The Emergence of Linezolid-Resistant Staphylococcus Epidermidis in the COVID-19 Hospitalized Intubated Patients in North Khorasan, Iran.

The present study aimed to investigate secondary bacterial infections among patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Coagulase-negative Staphylococci can infect immunocompromised patients. Linezolid resistance among Staphylococcus epidermidis is one of the most critical issues. In 2019, 185 SARS-CoV-2-positive patients who were admitted to North Khorasan Province Hospital (Bojnurd, Iran), were investigated. Patients having positive SARS-CoV-2 reverse transcriptase real-time polymerase chain reaction (RT-PCR) test results, who had a history of intubation, mechanical ventilation, and were hospitalized for more than 48 hours were included. After microbiological evaluation of pulmonary samples, taken from intubated patients with clinical manifestation of pneumonia, co-infections were found in 11/185 patients (5.94%) with S. epidermidis, Staphylococcus aureus, and Acinetobacter baumani, respectively. Remarkably, seven out of nine S. epidermidis isolates were linezolid resistant. Selected isolates were characterized using antimicrobial resistance patterns and molecular methods, such as Staphylococcal cassette chromosome mec (SCCmec) typing, and gene detection for ica, methicillin resistance (mecA), vancomycin resistance (vanA), and chloramphenicol-florfenicol resistance (cfr) genes. All of the isolates were resistant to methicillin, and seven isolates were resistant to linezolid. Nine out of 11 isolated belonged to the SCCmec I, while two belonged to the SCCmec IV. It should be noted that all patients had the underlying disease, and six patients had already passed away. The increasing linezolid resistance in bacterial strains becomes a real threat to patients, and monitoring such infections, in conjunction with surveillance and infection prevention programs, is very critical for reducing the number of linezolid-resistant Staphylococcal strains. A preprint of this study was published at https://europepmc.org/article/ppr/ppr417742.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

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.

Availability of drugs for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis in the World Health Organization European Region, October 2023.

The BPaLM regimen (bedaquiline, pretomanid, linezolid and moxifloxacin) recently recommended by the World Health Organization offers short, safe, and effective treatment for multidrug-resistant/rifampicin-resistant tuberculosis (TB). In a survey with national TB focal points in 18 central and western European countries to explore barriers for the implementation of BPaLM, only three reported full availability of pretomanid, a necessary component of this regimen. Implementation barriers included financing and procurement. Solutions on national and supranational level are needed to guarantee universal access.

Actinomycetoma in a patient with pre-existing sensorineural hearing loss: a linezolid-based treatment paradigm.

Mycetoma is a chronic granulomatous infectious disease with a triad of subcutaneous swelling, discharging sinuses and the presence of granules. The infection may occur following minor trauma or penetrating thorn injury. We report a case of a man in his 40s with a history of thorn prick 9 years ago, followed by the formation of painless discharging sinuses on the right foot for the past 2 years. Clinical, local epidemiological, histopathological examination and Gram stain confirmed the diagnosis of actinomycetoma. Prior to initiating the Welsh regimen, a pretreatment assessment of the patient's auditory function was conducted through pure tone audiometry, indicating the existence of pre-existing high-frequency bilateral sensorineural hearing loss. The patient was treated with linezolid as an alternative to amikacin, at a dosage of 600 mg two times per day, leading to complete resolution within 3 weeks. This underscores linezolid's efficacy as a safe and cost-effective alternative for actinomycetoma, without causing ototoxic side effects.

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis.

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

[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.

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.

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis.

The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.

A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach.

Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB-related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well-studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens.

Comparative analysis of linezolid, vancomycin, and hyperbaric oxygen therapies in a rat model of ventriculoperitoneal shunt infection.

