Antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) strains isolated at tertiary care hospital in Riyadh, Saudi Arabia.

Staphylococcus aureus is an important human pathogen that has a major impact on public health. The objective of the present work was to determine the prevalence and the pattern of antibiotic susceptibility in S aureus (MRSA) isolates from the King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia. The isolates were collected from different body sites of infection and the antibiotic susceptibility was confirmed on the Vitek 2 system. A total of 371 MRSA isolates from clinical samples were received over a 12-month period from January 2021 to December 2021. The results showed that infection was predominant among males (55.8%) and most of the isolates occurred in the older age groups, with a mean age of 43.7 years and an age span from <1 to 89 years old. The majority (34.5%) recovered from wound infection followed by (14.6%) from blood. We have observed peaks of MRSA infections during the autumn, especially in September and November. All MRSA isolates were resistant to Amoxicillin + clavulanic acid, Ampicillin, Imipenem, Oxacillin, Cloxacillin, and Penicillin while all isolates were sensitive to Daptomycin and Nitrofurantoin. Furthermore, Vancomycin was resistant in (0.3%) of MRSA isolates, and (2.9%) was resistant to Linezolid. The current study concluded that MRSA strains had developed resistance toward 24 tested antibiotics, including the previous effective drugs vancomycin and linezolid. Therefore, there is an urgent need for continuous review of infection control practices to prevent any further spread of resistant strains.

A multicenter clinical epidemiology of pediatric pneumococcal meningitis in China: results from the Chinese Pediatric Bacterial Meningitis Surveillance (CPBMS) 2019-2020.

Objective: To analyze the clinical epidemiological characteristics including clinical features, disease prognosis of pneumococcal meningitis (PM), and drug sensitivity of S. pneumoniae isolates in Chinese children. Methods: A retrospective analysis was performed on the clinical, laboratory microbiological data of 160 hospitalized children less than 15 years of age with PM from January 2019 to December 2020 in 33 tertiary hospitals in China. Results: A total of 160 PM patients were diagnosed, including 103 males and 57 females The onset age was 15 days to 15 years old, and the median age was 1 year and 3 months. There were 137 cases (85.6%) in the 3 months to <5 years age group, especially in the 3 months to <3 years age group (109 cases, 68.2%); S. pneumoniae was isolated from cerebrospinal fluid (CSF) culture in 95(35.6%), and 57(35.6%) in blood culture. The positive rates of S. pneumoniae detection by CSF metagenomic next-generation sequencing (mNGS)and antigen detection method were 40.2% (35/87) and 26.9% (21/78). Fifty-five cases (34.4%) had one or more predisposing factors of bacterial meningitis; and 113 cases (70.6%) had one or more extracranial infection diseases Fever (147, 91.9%) was the most common clinical symptom, followed by vomiting (61, 38.1%) and altered mental status (47,29.4%). Among 160 children with PM, the main intracranial imaging complications were subdural effusion and (or) empyema in 43 cases (26.9%), hydrocephalus in 24 cases (15.0%), cerebral abscess in 23 cases (14.4%), intracranial hemorrhage in 8 cases (5.0%), and other cerebrovascular diseases in 13 cases (8.1%) including encephalomalacia, cerebral infarction, and encephalatrophy. Subdural effusion and (or) empyema and hydrocephalus mainly occurred in children < 1 years old (90.7% (39/43) and 83.3% (20/24), respectively). 17 cases with PM (39.5%) had more than one intracranial imaging abnormality. S. pneumoniae isolates were completely sensitive to vancomycin (100.0%, 75/75), linezolid (100.0%,56/56), ertapenem (6/6); highly sensitive to levofloxacin (81.5%, 22/27), moxifloxacin (14/17), rifampicin (96.2%, 25/26), and chloramphenicol (91.3%, 21/23); moderately sensitive to cefotaxime (56.1%, 23/41), meropenem (51.1%, 23/45) and ceftriaxone (63.5, 33/52); less sensitive to penicillin (19.6%, 27/138) and clindamycin (1/19); completely resistant to erythromycin (100.0%, 31/31). The cure and improvement rate were 22.5% (36/160)and 66.3% (106/160), respectively. 18 cases (11.3%) had an adverse outcome, including 6 cases withdrawing treatment therapy, 5 cases unhealed, 5 cases died, and 2 recurrences. S. pneumoniae was completely susceptible to vancomycin (100.0%, 75/75), linezolid (100.0%, 56/56), and ertapenem (6/6); susceptible to cefotaxime, meropenem, and ceftriaxone in the order of 56.1% (23/41), 51.1% (23/45), and 63.5 (33/52); completely resistant to erythromycin (100.0%, 31/31). Conclusion: Pediatric PM is more common in children aged 3 months to < 3 years old. Intracranial complications mostly occur in children < 1 year of age with fever being the most common clinical manifestations and subdural effusion and (or) empyema and hydrocephalus being the most common complications, respectively. CSF non-culture methods can facilitate improving the detection rate of pathogenic bacteria. More than 10% of PM children had adverse outcomes. S. pneumoniae strains are susceptible to vancomycin, linezolid, ertapenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

