Treatment outcomes and adverse drug reactions among patients with drug-resistant tuberculosis receiving all-oral,long-term regimens:First record viewing report from Pakistan

Objective:To assess the effectiveness and adverse drug reactions of all-oral regimens for patients with multidrug-resistant tuberculosis.Methods:This retrospective study was conducted at 10 Programmatic Management of Drug Resistant Tuberculosis sites in Punjab province of Pakistan.Patients receiving treatment for drug resistant tuberculosis from July 2019 to December 2020 with at least interim result i.e.6th month culture conversion or final outcomes(cured,complete,lost to follow-up,failure,death)available,were included in the study.Data was extracted from electronic data management system.For the reporting and management of adverse drug events,active tuberculosis drug safety monitoring and management was implemented across all sites.All the data was analyzed using SPSS version 22.Results:Out of 947 drug resistant tuberculosis patients included in this study,579(68%)of the patients had final outcomes available.Of these,384(67.9%)successfully completed their treatment.Out of 368(32%)patients who had their interim results available,all had their 6th month culture negative.Combining new medications was thought to result in serious adverse outcomes such as QT prolongation.However,this study did not record any severe adverse events among patients.Conclusions:All-oral regimens formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to those obtained with traditional injectable treatment.

Neonatal methicillin-resistant Staphylococcus aureus pneumonia-related recurrent fatal pyopneumothorax: A case report and review of literature

BACKGROUND Although neonatal Staphylococcus aureus pneumonia is common and usually curable,it can also be refractory and life-threatening.Herein,we report a case of severe neonatal community-acquired methicillin-resistant Staphylococcus aureus(CA-MRSA)necrotizing pneumonia with bilateral recurrent pyopneumothorax,respiratory failure,heart failure,and cardiac arrest.We hope our report will add to the understanding of this disease.CASE SUMMARY An 18-d-old boy presented with cough for five days,fever for three days,and dyspnea for two days.Preadmission chest radiograph revealed high-density shadows in both lungs.On admission,his oxygen saturation fluctuated around 90%under synchronized intermittent mandatory ventilation.He was unconscious,with dyspnea,weak heart sounds and hepatomegaly.Moist crackles were present throughout his left lung,while the breath sounds in the right lung were decreased.After high-frequency oscillatory ventilation,empiric antimicrobials(meropenem and vancomycin),improved circulation,and right pleural cavity drainage for right pneumothorax(approximately 90%compression),his oxygen saturation level stayed above 95%,and recruitment of the right lung was observed.His condition did not deteriorate until the 5th day of hospitalization(DOH 5).On the morning of DOH 5,his oxygen saturation decreased.Subsequent chest radiograph showed bilateral pneumothorax with nearly 100%compression of the left lung.Desaturation was not relieved after urgent left pleural cavity drainage,and cardiac arrest occurred soon thereafter.Although his spontaneous heartbeat returned through emergency resuscitation and salvage antibacterial therapy(linezolid and levofloxacin)was administered given the detection and antimicrobial susceptibility of MRSA,he showed no improvement,with recurrent pyopneumothorax and continued drainage of purulent fluid and necrotic lung tissue fragments from the pleural cavity.Eventually,his parents refused extracorporeal membrane oxygenation(ECMO)and gave up all the treatments,and the newborn passed away soon after withdrawal on DOH 13.CONCLUSION Neonatal MRSA pneumonia can be refractory and lethal,especially in cases where necrotizing pneumonia leads to extensive lung necrosis and recurrent pneumothorax.Despite treatment with linezolid and other medical measures,it may still be ineffective.Currently,ECMO has been a remedial therapy,but if the lung tissue is too severely eroded to be repaired,it may be useless unless the infection can be controlled and lung transplantation can be performed.Regardless of whether ECMO is initiated,the key to successful treatment is to achieve control over the pneumonia caused by MRSA as soon as possible and to reverse lung injury as much as possible.

