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Introduction. Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. Aim. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. Methodology. Six-hundred-two patients with wound infections from two Phase 3, double-blinded, randomized, multicenter, active controlled trials (REVIVE-1/–2) were evaluated in a post hoc analysis of iclaprim 80 mg compared with vancomycin 15 mg kg–1 administered intravenously every 12 h for 5–14 days. The primary endpoint was to determine whether iclaprim was non-inferior (10 % margin) to vancomycin in achieving a ≥20 % reduction from baseline in lesion size 48–72 h after starting study drug (early clinical response [ECR]). Safety was assessed. Results. In REVIVE-1, ECR was 83.5 % with iclaprim versus 79.7 % with vancomycin (treatment difference 3.77%, 95 % CI −4.50%, 12.04%). In REVIVE-2, ECR was 82.7 % with iclaprim versus 76.3 % with vancomycin (treatment difference 6.38%, 95 % CI −3.35%, 16.12%). In the pooled dataset, iclaprim had similar ECR rates compared with vancomycin among wound infection patients (83.2 % vs 78.2 %) with a treatment difference of 5.01 % (95 % CI −1.29%, 11.32%). The safety profile was similar in iclaprim- and vancomycin-treated patients, except for a higher incidence of diarrhea with vancomycin (n=17) compared with iclaprim (n=6) and fatigue with iclaprim (n=17) compared with vancomycin (n=8). Conclusion. Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections.

Background: In this first in human study, PLG0206, a novel engineered cationic antimicrobial peptide was evaluated for safety, tolerability and pharmacokinetics when intravenously administered as a single dose to healthy subjects. Methods: Six cohorts of 8 subjects received escalating single IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1-to-4-hours. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 hours post infusion. Safety and tolerability were assessed throughout the study. Results: The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment emergent adverse events (TEAE) related to PLG0206 was low and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion related reactions, which were mitigated with increasing infusion time and volume. There were no serious adverse events (SAE), life-threatening events, or deaths throughout the study. IV PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. Conclusion: Following a single IV infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of IV PLG0206 as an antimicrobial agent.

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an antistaphylococcal lysin, was administered intravenously as a 6-mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein. (This study has been registered at ClinicalTrials.gov under identifier NCT03446053.).

Highly substituted pyridine scaffolds are found in many biologically active natural products and therapeutics. Accordingly, numerous complementary de novo approaches to obtain differentially substituted pyridines have been disclosed. This article delineates the evolution of the synthetic strategies designed to assemble the demanding tetrasubstituted pyridine core present in the limonoid alkaloids isolated from Xylocarpus granatum, including xylogranatopyridine B, granatumine A and related congeners. The most efficient and convergent construction of the core framework present in xylogranatopyridine B involved a Liebeskind pyridine synthesis and late-stage benzylic oxidation. By contrast, the synthesis of the bislactone limonoid alkaloids, such as granatumine A which exhibited moderate PTP1B-inhibitory activities, necessitated the development of a novel pyran-to-pyridine conversion. In addition, NMR calculations suggested structural misassignment of several limonoid alkaloids, and predicted their C3-epimers as the correct structures, which was further validated unequivocally through chemical synthesis. While preliminary results of the pNPP assays showed that these bislactone limonoid alkaloids were only weakly inhibitory against PTP1B, C3-deoxy-xylogranatin F, an unnatural synthetic analog, was demonstrated to be more potent than the other congeners.

Purpose This analysis evaluates the efficacy and safety of iclaprim versus vancomycin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in patients who were intravenous drug users (IVDUs). Methods A total of 621 patients who were IVDUs from 2 parallel Phase III, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed separately and pooled. This post hoc analysis summarizes the efficacy and safety profile of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg administered intravenously during 2 h every 12 h for 5–14 days among this population. The primary end point of these studies was to determine whether iclaprim was noninferior (10% margin) to vancomycin in achieving a ≥20% reduction in lesion size at 48–72 h after initiation of treatment with the study drug (early clinical response) in the intent-to-treat population. The safety profile was assessed based on adverse events and laboratory parameters. Findings Iclaprim had higher early clinical response rates (85.8%; 95% CI, 81.5%–89.4%) compared with vancomycin (79.8%; 95% CI, 74.8%–84.2%) among patients with ABSSSIs who were IVDUs, with a treatment difference of +6.00% (95% CI, 0.06–12.0). The safety profile was similar in the iclaprim and vancomycin arms, with 3.7% and 5.0%, respectively, of patients discontinuing study therapy because of adverse events and 1.9% and 3.4%, respectively, of patients developing serious adverse events. Implications Iclaprim had a higher early clinical response rate and favorable safety profile compared with vancomycin for the treatment of ABSSSIs in patients who were IVDUs. Iclaprim may be a valuable treatment option for ABSSSIs in this patient population.

