Objectives. The aim of this study was to assess the safety of early oral switch (EOS) prior to 14 days for low-risk Staphylococcus aureus bacteremia (LR-SAB), which is the primary treatment strategy employed at our institution. Usually recommended therapy is 14 days of intravenous (IV) antibiotics.

Methods. All patients with SAB at our hospital were identified between 1 January 2014 and 31 December 2018. Those meeting low-risk criteria (healthcare-associated, no evidence of deep infection or demonstrated involvement of prosthetic material, and no further positive blood cultures after 72-hours) were included in the study. The primary outcome was occurrence of a SAB-related complication within 90 days.

Results. There were 469 SAB episodes during the study period, 100 (21%) of whom met inclusion criteria. EOS was performed in 84 patients. In this group, line infection was the source in 79%, methicillin-susceptible S. aureus caused 95% of SABs and 74% of patients received IV flucloxacillin. The median duration of IV and oral antibiotics in the EOS group was 5 (IQR 4-6) and 10 days (IQR 9-14), respectively. Seventy-one percent of patients received flucloxacillin as their EOS agent. Overall, 86% of oral step-down therapy was with beta-lactams. One patient (1%) undergoing EOS had SAB relapse within 90 days. No deaths attributable to SAB occurred within 90 days.

Conclusions. In this low MRSA prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings.

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.

Continuous spread of antimalarial drug resistance is a threat to current chemotherapy efficacy. Therefore, characterizing the genetic diversity of drug resistance markers is needed to follow treatment effectiveness and further update control strategies. Here, we genotyped Plasmodium falciparum resistance gene markers associated with sulfadoxine-pyrimethamine (SP) and artemisinin-based combination therapy (ACT) in isolates from pregnant women in Ghana. The prevalence of the septuple IRNI-A/FGKGS/T pfdhfr/pfdhps haplotypes including the pfdhps A581G and A613S/T mutations was high at delivery among post-SP treatment isolates (18.2%) compared to those of first-antenatal care (before initiation of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP); 6.1%; p = 0.03). Regarding the pfk13 marker gene, two non-synonymous mutations (N458D and A481C) were detected at positions previously related to artemisinin resistance in isolates from Southeast-Asia. These mutations were predicted in silico to alter the stability of the pfk13 propeller-encoding domain. Overall, these findings highlight the need for intensified monitoring and surveillance on additional mutations associated with increased SP resistance as well as emergence of resistance against artemesinin derivatives.

Lipid II is an essential precursor of the bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II-binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e. HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against E. faecium than nisin (1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.

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.

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.

Objectives: Carbapenemase-producing Enterobacterales and specifically KPC-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp) is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than if caused by carbapenem-susceptible isolates.

Study design and methods: This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent Intensive Care Unit in a university hospital (> 40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression).

Results. We analyze 69 cases of K. pneumoniae VAP of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/mL). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [lsqb]HR[rsqb] 1.25; 95% CI: 0.46–3.41). Adequate targeted therapy (HR 0.03; 95% CI: <0.01–0.23) was associated with all-cause mortality.

Conclussion. Assuming the limitations due to the available sample size, the prognosis of VAP caused by KPC-Kp is similar to VAPs caused by carbapenem-susceptible K. pneumoniae when appropriate treatment is used.

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.

Bacteria of the genus Campylobacter are major foodborne pathogens which have become increasingly resistant to clinically important antimicrobial agents (1)....

The Cpx stress response is widespread among Enterobacteriaceae. We have previously reported a mutation in cpxA in a multidrug resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields to a single amino acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxA^Y144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the intimate interconnection between Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall active antibiotic or inactivation of penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increase phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to causes abnormal accumulation of muropeptides (disaccharide-pentapeptide, N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycan caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular the interaction between CpxA and CpxP, as a promising therapeutic target.

Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen.

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.

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This Phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (N = 22) were confined to the clinic at baseline, received oral gepotidacin 1,500 mg twice daily for 5 days (on-therapy; Days 1 to 5), and returned to the clinic for test-of-cure (Days 10 to 13) and follow-up (Day 28±3). Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 hours postdose. Steady state was attained by Day 3. Urinary exposure over the dosing interval increased from 3,742 μg.h/ml (Day 1) to 5,973 μg.h/ml (Day 4), with trough concentrations of 322 to 352 μg/ml from Day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥10⁵ CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <10³ CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up, respectively. Plasma area under the free-drug concentration-time curve over 24 hours at steady state divided by the MIC (fAUC_0-24/MIC) and urine AUC_0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (NCT03568942)

We report the first clinical Escherichia. coli strain EC3000 with concomitant chromosomal colistin and carbapenem resistance. A novel in-frame deletion, 6-11(RPISLR), in pmrB contributing to colistin resistance was verified using recombinant DNA techniques. Although decreased fitness compared to the wild-type (WT) strain or EC3000 revertant (chromosomal replacement of WT pmrB in EC3000), a portion of serially passaged EC3000 strains preserving colistin resistance without selective pressure raises the concern for further spread.