Efficacy of Linezolid in the management of pneumonic COVID-19 patients. Bioinformatics-based clinical study.

INTRODUCTION: At the beginning in July 2023, there has been a significant increase in daily hospital admissions attributed to the new variant of COVID-19. Aim of this study is to explore the clinical benefits and outcomes of using linezolid in the management of pneumonic COVID-19 patients. METHODOLOGY: The study included 230 patients with SARS-CoV-2 infection confirmed by RT-PCR. Group 1: 118 patients were managed with Linazolid alongside steroids. Group 2: (control group) patients treated according to the Protocol for Egyptian COVID-19 management outlines and WHO guidelines (112 patients). Each patient group was categorized into 3 age groups: 20-40 years, 41-65 years, and over 65 years. Patients were carefully followed up until recovery or mortality. A docking analysis was carried out to investigate the potential of linezolid to act as an Mpro inhibitor. RESULTS: Group 1's average recovery time was 15.1 days in contrast to 18.7 days for Group 2 (control). There were no deaths reported. In silico investigations revealed that Linezolid was able to achieve a binding mode comparable to that of the co-crystalized inhibitor. CONCLUSIONS: Linazolid is considered an effective antiviral weapon against SARS-COV-2. It could be used in the management plan of pneumonic individuals due to SARS-COV-2 infection. We recommend using it to combat the current wave caused by Omicron EG-5 Variant.

Synergistic interactions of essential oil components with antibiotics against multidrug-resistant Corynebacterium striatum.

AIM: In this study, it was aimed to examine the antibacterial activity of the essential oil components (EOCs), carvacrol (CAR), cinnamaldehyde (CIN), thymol (TH), alpha pinene (α-PN), eucalyptol (EU), limonene (LIM), and the antibiotics, linezolid (LZD), vancomycin (VAN), gentamicin (GEN), ciprofloxacin (CIP), clindamycin (CLN), and penicillin (PEN) against 50 multidrug resistant Corynebacterium striatum strains, and the synergistic interactions of CAR and CIN with the antibiotics against 10 randomly selected Coryne. striatum strains to explore synergistic interactions to determine if their combined use could enhance antibiotic activity and potentially reduce resistance. METHODS AND RESULTS: The activity of the EOCs and the antibiotics against Coryne. striatum strains isolated from clinical specimens, was examined by broth microdilution method. The synergistic interactions of the EOCs with the antibiotics against 10 randomly selected Coryne. striatum strains were determined by checkerboard method. EOCs, CIN, and CAR and antibiotics, LZD, VAN, GEN, CIP, and CLN were detected to have antibacterial activity against Coryne. striatum strains alone and either synergistic interactions were observed in combinations of the antibiotics with EOCs. CONCLUSIONS: All Coryne. striatum strains were determined to be susceptible to VAN and LZD and resistant to GEN, PEN, CIP, and CLN. Synergistic interactions were observed in all combinations of antibiotics tested with CAR and CIN.

