Banks can be as powerful and valued as the big technology firms. Yes, those trillion-dollar titans.

Stokvels are an important strategy for financial survival, so it's crucial to find a way to make them work during the pandemic, says Dr Norman Chivasa.

Strategic partnerships could be used to create win-win outcomes, says Sifiso Skenjana.

Penn State’s College of Agricultural Sciences is staying connected to alumni during the COVID-19 pandemic by moving its monthly Alumni Society board meetings and other alumni activities online.

With a fledgling democratic government and a formal peace process finally in place in the Democratic Republic of Congo (DRC), the country will celebrate its 50th year of independence next month.

For more than a year and a half, UN peacekeepers have continuously supported military operations conducted by the Congolese armed forces (FARDC) against the Rwandan rebels of the Democratic Forces for the Liberation of Rwanda (FDLR) in North and South Kivu.

The UN's release of a long awaited report on crimes committed in the Democratic Republic of Congo between 1993-2003 is not only an opportunity to re-examine the historical record of mass violence in DRC -- the scale and nature of which was often overlooked in the wake of the genocide in neighboring Rwanda -- but is also a chance to correct the terms of the deceptive and fragile peace some leaders wish to proclaim in the resource-rich Great Lakes region of Africa.

Rising piracy in the Gulf of Guinea, which supplies around 40 per cent of Europe’s oil and 29 per cent of the U.S.’s, demands effective regional security cooperation and better economic governance to prevent the region becoming another Gulf of Aden.

South Africa’s efforts to foster peace and security have placed it centre stage in some of the continent’s most intractable conflicts. This is an inevitable result of the quest to promote “African solutions for African problems”.

Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults.

Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported.

Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes.

Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes.

QPX7728 is a new ultra-broad-spectrum inhibitor of serine and metallo beta-lactamases from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A ESBLs (IC₅₀ range 1-3 nM) and carbapenemases such as KPC (IC₅₀ 2.9±0.4 nM) as well as class C P99 (IC₅₀ of 22±8 nM) with a potency that is comparable or higher than recently FDA approved BLIs avibactam, relebactam and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from A. baumannii (OXA-23/24/58, IC₅₀ range 1-2 nM) as well as MBLs such as NDM-1 (IC₅₀ 55±25 nM), VIM-1 (IC₅₀ 14±4 nM) and IMP-1 (IC₅₀ 610±70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high efficiency k₂/K ranging from of 6.3 x 10⁴ (for P99) to 9.9 x 10⁵ M^-1 s^-1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5-20 minutes for OXA carbapenemases from A. baumanii, ~50 minutes for OXA-48 and 2-3 hours for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on-fast-off kinetics, with K_is of 7.5±2.1 nM, 32±14 nM and 240±30 nM for VIM-1, NDM-1 and IMP-1, respectively. QPX7728 ultra-broad-spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

Since 2012, single low dose of primaquine (SLDPQ, 0.25mg/kg) has been recommended with artemisinin-based combination therapies, as first-line treatment of acute uncomplicated Plasmodium falciparum malaria, to interrupt its transmission, especially in low transmission settings of multidrug, including artemisinin, resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and lack of data on its efficacy.

In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. Transmission-blocking efficacy of SLDPQ was evaluated on Days 0, 1, 2, 3, 7, 14, 21, 28 and recrudescence by reverse transcriptase polymerase chain reaction (RT-PCR) (gametocyte prevalence) and membrane-feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP+SLDPQ reduced gametocyte carriage 3 fold compared to DP. Of 48 patients tested on Day 0, only three patients were infectious to mosquitoes (~6%). Post-treatment, three patients were infectious: on D14 (3.5%, 1/29), and on the first and seventh day of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission blocking efficacy.

Our study confirms effective gametocyte clearance of SLDPQ when combined with DP in multidrug resistant P. falciparum and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP and ASMQ-SLDPQ has been deployed to treat all P. falciparum symptomatic patients to further support the elimination of multidrug resistant P. falciparum in Cambodia.

Objectives: Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Yet, data of which combinations are most effective is lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa.

Methods: We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, meropenem, minocycline, rifampicin, temocillin, thiamphenicol or trimethoprim by automated time-lapse microscopy using predefined cut-off values indicating inhibition of growth (≤10⁶ CFU/mL) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments.