Oxazolidinones Antibiotics, Chemistry, Applications and Role in COVID-19 Treatment

Oxazolidinones are groups of synthetic antimicrobial agents, which have a novel chemical structure. Their mechanism of antimicrobial mainly bacteriostatic via inhibition of protein synthesis. Oxazolidinones are used in serious cases of bacterial infections. Their spectrum of action against a lot of microbes, which often infect humans vigorously, like penicillin and cephalosporin-resistant Streptococcus pneumonia, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Oxazolidinones chemical structure possesses a ring called oxazolidone, which is characterized by the S configuration of the substituent at C5, the acyl-amino-methyl group connected to C5 and the N-aryl substituent. Some oxazolidinones like linezolid were believed to have a role in COVID-19 treatment. It is also noticed that oxazolidinones have a role in improving clinical status of patients with COVID-19 and in decreasing the risk of mortality caused by co-infections. This review was conducted to discuss the chemistry, mechanism, applications and role of oxazolidinones in the treatment of COVID-19.

Linezolid:第一个应用于临床的噁唑啉酮类抗菌药

恶唑啉酮类为全新化学合成抗菌药 ,通过抑制细菌蛋白质合成起始阶段发挥抗菌作用。第一个应用于临床的口恶唑啉酮类药物 linezolid对革兰氏阳性菌有较强抗菌活性 ,抗菌活性与细菌耐药性无关 ;具有良好药物动力学特征 ;临床实验证明 ,对各种革兰氏阳性菌感染有良好疗效 。

Linezolid——一种新噁唑烷酮类抗微生物药物

噁唑烷酮类药物是一类新的抗微生物制剂,在体外实验和动物感染模型实验中,此类药对革兰氏阳性菌(抗生素敏感的和耐药的)有很强抗菌活性。临床试验证实Linezolid口服给药的相对生物利用度为100％,噁唑烷酮类与其它抗生素无交叉耐药,且通过抑制细菌蛋白质合成的早期阶段而起作用。实验未筛选出耐药突变种。

High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid

BACKGROUND： Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of throm- bocytopenia in patients with acute-on-chronic liver failure （ACLF） who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocyto- penia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients.

A validated stability-indicating LC method for the separation of enantiomer and potential impurities of Linezolid using polar organic mode

Although a number of methods are available for evaluating Linezolid and its possible impurities, a common method for separation if its potential impurities, degradants and enantiomer in a single method with good efficiency remain unavailable. With the objective of developing an advanced method with shorter runtimes, a simple, precise, accurate stability-indicating LC method was developed for the determination of purity of Linezolid drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of Linezolid along with the chiral impurity. This method can also be used for the estimation of assay of Linezolid in drug substance as well as in drug product. The method was developed using Chiralpak IA (250 mm 4.6 mm, 5 mm) column. A mixture of acetonitrile, ethanol, n-butyl amine and trifluoro acetic acid in 96:4:0.10:0.16 (v/v/v/v) ratio was used as a mobile phase. The eluted compounds were monitored at 254 nm. Linezolid was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability.

Clinical results of linezolid in arthroplasty and trauma related infections

AIM: To analyse the management of patients treated with linezolid for orthopaedic infections.METHODS: Twenty-two patients with orthopaedic related infections receiving a course of linezolid were reviewed retrospectively. Patients were classified into either post trauma, post arthroplasty and non trauma related infections. A diagnosis of infection was based on clinical findings, positive microbiological specimens, and positive signs of infection on radiological imaging and raised inflammatory markers. Pathogens isolated, inflammatory markers both at presentation and at final follow up, length of linezolid treatment, adverse drug reactions, concomitant anti-microbial therapy, length of hospital stay and any surgical interventions were recorded.RESULTS: Infections were classified as post arthroplasty(n = 10), post trauma surgery(n = 8) or nontrauma related infections(n = 4). Twenty patients(91%) underwent surgical intervention as part of their treatment. The number of required surgical procedures ranged from 1 to 6(mean = 2.56). Mean total length of stay per admission was 28.5 d(range 1-160 d). Furthermore, the mean duration of treatment with linezolid of patients who had resolution of symptoms was 31 d(range 10-84 d). All patients within this group were discharged on oral linezolid. Pathogens isolated included methicillin resistant Staphylococcus aureus, coagulase negative staphylococci, coliforms, enterococcus, Staphylococcus epidermidis, streptococcus viridans, Escherichia coli, group B streptococcus and pseudomonas. An overall 77% of patients demonstrated resolution of infections at follow-up, with mean C-reactive protein reducing from 123 mg/L to 13.2 mg/L.CONCLUSION: This study demonstrates that the use of linezolid offers excellent efficacy in orthopaedic related infections when used alongside appropriate surgical management.

