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.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Rapid Mycobacterium abscessus antimicrobial susceptibility testing based on antibiotic treatment response mapping via Raman Microspectroscopy.

OBJECTIVES: Antimicrobial susceptibility tests (ASTs) are pivotal tools for detecting and combating infections caused by multidrug-resistant rapidly growing mycobacteria (RGM) but are time-consuming and labor-intensive. DESIGN: We used a Mycobacterium abscessus-based RGM model to develop a rapid (24-h) AST from the beginning of the strain culture, the Clinical Antimicrobials Susceptibility Test Ramanometry for RGM (CAST-R-RGM). The ASTs obtained for 21 clarithromycin (CLA)-treated and 18 linezolid (LZD)-treated RGM isolates. RESULTS: CAST-R-RGM employs D2O-probed Raman microspectroscopy to monitor RGM metabolic activity, while also revealing bacterial antimicrobial drug resistance mechanisms. The results of clarithromycin (CLA)-treated and linezolid (LZD)-treated RGM isolates exhibited 90% and 83% categorical agreement, respectively, with conventional AST results of the same isolates. Furthermore, comparisons of time- and concentration-dependent Raman results between CLA- and LZD-treated RGM strains revealed distinct metabolic profiles after 48-h and 72-h drug treatments, despite similar profiles obtained for both drugs after 24-h treatments. CONCLUSIONS: Ultimately, the rapid, accurate, and low-cost CAST-R-RGM assay offers advantages over conventional culture-based ASTs that warrant its use as a tool for improving patient treatment outcomes and revealing bacterial drug resistance mechanisms.

Antimicrobial drug resistant features of Mycobacterium tuberculosis associated with treatment failure.

Tuberculosis stands as a prominent cause of mortality in developing countries. The treatment of tuberculosis involves a complex procedure requiring the administration of a panel of at least four antimicrobial drugs for the duration of six months. The occurrence of treatment failure after the completion of a standard treatment course presents a serious medical problem. The purpose of this study was to evaluate antimicrobial drug resistant features of Mycobacterium tuberculosis associated with treatment failure. Additionally, it aimed to evaluate the effectiveness of second line drugs such as amikacin, linezolid, moxifloxacin, and the efflux pump inhibitor verapamil against M. tuberculosis isolates associated with treatment failure. We monitored 1200 tuberculosis patients who visited TB centres in Lahore and found that 64 of them were not cured after six months of treatment. Among the M. tuberculosis isolates recovered from the sputum of these 64 patients, 46 (71.9%) isolates were simultaneously resistant to rifampicin and isoniazid (MDR), and 30 (46.9%) isolates were resistant to pyrazinamide, Resistance to amikacin was detected in 17 (26,5%) isolates whereas resistance to moxifloxacin and linezolid was detected in 1 (1.5%) and 2 (3.1%) isolates respectively. Among MDR isolates, the additional resistance to pyrazinamide, amikacin, and linezolid was detected in 15(23.4%), 4(2.6%) and 1(1.56%) isolates respectively. One isolate simultaneously resistant to rifampicin, isoniazid, amikacin, pyrazinamide, and linezolid was also identified. In our investigations, the most frequently mutated amino acid in the treatment failure group was Serine 315 in katG. Three novel mutations were detected at codons 99, 149 and 154 in pncA which were associated with pyrazinamide resistance. The effect of verapamil on the minimum inhibitory concentration of isoniazid and rifampicin was observed in drug susceptible isolates but not in drug resistant isolates. Rifampicin and isoniazid enhanced the transcription of the efflux pump gene rv1258 in drug susceptible isolates collected from the treatment failure patients. Our findings emphasize a high prevalence of MDR isolates linked primarily to drug exposure. Moreover, the use of amikacin as a second line drug may not be the most suitable choice in such cases.

Characteristics of Gram-positive cocci infection and the therapeutic effect after liver transplantation. / è‚ç§»æ¤æœ¯åŽé©å °æ°é˜³æ€§çƒèŒçš„æ„ŸæŸ“ç‰¹ç‚¹åŠé˜²æ²»æ•ˆæžœ.

OBJECTIVES: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections. METHODS: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed. RESULTS: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001). CONCLUSIONS: Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.

Attainment of Target Antibiotic Levels by Oral Treatment of Left-Sided Infective Endocarditis: A POET Substudy.

BACKGROUND: In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs). METHODS: Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated. RESULTS: A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%.Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for 2 oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for 1 antibiotic. One patient did not reach target for any of the 2 antibiotics. CONCLUSIONS: For the individual orally administered antibiotic, the majority reached the target level. Patients with sub-target levels were compensated by the administration of 2 different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.

Risk factors for mortality after linezolid treatment of vancomycin-resistant Enterococcus bloodstream infection.