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-hour dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five clinical H. influenzae isolates. These five isolates, which had MIC values of 1 or 2 mg/L, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log₁₀ colony forming units (CFU) from baseline at 24 hours and total-drug ELF AUC/MIC ratio for each isolate and the isolates pooled together were evaluated using Hill-type models and non-linear least squares regression. As evidenced by the high coefficient of determination (r²) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled together. The median total-drug ELF AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log₁₀ CFU/mL reductions from baseline at 24 hours was 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

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.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN/DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "see-saw effect", where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

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.

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.

Objectives: Empiric antibiotic prescribing can be supported by guidelines and/or local antibiograms, but these have limitations. We sought to use data from a comprehensive electronic health record to use statistical learning to develop predictive models for individual antibiotics that incorporate patient-, and hospital-specific factors. This paper reports on the development and validation of these models on a large retrospective cohort.

Methods: This is a retrospective cohort study including hospitalized patients with positive urine cultures in the first 48 hours of hospitalization at a 1500 bed, tertiary care hospital over a 4.5 year period. All first urine cultures with susceptibilities were included. Statistical learning techniques, including penalized logistic regression, were used to create predictive models for cefazolin, ceftriaxone, ciprofloxacin, cefepime, and piperacillin-tazobactam. These were validated on a held-out cohort.

Results: The final dataset used for analysis included 6,366 patients. Final model covariates included demographics, comorbidity score, recent antibiotic use, recent antimicrobial resistance, and antibiotic allergies. Models had acceptable to good discrimination in the training dataset and acceptable performance in the validation dataset, with a point estimate for area under the receiver operating characteristic curve (AUC) that ranged from 0.65 for ceftriaxone to 0.69 for cefazolin. All models had excellent calibration.

Conclusion: In this study we used electronic health record data to create predictive models to estimate antibiotic susceptibilities for UTIs in hospitalized patients. Our models had acceptable performance in a held-out validation cohort.

Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathologic bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard of care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis, and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal in vitro and in vivo. Similarly, locally-delivered diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of sub-therapeutic vancomycin. However, we also found that the resorbable polyurethane foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard of care antibiotic therapy for S. aureus osteomyelitis, but also highlight potential pitfalls encountered with local drug delivery.

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.

Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.

Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.

Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).

Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.

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.

Florfenicol belongs to a class of phenicol antimicrobials widely used as feed additives and for the treatment of respiratory infections. In recent years, increasing resistance to florfenicol has been reported in Campylobacter spp., the leading foodborne enteric pathogen causing diarrheal diseases worldwide. Here, we reported the identification of fexA, a novel mobile florfenicol resistance gene in Campylobacter. Of the 100 Campylobacter jejuni strains isolated from poultry in Zhejiang, China, nine of them were shown to be fexA positive, and their whole genome sequences were further determined by integration of Illumina short-read and MinION long-read sequencing. The fexA gene was found in the plasmid of one strain and chromosomes of eight strains, and its location was verified by S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting. Based on comparative analysis, the fexA gene was located within a region with the tet(L)-fexA-catA-tet(O) gene arrangement, demonstrated to be successfully transferrable among C. jejuni strains. Functional cloning indicated that acquisition of the single fexA gene significantly increased resistance to florfenicol, whereas its inactivation resulted in increased susceptibility to florfenicol in Campylobacter. Taken together, these results indicated that the emerging fexA resistance is horizontally transferable, which might greatly facilitate the adaptation of Campylobacter in food producing environments where florfenicols are frequently used.