Results: All strains were intermediate or resistant to polymyxin B, anti-pseudomonal β-lactams, ciprofloxacin and amikacin. Genes encoding β-lactamases (e.g., bla_PAO and bla_OXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol and trimethoprim. Time kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem.

Conclusion: Positive interactions were frequently found with the tested combinations, also against strains that harboured several resistance mechanisms to the single drugs and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.

Carbapenems are currently the preferred agents for the treatment of serious Acinetobacter infections. However, whether cefepime/cefpirome can be used to treat Acinetobacter bloodstream infection (BSI) if it is active against the causative pathogens is not clear. This study aimed to compare the efficacy of cefepime/cefpirome and carbapenem monotherapy in patients with Acinetobacter BSI. The population included 360 patients with monomicrobial Acinetobacter BSI receiving appropriate antimicrobial therapy admitted to four medical centres in Taiwan in 2012–2017. The predictors of 30-day mortality were determined by Cox regression analysis. The overall 30-day mortality rate in the appropriate antibiotic treatment group was 25.0% (90/360 patients), respectively. The crude 30-day mortality rates for cefepime/cefpirome and carbapenem therapy were 11.5% (7/61 patients) and 26.3% (21/80 patients), respectively. The patients receiving cefepime/cefpirome/carbapenem therapy were infected by Acinetobacter nosocomialis (51.8%), A. baumannii (18.4%) and A. pittii (12.1%). After adjusting for age, Sequential Organ Failure Assessment (SOFA) score, invasive procedures, and underlying diseases, cefepime/cefpirome therapy was not independently associated with a higher or lower 30-day mortality compared to the carbapenem therapy. SOFA score (hazard ratio [HR], 1.324; 95% confidence interval [CI], 1.137–1.543; P < 0.001) and neutropenia (HR, 7.060; 95% CI, 1.607–31.019; P = 0.010) were independent risk factors for 30-day mortality of patients receiving cefepime/cefpirome or carbapenem monotherapy. The incidence density of 30-day mortality for cefepime/cefpirome versus carbapenem therapy was 0.40% versus 1.04%. The therapeutic response of cefepime/cefpirome therapy was comparable to that of carbapenems among patients with Acinetobacter BSI receiving appropriate antimicrobial therapy.

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA.

Multi-drug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely-used antibiotic class, the β-lactams, including the most recent-generation carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and bound to four clinically-relevant carbapenem antibiotics (doripenem, ertapenem, imipenem and meropenem) are presented. Active site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, an early step in the conserved glycosylphosphotidyl inositol (GPI) post-translational modification pathway of surface proteins in eukaryotic cells. Inhibition of inositol acylation by MGX results in pleiotropic effects including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-live of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 post infection when compared to placebo. In addition, administration of fosmanogepix resulted in a 1-2 log reduction in both lung and kidney fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first in class treatment for invasive mucormycosis.

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.

The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.

These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

There is an urgent need for new, potent anti-tuberculosis (TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3, 4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent anti-tuberculosis activity. The minimum inhibitory concentrations of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/mL. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for Mycobacterium tuberculosis H37Rv was less than 1.91 x 10^-7. It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole genome and targeted sequencing of resistant isolates to OPC-167832 identified the decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of this compound, and further studies demonstrated inhibition of the DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3-4 drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed superior efficacy in reducing bacterial burden and preventing relapse compared to the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.

Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions such as thrombocytopenia when standard-dose linezolid is used than patients with LD who didn't use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. The study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established population pharmacokinetics model with the Phoenix NLME. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 L/h (95% confidence interval [CI]: 2.34-3.03 L/h); the volume of distribution (Vd) was 58.34 L (95% CI: 48.00-68.68 L). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (C_min, ss at 2-8 ug/mL) and effective targets (the ratio of AUC_0-24 at steady state to MIC, 80-100). In addition, for patients with severe LD (PTA <= 20%), the dosage (400 mg/24 h) was sufficient at an MIC <= 2 ug/mL. This study recommended therapeutic drug monitoring for patients with LD.

Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection.

The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens.

Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and there is a necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeting local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food-additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1%). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic/gellan formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacteria-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic/gellan formulations provided a release of L. paracasei cells over 24 hours that was sufficient to inhibit the growth of C. albicans with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic/gellan formulations also had inhibitory activity against Candida spp. biofilms by reducing the number of Candida spp. cells (p < 0.0001), decreasing the total biomass (p = 0.0003), and impairing hyphae formation (p = 0.0002), compared to the control group which received no treatment. Interestingly, probiotic formulation of 1% w/v gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log of CFU/mL after 10 days. This formulation inhibited the C. albicans growth (p < 0.0001), prevented the development of candidiasis lesions (p = 0.0013), and suppressed inflammation (p = 0.0006) when compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis.

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.

Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n=196) were assessed in 78 critically ill patients following continuous infusion of piperacillin/tazobactam (ratio 8:1). The initial dose of 8, 12 or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L), and the following PK/PD targets were evaluated: 100% fT>1xMIC and 100% fT>4xMIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into non-renal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT>1xMIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT>4xMIC. Probability of target attainment for a simulated cohort of patients showed, that increasing the daily dose by 4 g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT>4xMIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a CI regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

A total of 2,283 Salmonella spp. isolates were recovered from 18,334 samples including patients with diarrhea, food of animal origin and pets across 5 provinces of China. The highest prevalence of Salmonella spp. was detected in chicken meats (39.3%, 486/1,237). Fifteen serogroups and 66 serovars were identified, with Typhimurium and Enteritidis being the most dominant. Most (85.5%, 1,952/2,283) isolates exhibited resistant to ≥ 1 antimicrobial and 56.4% were multi-drug resistant (MDR). A total of 222 isolates harbored extended-spectrum β-lactamases (ESBLs), 200 of which were CTX-M-type that were mostly detected from chicken meat and turtle fecal. Overall, eight bla_CTX-M genes were identified, with bla_CTX-M-65, bla_CTX-M-123, bla_CTX-M-14, bla_CTX-M-79, and bla_CTX-M-130 being the most prevalent. Totally, 166 of the 222 ESBL-producing isolates had amino acid substitutions in GyrA (S83Y, S83F, D87G, D87N, and D87Y) and ParC (and S80I), whilst the PMQR-encoding genes oqxA/B, qepA, and qnrB/S were detected in almost all isolates. Of the fifteen sequence types (STs) identified in the 222 ESBLs, ST17, ST11, ST34, and ST26 ranked among the top 5 in the number of isolates. Our study revealed considerable serovars diversity, high prevalence of co-occurrence of MDR determinants, including CTX-M-type ESBLs, QRDRs mutations and PMQR genes. This is the first report of CTX-M-130 Salmonella spp. from patients with diarrhea and QRDRs mutations from turtle fecal samples. Our study emphasizes the importance of actions, both in the health care settings and in the veterinary medicine sector, to control the dissemination of MDR, especially the CTX-M Salmonella spp. isolates.

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor, baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11846 plasma concentration data items from 1827 subjects including 2341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications.

Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing < 80 kg and 80 mg for patients weighing ≥ 80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients.

The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

Globally, mutations in the katG gene account for the majority of isoniazid-resistant strains of Mycobacterium tuberculosis. Buyankhishig et al analyzed a limited number of Mycobacterium tuberculosis strains in Mongolia and found that isoniazid resistance was mainly attributable to inhA mutations. The GenoType® MTBDRplus assay was performed for isolates collected in the First National Tuberculosis Prevalence Survey and the Third Anti-Tuberculosis Drug Resistance Survey to investigate genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis in Mongolia. Of the 409 isoniazid-resistant isolates detected by the GenoType® MTBDRplus assay, 127 (31.1%) were resistant to rifampicin, 294 (71.9%) had inhA mutations without katG mutations, 113 (27.6%) had katG mutations without inhA mutations, and two (0.5%) strains had mutations in both the inhA and katG genes. Of the 115 strains with any katG mutation, 114 (99.1%) had mutations in codon 315 (S315T). Of the 296 trains with any inhA mutation, 290 (98.0%) had a C–15T mutation. The proportion of isoniazid-resistant strains with katG mutations was 25.3% among new cases and 36.2% among retreatment cases (p=0.03), as well as 17.0% among rifampicin-susceptible strains and 52.8% among rifampicin-resistant strains (p<0.01). Rifampicin resistance was significantly associated with the katG mutation (adjusted odds ratio 5.36, 95% CI 3.3–8.67, p<0.001). Mutations in inhA predominated in isoniazid-resistant tuberculosis in Mongolia. However, the proportion of katG mutations in isolates from previously treated cases was higher than that among new cases, and that in cases with rifampicin resistance was higher than that in cases without rifampicin resistance.