We herein disclose the first report of a first- row transition metal-catalyzed α,β-dehydrogenation of carbonyl compounds using allyl-nickel catalysis. This development overcomes several limitations of previously reported allyl-palladium-catalyzed oxidation, and is further leveraged for the development of an oxidative cycloalkenylation reaction that provides access to bicycloalke-nones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.

Purpose Extracellular protein toxins contribute to the pathogenesis of Staphylococcus aureus infections. The present study compared the effects of iclaprim and trimethoprim - two folic acid synthesis inhibitors - with nafcillin and vancomycin on production of Panton-Valentine leukocidin (PVL), alpha haemolysin (AH) and toxic-shock syndrome toxin I (TSST-1) in methicillin-resistant and vancomycin-intermediate S. aureus (MRSA and VISA, respectively). Methodology Northern blotting and RT-PCR were used to assess gene transcription; toxin-specific bioassays were used to measure protein toxin production. Results As shown previously, sub-inhibitory concentrations (sub-MIC) of nafcillin increased and prolonged MRSA toxin gene transcription and enhanced PVL, TSST-1 and AH production. Sub-inhibitory doses of iclaprim and trimethoprim delayed maximal AH gene (hla) transcription and suppressed AH production; both drugs delayed, but neither reduced, maximal TSST-1 production. Trimethoprim significantly increased lukF-PV expression and PVL production compared to both untreated and iclaprim-treated cultures. Higher concentrations of iclaprim and trimethoprim markedly suppressed MRSA growth, mRNA synthesis and toxin production. In VISA, iclaprim, vancomycin and nafcillin variably increased tst and hla expression, but only nafcillin increased toxin production. Despite its ability to increase hla expression, iclaprim was the most potent inhibitor of AH production. Conclusions We conclude that, due to its ability to suppress toxin production, iclaprim should be effective against severe staphylococcal infections caused by toxin-producing MRSA and VISA strains, especially given its ability to concentrate at sites of infection such as skin and skin structures and the lung.

The absence of novel antibiotics for drug-resistant and biofilm-associated infections is a global public health crisis. Antimicrobial peptides explored to address this need have encountered significant development challenges associated with size, toxicity, safety profile, and pharmacokinetics. We designed PLG0206, an engineered antimicrobial peptide, to address these limitations. PLG0206 has broad-spectrum activity against >1,200 multidrug-resistant (MDR) ESKAPEE clinical isolates, is rapidly bactericidal, and displays potent anti-biofilm activity against diverse MDR pathogens. PLG0206 displays activity in diverse animal infection models following both systemic (urinary tract infection) and local (prosthetic joint infection) administration. These findings support continuing clinical development of PLG0206 and validate use of rational design for peptide therapeutics to overcome limitations associated with difficult-to-drug pharmaceutical targets.