Spectrum and antibiotic sensitivity of bacterial keratitis: a retrospective analysis of eight years in a Tertiary Referral Hospital in Southwest China.

Purpose: The objective of this study was to investigate the epidemiological characteristics, distribution of isolates, prevailing patterns, and antibiotic susceptibility of bacterial keratitis (BK) in a Tertiary Referral Hospital located in Southwest China. Methods: A retrospective analysis was conducted on 660 cases of bacterial keratitis occurring between January 2015 and December 2022. The demographic data, predisposing factors, microbial findings, and antibiotic sensitivity profiles were examined. Results: Corneal trauma emerged as the most prevalent predisposing factor, accounting for 37.1% of cases. Among these cases, bacterial culture results were positive in 318 cases, 68 species of bacteria were identified. The most common Gram-Positive bacteria isolated overall was the staphylococcus epidermis and the most common Gram-Negative bacteria isolated was Pseudomonas aeruginosa. Methicillin-Resistant Staphylococci accounted for 18.1% of all Gram-Positive bacteria. The detection rate of P. aeruginosa showed an increasing trend over time (Rs=0.738, P=0.037). There was a significant decrease in the percentage of Gram-Negative microorganisms over time (Rs=0.743, P=0.035). The sensitivity of Gram-Positive bacteria to linezolid, vancomycin, tigecycline, quinupristin/dalfopristin, and rifampicin was over 98%. The sensitivity rates of Gram-Negative bacteria to amikacin, meropenem, piperacillin/tazobactam, cefoperazone sodium/sulbactam, ceftazidime, and cefepime were all above 85%. In patients with a history of vegetative trauma, the possibility of BK should be taken into account in addition to the focus on fungal keratitis. Conclusion: The microbial composition primarily consists of Gram-Positive cocci and Gram-Negative bacilli. Among the Gram-Positive bacteria, S. epidermidis and Streptococcus pneumoniae are the most frequently encountered, while P. aeruginosa is the predominant Gram-Negative bacteria. To combat Gram-Positive bacteria, vancomycin, linezolid, and rifampicin are considered excellent antimicrobial agents. When targeting Gram-Negative pathogens, third-generation cephalosporins exhibit superior sensitivity compared to first and second-generation counterparts. As an initial empirical treatment for severe cases of bacterial keratitis and those unresponsive to fourth-generation fluoroquinolones in community settings, the combination therapy of vancomycin and tobramycin is a justifiable approach. Bacterial keratitis can be better managed by understanding the local etiology and antibacterial drug susceptibility patterns.

In vitro activity of tedizolid against 43 species of Nocardia species.

The purpose of the present study was to evaluate the in vitro activity of tedizolid against several clinically significant species of Nocardia by comparing with that of linezolid. A total of 286 isolates of Nocardia species, including 236 clinical isolates recovered from patients in Japan and 50 strains (43 species) purchased from NITE Biological Resource Center, were studied. Antimicrobial susceptibility testing was performed using the broth microdilution method. For the 286 Nocardia isolates, the minimal inhibitory concentration (MIC)50 and MIC90 values of tedizolid were 0.25 and 0.5 µg/ml, and those of linezolid were 2 and 2 µg/ml, respectively. The distribution of the linezolid/tedizolid ratios (MICs of linezolid/MICs of tedizolid) showed that tedizolid had four- to eight-fold higher activity than linezolid in 96.1% (275/286) of Nocardia isolates. Both the tedizolid and linezolid MIC90 values for Nocardia brasiliensis were two-fold higher than those for the other Nocardia species. Both tedizolid and linezolid had low MIC values, 0.25-1 µg/ml and 0.5-4 µg/ml, respectively, even against nine isolates (five species) that were resistant to trimethoprim/sulfamethoxazole. One Nocardia sputorum isolate showed reduced susceptibility to tedizolid (4 µg/ml). Bioinformatics analysis suggests different resistance mechanisms than the oxazolidinone resistance seen in enterococci and staphylococci.

