinib increases Th1-based immune responses which is proposed as a mechanism for drug-induced uveitis. Its antiplatelet effect may explain the fibrinous nature of the inflammation and hyphaema.

PMID:33719653 | DOI:10.1177/11206721211001268