ConspectusThe development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has enabled new mechanistic strategies to achieve difficult chemical transformations, increased the value of abundant chemical building blocks, and pushed the boundaries of creative and strategic route design to improve step economy in multistep synthesis. Methodologies to introduce an olefin into saturated molecules continue to be essential transformations because of the plethora of reactions available for alkene functionalization. Of particular importance are dehydrogenation reactions adjacent to electron-withdrawing groups such as carbonyls, which advantageously provide activated olefins that can be regioselectively manipulated. Palladium catalysis occupies a central role in the most widely adopted carbonyl dehydrogenation reactions, but limits to the scope of these protocols persist.In this Account, we describe our group's contributions to the area of transition-metal-catalyzed dehydrogenation using palladium catalysis and more sustainable and economical nickel catalysis. These metals are used in conjunction with allyl and aryl halides or pseudohalides that serve as oxidants to access a unique mechanistic approach for one-step α,β-dehydrogenation of various electron-withdrawing groups, including ketones, esters, nitriles, amides, carboxylic acids, and electron-deficient heteroarenes. The pivotal reaction parameters that can be modified to influence reaction efficiency are highlighted, including base and oxidant structure as well as ligand and salt additive effects. This discussion is expected to serve as a guide for troubleshooting challenging dehydrogenation reactions and provide insight for future reaction development in this area.In addition to enabling dehydrogenation reactions, our group's allyl-Pd and -Ni chemistry can be used for C-C and C-X bond-forming reactions, providing novel disconnections with practical applications for expediting multistep synthesis. These transformations include a telescoped process for ketone α,β-vicinal difunctionalization; an oxidative enone β-functionalization, including β-stannylation, β-silylation, and β-alkylation; and an oxidative cycloalkenylation between unstabilized ketone enolates and unactivated alkenes. These bond-forming methodologies broaden the range of transformations accessible from abundant ketone, enone, and alkene moieties. Both the dehydrogenation and C-C and C-X bond-forming methodologies have been implemented in our group's total synthesis campaigns to provide step-efficient synthetic routes toward diverse natural products.Through the lens of multistep synthesis, the utility and robustness of our dehydrogenation and dehydrogenative functionalization methodologies can be better appreciated, and we hope that this Account will inspire practitioners to apply our methodologies to their own synthetic challenges.

Among hospitalized adults who received vancomycin for their skin and skin structure infection (SSSI), patients who experienced acute kidney injury (AKI) had considerably higher 30-day readmission rates. Nearly half of the observed 30-day readmissions were due to non-SSSI-related reasons, which is consistent with the persistent organ dysfunction observed among patients with AKI.

The efficacy of iclaprim against Staphylococcus aureus ATCC 25923 and its corresponding isogenic TK-deficient mutant S. aureus strain AH 1246 mixed with cytodex beads was studied in a mouse abscess infection model. Iclaprim (2–80 mg kg−1) administered as a single dose via the subcutaneous route (2 h post-infection) was efficacious against the TK-deficient mutant with 1 and 2 log10 c.f.u. reductions at the 24 h post initiation of treatment time point, at doses of 14.4 and 30 mg kg−1, respectively. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK-competent) S. aureus strain, ATCC 25923, at all doses tested. The PK/PD parameter which appeared to correlate best with efficacy was AUC/MIC (R 2=0.91). This study showed that TK-deficient mutants may be used to evaluate DHFRi activity and PK/PD relationship in a mouse abscess model.

The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models. However, for thymidine kinase (TK) deficient mutant bacteria, the presence of free thymidine does not impact the activity of DHFR inhibitors, and these mutants were used to assess the in vivo efficacy of the DHFR inhibitor, iclaprim. The efficacies of iclaprim, trimethoprim, and vancomycin were evaluated in a systemic mouse infection model. Female CD-1 mice were infected intraperitoneally (IP) with wild-type Staphylococcus aureus ATCC 25923 (MSSA) or AW 6 (MRSA) or their corresponding isogenic TK-deficient mutant S. aureus strains AH 1246 and AH 1252. Iclaprim showed potent antibacterial activity against both the TK-deficient mutant S. aureus strains, with PD50 values of 1.8 and

Iclaprim, a diaminopyrimidine antimicrobial, was compared with vancomycin for treatment of patients with acute bacterial skin and skin-structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). Here, the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies was explored. REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised, multicentre, active-controlled, non-inferiority (margin of 10%) trials, each designed to enrol 600 patients with ABSSSI using identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered intravenously every 12 h for 5-14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size [early clinical response (ECR)] at the early time point (ETP) (48-72 h after starting study drug) in the intent-to-treat population. In REVIVE-1, ECR at the ETP was 80.9% with iclaprim versus 81.0% with vancomycin (treatment difference -0.13%, 95% CI -6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim versus 76.7% with vancomycin (treatment difference 1.58%, 95% CI -5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim versus 78.8% with vancomycin (treatment difference 0.75%, 95% CI -3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (n = 7) compared with iclaprim (n = 0). Iclaprim achieved non-inferiority compared with vancomycin for ECR at the ETP and secondary endpoints with a similar safety profile in two phase 3 studies for treatment of ABSSSI suspected or confirmed as caused by Gram-positive pathogens. [Clinical Trials Registration. NCT02600611 and NCT02607618.].