OBJECTIVES: We analyzed the risk factors affecting linezolid treatment outcome in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI). METHODS: We conducted a multicenter observational study of patients who received linezolid 600 mg every 12 hours for VRE BSI. The primary outcome was 28-day mortality. The estimated area under the concentration-time curve and trough concentration were calculated. Multivariable logistic regression was used for the outcome analysis. RESULTS: A total of 170 patients were included: 114 (67.1%) survived and 56 (32.9%) did not. A total of 26 (18.2%) isolates showed a linezolid minimum inhibitory concentration (MIC) of ≤1 mg/l, 113 (79.0%) of 2 mg/l, and 4 (2.8%) of 4 mg/l. The univariable analysis showed that the linezolid MIC and concentration-time curve/MIC were not associated with mortality (P = 0.95 and P = 0.42, respectively). After adjusting for underlying comorbidity and disease severity, the linezolid dose per body weight (LDBW), body height, and interaction between them were independent risks for mortality. Marginal analysis showed that increasing the LDBW was protective in patients with a body height <160 cm. A trough concentration of >12.2 mg/l was a risk factor for thrombocytopenia. CONCLUSION: The LDBW and body height were interactively associated with clinical outcomes of linezolid treatment for VRE BSI.

UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

BACKGROUND: Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. METHODS: Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. CONCLUSION: This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

Characteristics of Gram-positive cocci infection and the therapeutic effect after liver transplantation / 中南大学学报(医学版)

OBJECTIVES@#Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections.@*METHODS@#In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed.@*RESULTS@#Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001).@*CONCLUSIONS@#Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.

Genetic and Chemical Screening Reveals Targets and Compounds to Potentiate Gram-Positive Antibiotics against Gram-Negative Bacteria.

Gram-negative bacteria are intrinsically resistant to a plethora of antibiotics that effectively inhibit the growth of Gram-positive bacteria. The intrinsic resistance of Gram-negative bacteria to classes of antibiotics, including rifamycins, aminocoumarins, macrolides, glycopeptides, and oxazolidinones, has largely been attributed to their lack of accumulation within cells due to poor permeability across the outer membrane, susceptibility to efflux pumps, or a combination of these factors. Due to the difficulty in discovering antibiotics that can bypass these barriers, finding targets and compounds that increase the activity of these ineffective antibiotics against Gram-negative bacteria has the potential to expand the antibiotic spectrum. In this study, we investigated the genetic determinants for resistance to rifampicin, novobiocin, erythromycin, vancomycin, and linezolid to determine potential targets of antibiotic-potentiating compounds. We subsequently performed a high-throughput screen of ∼50,000 diverse, synthetic compounds to uncover molecules that potentiate the activity of at least one of the five Gram-positive-targeting antibiotics. This led to the discovery of two membrane active compounds capable of potentiating linezolid and an inhibitor of lipid A biosynthesis capable of potentiating rifampicin and vancomycin. Furthermore, we characterized the ability of known inhibitors of lipid A biosynthesis to potentiate the activity of rifampicin against Gram-negative pathogens.

Model for Evaluating Antimicrobial Therapy To Prevent Life-Threatening Bacterial Infections following Exposure to a Medically Significant Radiation Dose.

More evidence is needed to support recommendations for medical management of acute radiation syndrome (ARS) and associated infections resulting from a radiological/nuclear event. While current guidelines recommend the administration of antibiotics to chemotherapy patients with febrile neutropenia, the clinical benefit is unclear for acute radiation injury patients. A well-characterized nonhuman primate (NHP) model of hematopoietic ARS was developed that incorporates supportive care postirradiation. This model evaluated the efficacy of myeloid growth factors within 24 to 48 h after total body irradiation (TBI). However, in this model, NHPs continued to develop life-threatening bacterial infections, even when granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was administered in combination with antibiotic monotherapy. In this study, we evaluated the efficacy of combination antibiotic therapies administered to NHPs following 7.4-Gy TBI to understand the occurrence of bacterial infection in NHPs with hematopoietic ARS. We compared enrofloxacin-linezolid, enrofloxacin-cefepime, and enrofloxacin-ertapenem to enrofloxacin monotherapy. The primary endpoint was 60-day postirradiation mortality, with secondary endpoints of overall survival time, incidence of bacterial infection, and bacteriologic culture with antimicrobial susceptibility testing. We observed that enrofloxacin-ertapenem significantly increased survival compared to enrofloxacin monotherapy. Bacteria isolated from nonsurviving macaques with systemic bacterial infections exhibited uniform resistance to enrofloxacin and variable resistance to beta-lactam antibiotics, linezolid, gentamicin, and azithromycin. Multidrug antibiotic resistance was observed in Enterococcus spp. and Escherichia coli. We conclude that antibiotic combination therapies appear to be more effective than monotherapy alone but acknowledge that more work is needed to identify an optimal antimicrobial therapy.