Polycystic intrahepatic infection caused by Enterococcus casseliflavus: a case report and literature review.

BACKGROUND: Enterococcus casseliflavus is a rare pathogenic bacterium that is characterized by vancomycin resistance and can lead to multiple infections in the human body. This report describes a rare case of polycystic intrahepatic infection with E. casseliflavus which necessitated antibiotic treatment and surgical intervention involving cystic drainage. CASE PRESENTATION: A 59-year-old woman, a long-term hemodialysis patient, was hospitalized due to a 5-day history of fever, abdominal pain, and diarrhea, which were possibly caused by the ingestion of contaminated food. Her blood culture yielded a positive result for E. casseliflavus, and she was initially treated with piperacillin/tazobactam and linezolid. Later, the antibiotic regimen was adjusted to include meropenem and linezolid. Despite treatment, her body temperature remained elevated. However, subsequent blood cultures were negative for E.casseliflavus.Conventional CT scans and ultrasound examinations did not identify the source of infection. However, a PET-CT examination indicated an intrahepatic cyst infection. Following MRI and ultrasound localization, percutaneous intrahepatic puncture and drainage were performed on the 20th day. Fluoroquinolones were administered for 48 days. On the 32nd day, MRI revealed a separation within the infected cyst, leading to a repeat percutaneous drainage at a different site. Subsequently, the patient's temperature returned to normal. The infection was considered resolved, and she was discharged on the 62nd day. Follow-up results have been favorable thus far. CONCLUSIONS: Based on the findings from this case, it is recommended to promptly conduct PET-CT examination to exclude the possibility of intracystic infection in cases of polycystic liver infection that are challenging to control. Furthermore, timely consideration should be given to puncture drainage in difficult cases.

[A multi-center epidemiological study on pneumococcal meningitis in children from 2019 to 2020]. / 2019­2020å¹´160ä¾‹å„¿ç«¥è‚ºç‚Žé“¾çƒèŒè„‘è†œç‚Žä¸´åºŠæµè¡Œç— å­¦å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children. METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country. RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes. CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

Spider chart, greenness and whiteness assessment of experimentally designed multivariate models for simultaneous determination of three drugs used as a combinatory antibiotic regimen in critical care units: Comparative study.

In this study, five earth-friendly spectrophotometric methods using multivariate techniques were developed to analyze levofloxacin, linezolid, and meropenem, which are utilized in critical care units as combination therapies. These techniques were used to determine the mentioned medications in laboratory-prepared mixtures, pharmaceutical products and spiked human plasma that had not been separated before handling. These methods were named classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm partial least squares (GA-PLS), and artificial neural network (ANN). The methods used a five-level, three-factor experimental design to make different concentrations of the antibiotics mentioned (based on how much of them are found in the plasma of critical care patients and their linearity ranges). The approaches used for levofloxacin, linezolid, and meropenem were in the ranges of 3-15, 8-20, and 5-25 µg/mL, respectively. Several analytical tools were used to test the proposed methods' performance. These included the root mean square error of prediction, the root mean square error of cross-validation, percentage recoveries, standard deviations, and correlation coefficients. The outcome was highly satisfactory. The study found that the root mean square errors of prediction for levofloxacin were 0.090, 0.079, 0.065, 0.027, and 0.001 for the CLS, PCR, PLS, GA-PLS, and ANN models, respectively. The corresponding values for linezolid were 0.127, 0.122, 0.108, 0.05, and 0.114, respectively. For meropenem, the values were 0.230, 0.222, 0.179, 0.097, and 0.099 for the same models, respectively. These results indicate that the developed models were highly accurate and precise. This study compared the efficiency of artificial neural networks and classical chemometric models in enhancing spectral data selectivity for quickly identifying three antimicrobials. The results from these five models were subjected to statistical analysis and compared with each other and with the previously published ones. Finally, the whiteness of the methods was assessed by the recently published white analytical chemistry (WAC) RGB 12, and the greenness of the proposed methods was assessed using AGREE, GAPI, NEMI, Raynie and Driver, and eco-scale, which showed that the suggested approaches had the least negative environmental impact. Furthermore, to demonstrate solvent sustainability, a greenness index using a spider chart methodology was employed.