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

The off-label use of third generation cephalosporin (3GC) during in ovo vaccination or vaccination of newly hatched chicks, was a common practice worldwide. CMY-2-producing Escherichia coli have been disseminated among broiler production. The objectives of this study were to determine the epidemiological linkage of bla_CMY-2-positive plasmids among broilers both within and outside Japan because grandparent stock and parent stock were imported in Japan. We examined the whole genome sequences of 132 3GC-resistant E. coli isolates collected from healthy broilers during 2002-2014. The predominant 3GC-resistance gene was bla_CMY-2, which was detected in the plasmids of 87 (65.9%) isolates. The main plasmid replicon types were IncI1-I (n=21; 24.1%), IncI (n=12; 13.8%), IncB/O/K/Z (n=28; 32.2%), and IncC (n=22; 25.3%). Those plasmids were subjected to gene clustering and network analyses and plasmid multi-locus sequence typing (pMLST). The chromosomal DNA of isolates was subjected to MLST and single nucleotide variant (SNV)-based phylogenetic analysis.

MLST and SNV-based phylogenetic analysis revealed high diversity of E. coli isolates. ST429 harboring bla_CMY-2-positive IncB/O/K/Z was closely related to isolates from broiler in Germany harboring bla_CMY-2-positive IncB/O/K/Z. pST55-IncI and pST12-IncI1-I and pST3-IncC were prevalent in western Japan. pST12-IncI1-I and pST3-IncC were closely related to those detected in E. coli isolates from chicken in American continent, whereas 26 IncB/O/K/Z were related to those in Europe. These data will be useful to reveal the whole picture of transmission of CMY-2-producing bacteria in and out of Japan.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

Local stocks advanced for a second consecutive session on Thursday as global markets remained resurgent.

Still, there was disappointment in terms of economic data following the release of the SACCI Business Confidence index data for April which came in at 77.8, compared to a forecast of 89.2.

BACKGROUND AND OBJECTIVES:

Antibiotic therapy is often prescribed for suspected community-acquired pneumonia (CAP) in children despite a lack of knowledge of causative pathogen. Our objective in this study was to investigate the association between antibiotic prescription and treatment failure in children with suspected CAP who are discharged from the hospital emergency department (ED).

BACKGROUND:

For children who cannot be discharged from the emergency department, definitive care has become less frequent at most hospitals. It is uncertain whether this is true for common conditions that do not require specialty care. We sought to determine how the likelihood of definitive care has changed for 3 common pediatric conditions: asthma, croup, and gastroenteritis.

BACKGROUND:

Mexican-origin women breastfeed at similar rates as white women in the United States, yet they usually breastfeed for less time. In our study, we seek to identify differences in Mexican-origin women’s breastfeeding intentions, initiation, continuation, and supplementation across nativity and country-of-education groups.

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

BACKGROUND AND OBJECTIVES:

Annual incidence of venous thromboembolism (VTE) including postoperative VTE in hospitalized children is rising significantly. A growing body of evidence supports the role of red blood cells (RBCs) in pathologic thrombosis. In this study, we examined the association of perioperative RBC transfusion with postoperative VTE in pediatric patients.

OBJECTIVES:

Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians.

Elizabeth Stringer Keefe, Becky Shiring, Katie Robinson, Dr. Sonny Magana and Dr. Monica Burns contribute their suggestions on using tech to differentiate instruction.

Two of Penn State’s most generous supporters and prominent alumni leaders have made a new commitment to support students impacted by the COVID-19 crisis. Helen S. Hintz, 1960, and Edward “Ed” R. Hintz, 1959, have directed $100,000 to the Student Care and Advocacy Emergency Fund.

The Penn State Smeal College of Business Center for the Business of Sustainability recently hosted the first in a series of virtual fireside discussions titled “The Impact of Coronavirus on Sustainability and Social Impact,” to explore how recent momentum in sustainability efforts has been altered.

Penn State Health Milton S. Hershey Medical Center has begun enrolling participants in an international clinical trial evaluating an investigational antiviral drug, remdesivir, for treatment of coronavirus disease 2019 (COVID-19).

The Penn State Center for Structural Oncology is shifting some of its focus from fighting cancer to fighting COVID-19, with three projects.

Both in and out of the virtual classroom, Penn State Lehigh Valley departments are connecting with students during remote learning

Beth E. Michalec, lecturer of corporate communication at Penn State Lehigh Valley, earned a doctorate in rhetoric from Duquesne University. Michalec was selected as a Fulbright specialist in June 2019 by the U.S. Department of State.

Although complications caused by the coronavirus pandemic have temporarily halted the Fulbright Specialist Program, Nichola D. Gutgold looks forward to officially joining the Roster after the U.S. Department of State determines that projects can resume.

Sabric, a financial crime information centre, shares its tips on staying safe over the festive season.

The Garmin Forerunner 935, which sits at the top of the Forerunner hierarchy thanks to highly customizable running and triathlon features, is $128 off on Amazon today.