Iclaprim is under clinical development for treating acute bacterial skin and skin structure infections (ABSSSI) and nosocomial pneumonia most often due to Gram-positive bacteria, including infections due to drug-resistant bacteria. In two recent Phase III studies of patients with acute bacterial skin and skin structure infections, intravenous iclaprim 80 mg every 12 h was noninferior to dose-adjusted vancomycin. Additional studies are planned for patients with nosocomial pneumonia. Iclaprim represents an alternative for the treatment of severe skin and pulmonary infections due to Gram-positive bacteria.

The use of allyl-palladium catalysis for the one-step α,β-dehydrogenation of ketones via their zinc enolates is reported. The optimized protocol utilizes commercially available Zn(TMP)(2) as base and diethyl allyl phosphate as oxidant. Notably, this transformation operates under salt-free conditions and tolerates a diverse scope of cycloalkanones.

LSVT-1701 (previously known as SAL200), is a novel, recombinantly-produced, bacteriophage-encoded lysin that specifically targets staphylococci via cell wall enzymatic hydrolysis. In vitro activities of LSVT-1701 and comparators were tested against 415 Staphylococcus aureus and coagulase-negative staphylococci (CoNS) clinical isolates expressing various resistance phenotypes. The isolates were collected worldwide from 2002 to 2019 and tested for in vitro susceptibility using broth microdilution methodology performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and EUCAST criteria. MIC90 for all S. aureus, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, and CoNS, were 2, 2, 2 and 2 µg/ml, respectively. LSVT-1701's activity was not adversely affected by resistance to antimicrobial comparators against this worldwide collection of S. aureus and CoNS clinical isolates. The results of this study support further clinical development of LSVT-1701 to treat staphylococcal infections, including those caused by multidrug resistance isolates.

Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5–14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, −0.13%; 95% confidence interval, −6.42%–6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. Clinical Trials Registration: NCT02600611.

The telescoping of allyl-palladium catalyzed ketone dehydrogenation with organocuprate conjugate addition chemistry allows for the introduction of aryl, heteroaryl, vinyl, acyl, methyl, and other functionalized alkyl groups chemoselectively to a wide variety of unactivated ketone compounds via their enone counterparts. The compatibility of the dehydrogenation conditions additionally allows for efficient trapping of the intermediate enolate with various electrophiles. The utility of this approach is demonstrated by comparison to several previously reported multistep sequences.

We report herein general conditions for a zinc-mediated anionic cyclization of unstabilized ketone enolates. This anionic cyclization allows access to various carbocyclic architectures by utilizing abundant ketones and unactivated alkenes as precursors. The transformation is enabled by the use of Zn(TMP)2 as base and Zn(OTf)2 as an additive. The resulting alkylzinc species can be intercepted by electrophiles for tandem C–X and C–O bond formation.

We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam-β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter, including multidrug-resistant and extensively-drug-resistant strains. None of the newer β-lactam-β-lactamase combination drugs showed increased activity compared to that of the older agents against Stenotrophomonas maltophilia or Pandoraea spp.

This manuscript describes the first practical benzylic dehydrogenation of electron-deficient heteroarenes, including pyridines, pyrazines, pyrimidines, pyridazines, and triazines. This transformation allows for the efficient benzylic oxidation of heteroarenes to afford heterocyclic styrenes by the action of nickel catalysis paired with an unconventional bromothiophene oxidant.

The objective of this pilot study was to examine the activity of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, in an in vitro infection model of infection with Toxoplasma gondii. Toxoplasma growth was assessed by enzyme linked immunoassay (ELISA) performed directly on the fixed cultures using a peroxidase labeled monoclonal antibody directed against the SAG-l surface protein of T. gondii. For each well, the results were expressed as optical density (OD) values. Iclaprim inhibited T. gondii growth at concentrations between 0.1 and 10 mg/L; the IC50 was estimated at 0.26 mg/L (95% confidence interval 0.22-0.33). Iclaprim was about 10 times more active than trimethoprim, which had an IC50 of 2.3 mg/L. Iclaprim demonstrated synergistic effects at concentrations of 0.02, 0.05 and 0.1 mg/L when combined with subinhibitory concentrations of sulfamethoxazole (0.1 or 0.02 mg/L). These results show that iclaprim is a potent inhibitor of T. gondii growth in vitro. In addition, iclaprim exhibited synergy in vitro when tested in the presence of sulfamethoxazole. Iclaprim should be further investigated as an agent for the treatment or prophylaxis of toxoplasmosis.