[Advances in antibiotic therapy for tuberculosis]. / Avancées dans l'antibiothérapie de la tuberculose.

ADVANCES IN ANTIBIOTIC THERAPY FOR TUBERCULOSIS. Treatment of tuberculosis is experiencing significant advancements. For the first time, a therapeutic regimen based on rifapentine and moxifloxacin allows for a reduction of treatment duration of drug-susceptible tuberculosis from 6 to 4 months. Regarding multidrug-resistant tuberculosis, combinations of new antituberculosis drugs (bedaquiline, linezolid, delamanid/pretomanid, moxifloxacin) have the potential to reduce the treatment duration from 20 to 6 months. Additionally, considering the extent of anatomical involvement and bacterial burden allows for strategies that involve variable treatment durations based on the severity of the disease. The new tuberculosis treatments thus appear to be shorter and more personalized.

AVANCÉES DANS L'ANTIBIOTHÉRAPIE DE LA TUBERCULOSE. Le traitement de la tuberculose connaît de grandes avancées. Pour la première fois, un protocole thérapeutique à base de rifapentine et moxifloxacine permet de réduire de six à quatre mois la durée du traitement des tuberculoses à bacilles sensibles. S'agissant des tuberculoses à bacilles multirésistants, des combinaisons de nouveaux antituberculeux (bédaquiline, linézolide, délamanide-prétomanide, moxifloxacine) permettent de réduire de vingt à six mois la durée du traitement. Enfin, la prise en compte de l'importance de l'atteinte anatomique et de la charge bacillaire permet d'envisager des stratégies incluant des durées de traitement variables selon l'importance de l'atteinte. Les nouveaux traitements de la tuberculose apparaissent donc plus courts et plus personnalisés.

Recent advances in the exploration of oxazolidinone scaffolds from compound development to antibacterial agents and other bioactivities.

Bacterial infections cause a variety of life-threatening diseases, and the continuous evolution of drug-resistant bacteria poses an increasing threat to current antimicrobial regimens. Gram-positive bacteria (GPB) have a wide range of genetic capabilities that allow them to adapt to and develop resistance to practically all existing antibiotics. Oxazolidinones, a class of potent bacterial protein synthesis inhibitors with a unique mechanism of action involving inhibition of bacterial ribosomal translation, has emerged as the antibiotics of choice for the treatment of drug-resistant GPB infections. In this review, we discussed the oxazolidinone antibiotics that are currently on the market and in clinical development, as well as an updated synopsis of current advances on their analogues, with an emphasis on innovative strategies for structural optimization of linezolid, structure-activity relationship (SAR), and safety properties. We also discussed recent efforts aimed at extending the activity of oxazolidinones to gram-negative bacteria (GNB), antitumor, and coagulation factor Xa. Oxazolidinone antibiotics can accumulate in GNB by a conjugation to siderophore-mediated ß-lactamase-triggered release, making them effective against GNB.

Drug-resistant tuberculosis is a global cause of concern.

The number of patients with drug-resistant tuberculosis (DR-TB) is increasing worldwide. This review summarises the global epidemiology of DR-TB and current treatment challenges. Luckily, novel regimens comprising bedaquiline, pretomanid, linezolid, and moxifloxacin have seemingly mitigated the global threat posed by DR-TB. However, emerging resistance against bedaquiline and pretomanid, among other factors, persists as ongoing concerns in the global fight against DR-TB. While the new regimens are groundbreaking, the sustained development of novel drugs targeting the most resistant forms of tuberculosis is of utmost importance for future efforts against DR-TB.

Linezolid-Induced Thrombocytopenia in Patients with Renal Impairment: A Case Series, Review and Dose Advice.

BACKGROUND AND OBJECTIVE: Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines. METHODS: We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients. RESULTS: Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication. CONCLUSION: Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2 days of standard dosing for all patients with an estimated glomerular filtration of <60 mL/min/1.73 m2. Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.