The In Vitro Antimicrobial and Antibiofilm Activities of Lysozyme against Gram-Positive Bacteria.

Objective: To analyze the in vitro antibacterial and antibiofilm activities of lysozyme (LYS) and its combination with various drugs against Gram-positive bacteria (GPB, n = 9), thus to provide an exploration direction for drug development. Methods: The minimum inhibitory concentrations (MICs) of linezolid (LZD), amikacin (AMK), ceftriaxone/sulbactam (CRO/SBT), cefotaxime/sulbactam (CTX/SBT), piperacillin/sulbactam (PIP/SBT), doxycycline (DOX), levofloxacin (LVX), amoxicillin/clavulanate potassium (7 : 1, AK71), imipenem (IPM), azithromycin (AZM), and their combinations with LYS were determined with tuber twice dilution. The antimicrobial and antibiofilm activities of LYS, AZM, LVX, and their combinations with others were evaluated through MTT and crystal violet assay. Results: High-dose LYS (30 µg/mL) combined with PIP/SBT and AK71, respectively, showed synergistic antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), while it showed no synergistic activities when combined with other drugs. LYS and AZM inhibited the biofilm formation of one MRSA strain, but they and LVX had no similar activities against methicillin-resistant Staphylococcus epidermidis (MRSE) or vancomycin-resistant Enterococcus faecium (VREF). Particularly, LYS increased the permeability of biofilms of MRSA 33 and exhibited antibiofilm activities against MRSA 31 (inhibition rate = 38.1%) and MRSE 61 (inhibition rate = 46.6%). The combinations of PIP/SBT+LYS, AMK+LYS, and LZD+LYS showed stronger antibiofilm activities against MRSA 62, MRSE 62, MRSE 63, and VREF 11. Conclusion: The antimicrobial and antibiofilm activities of LYS against MRSA were better than AZM, while that of LYS against MRSE and VREF, respectively, was similar with AZM and LVX.

A Structurally Characterized Staphylococcus aureus Evolutionary Escape Route from Treatment with the Antibiotic Linezolid.

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen that presents great health concerns. Treatment requires the use of last-line antibiotics, such as members of the oxazolidinone family, of which linezolid is the first member to see regular use in the clinic. Here, we report a short time scale selection experiment in which strains of MRSA were subjected to linezolid treatment. Clonal isolates which had evolved a linezolid-resistant phenotype were characterized by whole-genome sequencing. Linezolid-resistant mutants were identified which had accumulated mutations in the ribosomal protein uL3. Multiple clones which had two mutations in uL3 exhibited resistance to linezolid, 2-fold higher than the clinical breakpoint. Ribosomes from this strain were isolated and subjected to single-particle cryo-electron microscopic analysis and compared to the ribosomes from the parent strain. We found that the mutations in uL3 lead to a rearrangement of a loop that makes contact with Helix 90, propagating a structural change over 15 Å away. This distal change swings nucleotide U2504 into the binding site of the antibiotic, causing linezolid resistance. IMPORTANCE Antibiotic resistance poses a critical problem to human health and decreases the utility of these lifesaving drugs. Of particular concern is the "superbug" methicillin-resistant Staphylococcus aureus (MRSA), for which treatment of infection requires the use of last-line antibiotics, including linezolid. In this paper, we characterize the atomic rearrangements which the ribosome, the target of linezolid, undergoes during its evolutionary journey toward becoming drug resistant. Using cryo-electron microscopy, we describe a particular molecular mechanism which MRSA uses to become resistant to linezolid.

WCK 4034: A promising oxazolidinone for treating gram positive infections.

Increased resistance to gram positive infections have highlighted the limitations of currently available drug treatments including penicillins, macrolides and glycopeptides. As an alternative to address these challenges; Linezolid, the first antibiotic from oxazolidinone class, have shown the promising activities against such infections, although associated toxicological issues limiting the use of linezolid for prolonged treatments. In order to circumvent disadvantages allied with the marketed drugs, we herein reporting the synthesis of WCK 4034, an oxazolidinone antibiotic through our structure activity relationship (SAR) program. Through this exercise, WCK 4034, has shown competitive MIC values against Methicillin Sensitive S. aureus (MSSA, Sta-001), Methicillin Resistant S. aureus (MRSA, Sta-032), S. pneumoniae ATCC 49619 and H. influenza ATCC 35054 species as like linezolid. Although with an additional advantage; WCK 4034 has been found superior during dog PK studies as compare to Linezolid. With the preliminary studies in our hand, we herein assuming these improved pharmacokinetic values would be helpful. Moreover, WCK 4034 has successfully completed pre-clinical studies and ready to enter the clinical space, and paved the way for in house development of other oxazolidinone NCEs.