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicentre trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90ms mean QTc-prolongation per 100ng/mL increase in piperaquine concentration. The effect of piperaquine on absolute QTc-interval estimated a mean maximum QTc-interval of 456ms (EC₅₀=209ng/mL). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98-2.46% risk of having QTc-prolongation > 60ms in all treatment settings. Although piperaquine administration resulted in QTc-prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern.

Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate.

Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01-0.66 μg/ml) and micafungin levels (<0.01-0.16 μg/ml) were lower than the simultaneous plasma concentrations (0.77-5.07 μg/ml and 1.21-8.70 μg/ml, respectively). In cerebral cortex, anidulafungin and micafungin levels were 0.21-2.34 μg/g and 0.18-2.88 μg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.

One of the reasons for the lengthy tuberculosis (TB) treatment is the difficult to treat non-multiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our pre-clinical drug development pipeline. In most available dormancy models it takes a long time to create a dormant state and it is difficult to identify and quantify this non-multiplying condition.

The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes non-multiplying after 10 days of streptomycin starvation, but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetic model to assess the difference in the activity of isoniazid, rifampicin, moxifloxacin and bedaquiline against log-phase growth compared to the non-multiplying M. tuberculosis subpopulation by CFU counting including a novel AUC-based approach as well as time-to-positivity (TTP) measurements.

We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampicin and high dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value as it identifies a specific mycobacterial subpopulation that is non-culturable on solid media.

In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

A case of M. leprae rifampicin resistance after irregular anti-leprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampicin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVB^res) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVB^res was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October, 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously-developed population pharmacokinetic (PK) model based on Phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 Phase 1 studies used to develop the previous model were pooled with data from three additional Phase 1 studies, a Phase 1b uncomplicated urinary tract infection study, one Phase 3 CABP study, and two Phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a sub-compartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females relative to males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external Phase 3 ABSSSI dataset. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA₄ receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.

Exploring different ways of minimising linezolid toxicity without compromising efficacy is a major quest in the treatment of drug resistant tuberculosis (TB)....

Linezolid has strong antimicrobial activity against the multidrug-resistant (MDR) strains of Mycobacterium tuberculosis. Little is known about the distribution of linezolid in tuberculosis (TB) lesions in patients with MDR-TB. The aim of this study is to evaluate the distribution of linezolid in TB lesions in patients with spinal MDR-TB. Nine patients with spinal MDR-TB were enrolled prospectively from August 2019 to February 2020. The patients received a linezolid-containing anti-TB treatment regimen and needed surgery for the removal of TB lesions. During the operation, nine blood samples, eight diseased bone tissue samples, seven pus samples and four granulation tissue samples were collected simultaneously and 2 h after the oral administration of 600 mg of linezolid. Linezolid concentrations in plasma, diseased bone tissue, pus, and granulation tissue samples were subjected to high-performance liquid chromatography–tandem mass spectrometry. At sample collection, the mean concentrations of linezolid in plasma, diseased bone tissue, pus, and granulation tissue samples of the nine patients were 11.14 ± 5.82, 5.94 ± 4.27, 11.09 ± 4.58, 14.08 ± 10.61 mg/L, respectively. The mean ratios of linezolid concentration in diseased bone/plasma, pus/plasma, and granulation/plasma were 53.84%, 91.69%, and 103.57%, respectively. The mean ratios of linezolid concentration in pus/plasma and granulation/plasma were higher than those in diseased bone/plasma, and the difference was statistically significant (t =-2.810, p = 0.015; t =-4.901, p = 0.001). In conclusion, linezolid had different concentration distributions in different types of TB infected tissues in patients with spinal MDR-TB.

We thank Kim and colleagues for their interest in our study....

Six sources confirmed Apple changed its mind on end-to-end encrypted backups two years ago following an FBI complaint and concerns users could lose access to their own data.