Prevalence of linezolid resistance in Streptococcus pneumoniae isolates: a systematic review and meta-analysis.

Aim: This study aimed to understand the current level of linezolid (LNZ) resistance in Streptococcus pneumoniae isolates reported over the past 10 years. Material & methods: An electronic search was conducted for the following keywords: ((Streptococcus pneumoniae [title/abstract]) OR (Pneumococcus [title/abstract]) OR (Pneumococci [title/abstract]) AND (linezolid [title/abstract]) OR (Zyvox [title/abstract])) OR (Zyvoxid [title/abstract])). Result: Out of all the studies, 80 had a cross-sectional design, while 11 followed a cohort approach. The prevalence of LNZ resistance among S. pneumoniae isolates ranged from 0% to 4.86%. Discussion: Urgent, high-powered, randomized, controlled trials with participants from endemic regions are needed to gain a comprehensive understanding of the impact on and significance of LNZ treatment to patients.

Association of clinical factors with thrombocytopenia in patients receiving linezolid treatment: a retrospective study.

INTRODUCTION: Linezolid (LZD) plays an important role in the treatment of severe infections caused by Gram-positive bacteria. Thrombocytopenia is regarded as one of the most common side effects of linezolid, which results from the destruction of platelets or myelosuppression. The study aimed to identify the risk factors associated with the development of thrombocytopenia in Vietnamese patients. METHODOLOGY: This retrospective, descriptive cross-sectional study was performed on adult patients who received parenteral LZD therapy (1,200 mg/day) in at least 3 days between January 2020 and June 2021 at a tertiary referral hospital in Vietnam. Thrombocytopenia was defined as either a final platelet count of less than 100 G/L or a 25% decrease in platelet count from baseline. Multivariate logistic regression analysis was applied to predict risk factors associated with LZD-induced thrombocytopenia. RESULTS: In the 208 patients included in the study, the average age was 69 and males accounted for 73.1%. LZD-induced thrombocytopenia occurred in 37% of patients. LZD-induced thrombocytopenia was significantly associated with shock (HR = 8.26, 95% CI 3.82 - 17.84, p < 0.001), baseline creatinine clearance (HR = 1.02, 95% CI [1.01 - 1.03], p = 0.002), and duration of LZD treatment of at least 14 days (HR = 4.45, 95% CI [1.83 - 11.05], p = 0.001). CONCLUSIONS: The results showed that thrombocytopenia was fairly common in patients using linezolid. Shock, renal failure, and duration of linezolid therapy of at least 14 days were significant risk factors for the incidence of linezolid-induced thrombocytopenia.

Mapping the widespread distribution and transmission dynamics of linezolid resistance in humans, animals, and the environment.

BACKGROUND: The rise of linezolid resistance has been widely observed both in clinical and non-clinical settings. However, there were still data gaps regarding the comprehensive prevalence and interconnections of linezolid resistance genes across various niches. RESULTS: We screened for potential linezolid resistance gene reservoirs in the intestines of both humans and animals, in meat samples, as well as in water sources. A total of 796 bacteria strains out of 1538 non-duplicated samples were identified to be positive for at least one linezolid resistance gene, optrA, poxtA, cfr, and cfr(D). The prevalence of optrA reached 100% (95% CI 96.3-100%) in the intestines of pigs, followed by fish, ducks, and chicken at 77.5% (95% CI 67.2-85.3%), 62.0% (95% CI 52.2-70.9%), and 61.0% (95% CI 51.2-70.0%), respectively. The meat and water samples presented prevalences of 80.0% (95% CI 70.6-87.0%) and 38.0% (95% CI 25.9-51.9%), respectively. The unreported prevalence of the cfr(D) gene was also relatively higher at 13.0% (95% CI 7.8-21.0%) and 19.0% (95% CI 10.9-25.6%) for the feces samples of ducks and pigs, respectively. Enterococci were the predominant hosts for all genes, while several non-enterococcal species were also identified. Phylogenetic analysis revealed a significant genetic distance among linezolid resistance gene reservoirs, with polyclonal structures observed in strains within the same niche. Similar genetic arrays harboring assorted insertion sequences or transposons were shared by reservoirs displaying heterogeneous backgrounds, though large diversity in the genetic environment of linezolid resistance genes was also observed. CONCLUSIONS: The linezolid resistance genes were widespread among various niches. The horizontal transfer played a crucial role in driving the circulation of linezolid resistance reservoirs at the human-animal-environment interfaces. Video Abstract.