PURPOSE: Staphylococcus epidermidis is the most common causative microorganism of ventriculoperitoneal shunt infections. This study aimed to compare linezolid and vancomycin treatments and to examine the effect of these antibiotics alone and combined with hyperbaric oxygen therapy on the amount of bacterial colonies in the experimental S. epidermidis shunt infection model. METHODS: A shunt catheter was placed in the cisterna magna of 49 adult male Wistar albino rats. The rats were randomly divided into seven groups, as follows: sterile control, infected control, vancomycin, linezolid, hyperbaric oxygen, vancomycin + hyperbaric oxygen, linezolid + hyperbaric oxygen. In all groups except the sterile control group, 0.2 ml 107 CFU/mL S. epidermidis was inoculated to the cisterna magna. Parenteral vancomycin was administered 40 mg/kg/day to the vancomycin groups, and 50 mg/kg/day of enteral linezolid to the linezolid groups. Hyperbaric oxygen groups were given 100% oxygen at a pressure of 2.4 ATA for 50 min a day. One day after the last treatment, colony quantities in the shunt catheters and CSF were analyzed. RESULTS: The number of CSF colonies in the linezolid group was significantly lower than in the vancomycin group (p < 0.05). The number of CSF colonies in the linezolid + HBO group was significantly lower than in the vancomycin + HBO group (p < 0.05). CONCLUSIONS: Linezolid treatment was found to be more effective than vancomycin in ventriculoperitoneal shunt infection caused by S. epidermidis. There was no statistical difference among other treatment groups. Hyperbaric oxygen therapy is shown to contribute to the sterilization of cultures.

Efficacy and safety of omadacycline for treating complicated skin and soft tissue infections: a meta-analysis of randomized controlled trials.

OBJECTIVE: In the present study, we aimed to compare the clinical efficacy and safety of omadacycline (OMC) with its comparators for the treatment of complicated skin and soft tissue infections (cSSTIs) in adult patients. METHODS: Randomized controlled trials (RCTs) evaluating OMC for cSSTIs were searched in databases of PubMed, Embase, Cochrane, Web of Science, and Clinical Trial, up to July 2022. The primary outcomes were clinical efficacy and microbiological response, with secondary outcome was safety. RESULTS: Four RCTs consisting of 1,757 patients were included, with linezolid (LZD) as a comparator drug. For clinical efficacy, OMC was not inferior to LZD in the modified intent-to-treat (MITT) (OR: 1.24, 95% Cl: [0.93, 1.66], P = 0.15) and clinically evaluable (CE) populations (OR: 1.92, 95% Cl: [0.94, 3.92], P = 0.07). For microbiological response, OMC was numerically higher than LZD in the microbiologically evaluable (ME) (OR: 1.74, 95% Cl: [0.81, 3.74], P = 0.16) and microbiological MITT (micro-MITT) populations (OR: 1.27, 95% Cl: [0.92, 1.76], P = 0.14). No significant difference was found in subpopulations of monomicrobial or polymicrobial mixed infection populations. The mortality and adverse event rates were similar between OMC and LZD. CONCLUSIONS: OMC was as good as LZD in terms of clinical efficacy and microbiological response, and has similar safety issues in treating cSSTIs. OMC might be a promising option for treating cSSTIs in adult patients.

Risk factors and outcome associated with the acquisition of MDR linezolid-resistant Enterococcus faecium: a report from tertiary care centre.

OBJECTIVE: The aim of the study was to determine the resistance profile of linezolid-resistant Enterococcus faecium (LREfm) and to investigate risk factors and outcomes associated with LREfm infections. MATERIAL AND METHODS: A prospective case-control study was undertaken (2019 to 2022) and included 202 patients with LREfm infections (cases) and 200 controls with LSEfm infections. Clinical data was prospectively collected and analysed for risk factors and outcomes. Antimicrobial susceptibility was performed, and resistance profile was studied using WHOnet. RESULTS: Risk factors associated with LREfm infection were site of infection UTI (OR 5.87, 95% CI 2.59-13.29, p ≤ 0.001), prior use of carbapenem (OR 2.85 95% CI 1.62-5.02, p ≤ 0.001) and linezolid (OR 10.13, 95% CI 4.13-24.82, p ≤ 0.001), use of central line (OR 5.54, 95% CI 2.35-13.09, p ≤ 0.001), urinary catheter (OR 0.29, 95% CI 0.12-0.70, p ≤ 0.001) and ventilation (OR 14.87, 95% CI 7.86-28.11, p ≤ 0.007). The hospital stay 8-14 days (< 0.001) prior to infection and the mortality rate (p = 0.003) were also significantly high among patients with LREfm infections. Linezolid and vancomycin resistance coexisted; further, MDR, XDR and PDR phenotypes were significantly higher among LREfm. CONCLUSION: This study provided insight into epidemiology of MDR LREfm in a setting where linezolid use is high. The main drivers of infections with LREfm are multiple, including use of carbapenems and linezolid. Invasive procedures and increased hospital stay facilitate spread through breach in infection control practises. As therapeutic options are limited, ongoing surveillance of LREfm and VRE is critical to guide appropriate use of linezolid and infection control policies.

Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). METHODS: We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. FINDINGS: Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference -29·6, 95% CI -50·5 to -8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. INTERPRETATION: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. FUNDING: European Research Council and Fondo de Investigaciones Sanitarias.

Disseminated nocardiosis with persistent neurological disease.

A man in his 80s with a history of sarcoidosis on chronic prednisone presented to the emergency department with several days of dyspnoea. A chest X-ray showed signs of pneumonia, and the patient was admitted. Blood and pleural fluid cultures grew Nocardia farcinica; therefore, the patient was started on treatment with trimethoprim-sulbactam and imipenem. Brain imaging showed evidence of dissemination of the infection to the central nervous system (CNS). The patient's admission was complicated by pleural effusions, acute kidney injury and pancytopenia, and therefore, his antibiotic regimen was ultimately transitioned from trimethoprim-sulfamethoxazole (TMP-SMX), meropenem and linezolid to imipenem and tedizolid. The patient received imipenem and tedizolid for the remainder of the admission. A repeat MRI of the brain was performed after 6 weeks of this dual antibiotic therapy, which unfortunately revealed persistent CNS disease. His regimen was then broadened to TMP-SMX, linezolid and imipenem. Despite these measures, however, the patient ultimately passed away from the infection.

Cost-effectiveness of linezolid to ventilator-associated pneumonia in Colombia.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is a prominent cause of morbidity and mortality in intensive care unit (ICU) patients. Due to the increase in Methicillin resistant Staphylococcus aureus infection, it is important to consider other more effective and safer alternatives compared to vancomycin. This motivates evaluating whether the use of an apparently more expensive drug such as linezolid can be cost-effective in Colombia. METHODS: A decision tree was used to simulate the results in terms of the cost and proportion of cured patients. In the simulation, patients can receive antibiotic treatment with linezolid (LZD 600 mg IV/12 h) or vancomycin (VCM 15 mg/kg iv/12 h) for 7 days, patients they can experience events adverse (renal failure and thrombocytopenia). The model was analyzed probabilistically, and a value of information analysis was conducted to inform the value of conducting further research to reduce current uncertainties in the evidence base. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of US$5180. RESULTS: The mean incremental cost of LZD versus VCM is US$-517. This suggests that LZD is less costly. The proportion of patients cured when treated with LZD compared with VCM is 53 vs. 43%, respectively. The mean incremental benefit of LZD versus VCM is 10 This position of absolute dominance (LZD has lower costs and higher proportion of clinical cure than no supplementation) is unnecessary to estimate the incremental cost-effectiveness ratio. There is uncertainty with a 0.999 probability that LZD is more cost-effective than VCM. Our base-case results were robust to variations in all assumptions and parameters. CONCLUSION: LNZ is a cost-effective strategy for patients, ≥ 18 years of age, with VAP in Colombia- Our study provides evidence that can be used by decision-makers to improve clinical practice guidelines.

High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes.

Heteroresistance (HR) is an enigmatic phenotype where, in a main population of susceptible cells, small subpopulations of resistant cells exist. This is a cause for concern, as this small subpopulation is difficult to detect by standard antibiotic susceptibility tests, and upon antibiotic exposure the resistant subpopulation may increase in frequency and potentially lead to treatment complications or failure. Here, we determined the prevalence and mechanisms of HR for 40 clinical Staphylococcus aureus isolates, against 6 clinically important antibiotics: daptomycin, gentamicin, linezolid, oxacillin, teicoplanin, and vancomycin. High frequencies of HR were observed for gentamicin (69.2%), oxacillin (27%), daptomycin (25.6%), and teicoplanin (15.4%) while none of the isolates showed HR toward linezolid or vancomycin. Point mutations in various chromosomal core genes, including those involved in membrane and peptidoglycan/teichoic acid biosynthesis and transport, tRNA charging, menaquinone and chorismite biosynthesis and cyclic-di-AMP biosynthesis, were the mechanisms responsible for generating the resistant subpopulations. This finding is in contrast to gram-negative bacteria, where increased copy number of bona fide resistance genes via tandem gene amplification is the most prevalent mechanism. This difference can be explained by the observation that S. aureus has a low content of resistance genes and absence of the repeat sequences that allow tandem gene amplification of these genes as compared to gram-negative species.