Staphylococcus aureus is the most common non-gonococcal aetiology of septic arthritis. The efficacy of iclaprim against S. aureus LS-1, a clinical strain identified from a patient with septic arthritis, was studied in MF1 mice to evaluate the activity of iclaprim, which is in clinical development, in preventing joint infections. Iclaprim (2.5-80 mg kg- 1) administered as a single dose via the tail vein reduced the incidence of S. aureus septic arthritis and mortality in an experimental murine model of septic arthritis.

Iclaprim is a novel diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 1365 Gram-positive clinical isolates from patients with skin and skin structure infections (SSSI) from the United States, Asia Pacific, Latin America, Europe, Africa or Middle East collected between 2013 and 2017 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. MIC90 for all S.aureus, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Streptococcus pyogenes, S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae and S. intermedius were 0.12, 0.12, 0.5, 0.03, 0.5, ≤0.004, ≤0.004, 0.12, and 0.008 μg/ml, respectively. The MIC for iclaprim was 8 to 32-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. Iclaprim demonstrated lower MICs than trimethoprim against a collection (2013–2017) of Gram-positive clinical isolates from patients with SSSI from the United States, Asia Pacific, Latin America, and Europe.

The incidence and patient outcomes of Staphylococcus aureus isolates by iclaprim MIC was determined among patients from two phase 3 studies for the treatment of acute bacterial skin and skin structure infections (ABSSSI), REVIVE-1 and -2. Iclaprim MIC90 values were 0.12 µg ml-1 for S. aureus (0.12 µg ml-1 against methicillin-sensitive and 0.25 µg ml-1 against methicillin-resistant S. aureus). The incidence of culture confirmed S. aureus isolates among patients with ABSSSI with an iclaprim MIC > 8 µg ml-1 was 2.0 % (16/790). The clinical outcomes varied by MICs for early clinical response (63-100 %), end of therapy response (81-100 %) and the test of cure response (75-100 %). For microbiological outcomes of these infections, the end of therapy response was 80-100 % and the test of cure response was 88-100 %.

In this pilot study, the in vitro antimicrobial activity of iclaprim, a diaminopyrimidine, tested in combination with other antimicrobials against recent and common Gram-positive and Gram-negative respiratory pathogens, was examined by the checkerboard method. The range of minimal inhibitory concentrations (MICs) for iclaprim against all bacteria tested in the study was 0.03 to >128 µg ml−1. Iclaprim exhibited synergy with sulfamethoxazole against 11 of the 16 bacterial strains tested, with mean fractional inhibitory concentration index (FICI) values of 0.2–0.5. Synergy with sulfamethoxazole was demonstrated against all Gram-positive bacteria and selected Gram-negative bacteria. Neither synergy nor antagonism was observed for combinations of iclaprim with ampicillin, meropenem, tetracycline, levofloxacin, aztreonam, piperacillin/tazobactam, colistin, cefepime or gentamicin against any of the bacterial strains tested. The significant reduction in the MIC values observed with the combination of iclaprim and sulfamethoxazole demonstrates that this regimen could be effective against common Gram-positive and selected Gram-negative respiratory bacteria.

Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, β-hemolytic streptococci, and Streptococcus anginosus group, underwent antibacterial susceptibility testing. Iclaprim had an MIC(90) of 0.12 μg/ml for S. aureus (0.12 μg/ml for methicillin susceptible, 0.25 μg/ml for methicillin resistant), 0.25 μg/ml for β-hemolytic streptococci, and 0.008 μg/ml for S. anginosus group. Iclaprim demonstrated potent activity against these Gram-positive ABSSSI isolates.

This report demonstrates the possibility of a nickel-catalyzed difunctionalization of unactivated alkenes initiated by an unstabilized enolate nucleophile. The process tolerates a diverse range of electrophiles, including aryl, heteroaryl, alkenyl, and amino electrophiles. An electron-deficient phosphine ligand and a tetrabutylammonium salt additive were crucial for promoting efficient vicinal difunctionalization.