Predictive Modeling of Drug-Related Adverse Events with Real-World Data: A Case Study of Linezolid Hematologic Outcomes.

Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia and anemia, in a cohort of patients treated with linezolid for 3 or more days. Features for model input were extracted at linezolid initiation (index), and outcomes were characterized from index to 14 days post-treatment. Random forest classification (RFC) was used for AE prediction, and reduced feature models were evaluated using cumulative importance (cImp) for feature selection. Grade 3+ thrombocytopenia and anemia occurred in 31% of 2,171 and 56% of 2,170 evaluable patients, respectively. Of the total 53 features, as few as 7 contributed at least 50% cImp, resulting in prediction accuracies of 70% or higher and area under the receiver operating characteristic curves of 0.886 for grade 3+ thrombocytopenia and 0.759 for grade 3+ anemia. Sensitivity analyses in strictly defined patient subgroups revealed similarly high predictive performance in full and reduced feature models. A logistic regression model with the same 50% cImp features showed similar predictive performance as RFC and good concordance with RFC probability predictions after isotonic calibration, adding interpretability. Collectively, this work demonstrates potential for machine learning prediction of AE risk in real-world patients using few variables regularly available in EHRs, which may aid in clinical decision making and/or monitoring.

3D printed PLGA scaffold with nano-hydroxyapatite carrying linezolid for treatment of infected bone defects.

BACKGROUND: Linezolid has been reported to protect against chronic bone and joint infection. In this study, linezolid was loaded into the 3D printed poly (lactic-co-glycolic acid) (PLGA) scaffold with nano-hydroxyapatite (HA) to explore the effect of this composite scaffold on infected bone defect (IBD). METHODS: PLGA scaffolds were produced using the 3D printing method. Drug release of linezolid was analyzed by elution and high-performance liquid chromatography assay. PLGA, PLGA-HA, and linezolid-loaded PLGA-HA scaffolds, were implanted into the defect site of a rabbit radius defect model. Micro-CT, H&E, and Masson staining, and immunohistochemistry were performed to analyze bone infection and bone healing. Evaluation of viable bacteria was performed. The cytocompatibility of 3D-printed composite scaffolds in vitro was detected using human bone marrow mesenchymal stem cells (BMSCs). Long-term safety of the scaffolds in rabbits was evaluated. RESULTS: The linezolid-loaded PLGA-HA scaffolds exhibited a sustained release of linezolid and showed significant antibacterial effects. In the IBD rabbit models implanted with the scaffolds, the linezolid-loaded PLGA-HA scaffolds promoted bone healing and attenuated bone infection. The PLGA-HA scaffolds carrying linezolid upregulated the expression of osteogenic genes including collagen I, runt-related transcription factor 2, and osteocalcin. The linezolid-loaded PLGA-HA scaffolds promoted the proliferation and osteogenesis of BMSCs in vitro via the PI3K/AKT pathway. Moreover, the rabbits implanted with the linezolid-loaded scaffolds showed normal biochemical profiles and normal histology, which suggested the safety of the linezolid-loaded scaffolds. CONCLUSION: Overall, the linezolid-loaded PLGA-HA scaffolds fabricated by 3D printing exerts significant bone repair and anti-infection effects.

Linezolid brain penetration in neurointensive care patients.

BACKGROUND: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. OBJECTIVES: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. PATIENTS AND METHODS: Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. RESULTS: The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L. CONCLUSIONS: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.

Unlocking Amides: A General Method for the Self-Immolative Release of Amide-Containing Molecules.

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload-release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide-containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA-approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method.