Pretomanid for tuberculosis: a systematic review.

BACKGROUND: Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed. OBJECTIVES: To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis. DATA SOURCES: Pubmed, clinicaltrials.gov. and Cochrane library. STUDY ELIGIBILITY CRITERIA: Quantitative studies presenting original data on clinical efficacy or safety of pretomanid. PARTICIPANTS: Patients with tuberculosis. INTERVENTIONS: Treatment with pretomanid or pretomanid-containing regimens in minimum one study group. METHODS: Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated. RESULTS: Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1-2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2-8) patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59-100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83-95) on pretomanid-bedaquiline-linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported. CONCLUSIONS: Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.

Selenium Nanoparticles as Candidates for Antibacterial Substitutes and Supplements against Multidrug-Resistant Bacteria.

In recent years, multidrug-resistant (MDR) bacteria have increased rapidly, representing a major threat to human health. This problem has created an urgent need to identify alternatives for the treatment of MDR bacteria. The aim of this study was to identify the antibacterial activity of selenium nanoparticles (SeNPs) and selenium nanowires (SeNWs) against MDR bacteria and assess the potential synergistic effects when combined with a conventional antibiotic (linezolid). SeNPs and SeNWs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), zeta potential, and UV-visible analysis. The antibacterial effects of SeNPs and SeNWs were confirmed by the macro-dilution minimum inhibitory concentration (MIC) test. SeNPs showed MIC values against methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant enterococci (VRE) at concentrations of 20, 80, 320, and >320 µg/mL, respectively. On the other hand, SeNWs showed a MIC value of >320 µg/mL against all tested bacteria. Therefore, MSSA, MRSA, and VRSA were selected for the bacteria to be tested, and SeNPs were selected as the antimicrobial agent for the following experiments. In the time-kill assay, SeNPs at a concentration of 4X MIC (80 and 320 µg/mL) showed bactericidal effects against MSSA and MRSA, respectively. At a concentration of 2X MIC (40 and 160 µg/mL), SeNPs showed bacteriostatic effects against MSSA and bactericidal effects against MRSA, respectively. In the synergy test, SeNPs showed a synergistic effect with linezolid (LZD) through protein degradation against MSSA and MRSA. In conclusion, these results suggest that SeNPs can be candidates for antibacterial substitutes and supplements against MDR bacteria for topical use, such as dressings. However, for use in clinical situations, additional experiments such as toxicity and synergistic mechanism tests of SeNPs are needed.

Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations.

The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.

In-Host Emergence of Linezolid Resistance in a Complex Pattern of Toxic Shock Syndrome Toxin-1-Positive Methicillin-Resistant Staphylococcus aureus Colonization in Siblings with Cystic Fibrosis.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause chronic lung infections in patients with Cystic Fibrosis (CF). One option for managing them is the use of linezolid. We hereby report the in-host emergence of linezolid resistance (LR) in MRSA in CF siblings via a population analysis. A collection of 171 MRSA strains from 68 samples were characterized by determining their linezolid Minimal Inhibitory Concentrations (MICs), analyzing the locus of staphylococcal protein A (spa) and whole genome sequencing. Courses of linezolid were retraced. Strains belonged to three spa types (t002, t045, t127) and two sequence types (ST1, ST5). Emergence of LR occurred under treatment, one year apart in both siblings, in the CC5-MRSA-I Geraldine clone harboring the toxic shock syndrome toxin-1-encoding gene. Resistance was related to a G2576T substitution present in a variable number of 23S rRNA gene copies. Susceptible and resistant strains were co-isolated within samples. Single Nucleotide Polymorphism-based analysis revealed complex colonizations by highly diversified, clonally related populations. LR remains rare in MRSA and there are very few longitudinal analyses documenting its emergence. Analyzing a large MRSA collection revealed new aspects of LR emergence: it emerges in specific subclonal lineages resulting from adaptive diversification of MRSA in the CF lung and this heterogeneity of intra-sample resistance may contribute to compromising antibiotic management.

First case of abdominal infection caused by bacteroides fluxus.

Bacteroides fluxus is a Gram-negative anaerobic bacillus isolated from human faeces in healthy individuals. Until now, this bacterium had not been involved in human diseases. We report the first case of abdominal infection due to this microorganism in an elderly patient. A 76-year-old man with a history of chronic pulmonary obstructive disease presented with dyspnea, orthopnea and cough. The clinical evolution worsened with both a colonic ischemia and further diffuse peritonitis of pancreatic origin. Peritoneal fluid was obtained and the culture yielded B. fluxus in pure culture. Resistance to penicillin, amoxicillin-clavulanate, clindamycin and moxifloxacin was documented. Treatment with meropenem + linezolid was started, but the patient finally died due to a multiorganic failure.