A Convenient Synthesis of Antibacterial Linezolid from (S)-Glyceraldehyde Acetonide

A convenient synthesis of oxazolidinone antibacterial linezolid from readily available L-ascorbic acid is described. The key steps include reductive amination of arylamine and （S）-glyceraldehyde acetonide in the presence of NaBH4 and 4A sieve, followed by hydrolysis and regioselective cyclization.

Daptomycin and linezolid for severe methicillin-resistant Staphylococcus aureus psoas abscess and bacteremia:A case report and review of the literature

BACKGROUND Vancomycin remains a first-line treatment drug as per the treatment guidelines for methicillin-resistant Staphylococcus aureus(MRSA)bacteremia.However,a number of gram-positive cocci have developed resistance to several drugs,including glycopeptides.Therefore,there is an urgent need for effective and innovative antibacterial drugs to treat patients with infections caused by drugresistant bacteria.CASE SUMMARY A 24-year-old male was admitted to hospital owing to lumbago,fever,and hematuria.Computed tomography(CT)results showed an abscess in the psoas major muscle of the patient.Repeated abscess drainage and blood culture suggested MRSA,and vancomycin was initiated.However,after day 10,CT scans showed abscesses in the lungs and legs of the patient.Therefore,treatment was switched to daptomycin.Linezolid was also added considering inflammation in the lungs.After 10 d of the dual-drug anti-MRSA treatment,culture of the abscess drainage turned negative for MRSA.On day 28,the patient was discharged without any complications.CONCLUSION This case indicates that daptomycin combined with linezolid is an effective remedy for bacteremia caused by MRSA with pulmonary complications.

Successful treatment of disseminated nocardiosis diagnosed by metagenomic next-generation sequencing:A case report and review of literature

BACKGROUND Nocardia paucivorans is an infrequently found bacterium with the potential to cause severe infection,with a predilection for the central nervous system,both in immunocompromised and immunocompetent individuals.Rapid etiological diagnosis of nocardiosis can facilitate timely and rational antimicrobial treatment.Metagenomic next-generation sequencing(m NGS)can improve the rate and reduce the turnaround time for the detection of Nocardia.CASE SUMMARY A 49-year-old man was admitted to hospital with cough and hemoptysis.Imaging revealed pulmonary consolidation as well as multiple brain lesions.Nocardia asiatica and Nocardia beijingensis were rapidly detected by m NGS of bronchoalveolar lavage fluid(BALF)while bacterial culture of BALF and pathological biopsy of lung tissue were negative.In early stages,he was treated with trimethoprim-sulfamethoxazole(TMP-SMZ)and linezolid by individual dose adjustment based on serum concentrations and the adverse effects of thrombocytopenia and leukopenia.The treatment was then replaced by TMP-SMZ and ceftriaxone or minocycline.He was treated with 8 mo of parenteral and/or oral antibiotics,and obvious clinical improvement was achieved with resolution of pulmonary and brain lesions on repeat imaging.CONCLUSION m NGS provided fast and precise pathogen detection of Nocardia.In disseminated nocardiosis,linezolid is an important alternative that can give a better outcome with the monitoring of linezolid serum concentrations and platelet count.

The Prevalence of Methicillin-Resistant Staphylococcus aureus Colonization in Patients with Complicated Skin and Skin Structure Infections after Treatment with Linezolid or Vancomycin

Background: Complicated skin and skin structure infections (cSSSIs) due to Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are associated with significant morbidity. Re-ducing MRSA carriage has been a focus of infection control interventions. The prevalence of MRSA colonization after successful treatment of a MRSA cSSSI is unknown. Methods: Secondary analysis of a randomized controlled trial comparing linezolid and vancomycin for the treatment of MRSA cSSSI. Adult patients that had a colonization culture, confirmed MRSA cSSSI, received at least one dose of study treatment, and had an outcome recorded at end of study. Patient, clinical characteristics and prevalence of colonization were compared by treatment regimens. A multivariate regression model identified predictors of MRSA colonization at EOS. Results: There were 456 patients evaluated. The prevalence of MRSA colonization was higher for vancomycin treated patients compared to linezolid treated patients at end of treatment (EOT) (28% vs. 5%, p < 0.001) and EOS (34% vs. 22%, p < 0.01). Independent predictors of colonization at EOS after treatment for a MRSA cSSSI included diagnosis, primarily driven by abscess, black race, treatment with vancomycin, MRSA mixed infection and male gender. Conclusion: Patients treated with linezolid for a cSSSI had less MRSA colonization at EOT and EOS compared to those treated with vancomycin. Multiple independent predictors of MRSA colonization were identified. Additional studies evaluating the relationship of MRSA colonization after treatment of cSSSI are needed.

新型噁唑烷酮类抗菌药——Linezolid的药理及临床评价

目的:介绍新型(口恶)唑烷酮类抗菌药——Linezolid(LNZ)。方法:综述LNZ的药理作用、药动学特性、适应证、用法、用量、不良 反应以及与其它药物的相互作用等情况。结果与结论:LNZ可治疗多种耐药菌感染,且在临床应用中的耐受性良好,具有广阔的应 用前景。

Is Dose Adjustment Based on Several Factors of Body Size Descriptors Effective for Prevention of Thrombocytopenia by Linezolid Therapy in Hemodialysis Patients?

Previous study suggested that low body weight was one of the risk factors of thrombocytopenia induced by linezolid in non-hemodialysis patients. However, there have been little investigations for the linezolid-induced thrombocytopenia in hemodialysis patients. This study was to evaluate the association between several factors of body size descriptors and thrombocytopenia in hemodialysis-patients. No factor of body size descriptors showed significant correlation with linezolid-induced thrombocytopenia (patients with thrombocytopenia vs patients without thrombocytopenia: body weight;60.0 kg vs 55.3 kg, p = 0.82: body mass indices;21.1 kg/m2 vs 21.2 mg/m2, p = 0.44: ideal body weight;61.2 kg vs 59.5 kg, p = 0.21: lean body weight;50.1 kg vs 45.7 kg, p = 0.64: dosage amount;20.0 mg/kg vs 21.7 mg/kg, p = 0.74: body surface area;1.65 m2 vs 1.54 m2, p = 0.43). There were not significant differences in the body size descriptors between linezolid therapy for more than 14 days and for less than 13 days (more than 14 days vs less than 13 days: body weight;53.5 kg vs 56.8 kg, p = 0.75: body mass indices;20.9 kg/m2 vs 21.1 mg/m2, p = 0.47: ideal body weight;60.3 kg vs 59.9 kg, p = 0.17: lean body weight;44.3 kg vs 47.7 kg, p = 0.56: dosage amount;22.4 mg/kg vs 21.1 mg/kg, p = 0.67: body surface area;1.51 m2 vs 1.59 m2, p = 0.37). Our data suggested that dosage adjustment of linezolid based on body weight was not recommended in hemodialysis-patients.

Linezolid resistant Staphylococcus haemolyticus:First case report from India

Linezolid is being increasingly used in the treatment of infections with gram-positive organisms especially methicillin resistant Staphylococcal isolates.Though resistance to this antimicrobial is emerging but it is extremely rare.Here we document first case of linezolid resistant Staphylococcus haemolyticus(S.haemolyticus) from India.This organism was isolated from pus oozing from a postsurgical site in 61 year old male hailing from an adjoining state of Haryana.