Iclaprim is a selective bacterial dihydrofolate reductase (DHFR) inhibitor. Although there are alternative options for the treatment of acute bacterial skin and skin structure infections (ABSSSI), iclaprim is differentiated from other available antibiotics. Areas covered: Iclaprim is under clinical development for ABSSSI. This review summarizes the mechanism of action, pharmacokinetics, microbiology, clinical development program, and the differentiation of iclaprim from other antibiotics. Expert commentary: Iclaprim has a different mechanism of action (DHFR inhibitor) compared to most other antibiotics, is active and rapidly bactericidal against Gram-positive pathogens including antibiotic-resistant pathogens, and suppresses bacterial exotoxins (alpha hemolysin, Panton Valentine leukocidin, and toxic shock syndrome toxin-1). Compared to trimethoprim, iclaprim has lower MIC

Objectives The objective of this study was to determine the in vitro activity of iclaprim and comparator agents against 7618 Gram-positive clinical isolates collected in the periods 2004–2006, 2012–2014 and 2015–2016. Methods Antimicrobial susceptibility testing was performed by the broth microdilution method and the minimum inhibitory concentrations (MICs) were interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Results Iclaprim MIC50/MIC90 values were 0.06/0.12 μg/mL for Staphylococcus aureus, including methicillin-susceptible and methicillin-resistant strains, and 0.015/0.03, 0.12/0.5 and 0.03/0.06 μg/mL, respectively, for Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus dysgalactiae over 8 years within the period from 2004 to 2016. Iclaprim was 8–32-fold more potent than trimethoprim. Against S. aureus, including methicillin-resistant strains, iclaprim was more active than standard-of-care intravenous antibiotics used to treat Gram-positive skin infections. Iclaprim was up to 16-fold more potent than vancomycin and linezolid and was 4–8-fold more potent than daptomycin. Conclusions Iclaprim demonstrated potent and consistent activity among Gram-positive clinical isolates collected globally between 2004 and 2016.

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, −5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02607618","term_id":"NCT02607618"}}NCT02607618.)

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is highly active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 2814 Gram-positive clinical isolates from the United States, Asia Pacific, Latin American and Europe collected between 2012 and 2014 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC50/MIC90 for all S. aureus, methicillin susceptible S. aureus, methicillin resistant S. aureus, beta-hemolytic streptococci, and Streptococcus pneumoniae were 0.06/0.12, 0.06/0.12, 0.06/0.5, 0.06/0.25, and 0.06/2 μg/mL, respectively. Iclaprim was 8 to 32-fold more potent than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. The MIC90 of iclaprim was also lower than most of the comparators including linezolid and vancomycin against Gram-positive pathogens. Iclaprim demonstrated potent activity against a contemporary collection (2012–2014) of Gram-positive clinical isolates from the United States, Asia Pacific, Latin America and Europe.

The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against Staphylococcus aureus ATCC 29213 and Staphylococcus pneumoniae ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for S. aureus ( R 2 , 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (% T >MIC) were strongly associated with effect ( R 2 , 0.86 for both parameters) for S. pneumoniae .

Background Opioid addiction in the United States has reached epidemic proportions threatening public health. This analysis evaluates the baseline characteristics and bacterial causes of ABSSSI in patients who were IVDU from two parallel Phase 3 trials comparing the treatment of iclaprim with vancomycin. Methods A total of 621 patients who were IVDU from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed both separately and pooled. This post-hoc analysis summarizes the baseline bacterial causes of ABSSSI identified among IVDU. Per protocol, ABSSSI (major abscesses, cellulitis, or wound infections) were defined as having either the presence of purulent or seropurulent drainage before or after surgical intervention of the wound or at least 3 of the following signs and symptoms: discharge, erythema (extending at least 2 cm beyond the wound edge in any direction), swelling and/or induration, heat and/or localized warmth, and/or pain and/or tenderness to palpation. IVDU was defined based on subjected-reported medical history. At the baseline visit, ABSSSI were sampled for microbiological culture. Cultures were performed locally, and isolates were submitted to the central microbiology laboratory. Results Among IVDU with ABSSSI, average age was 44 years, 67.6% were male, average lesion size was 322 cm2, 10.8% had abnormal renal function (CrCl ≤ 90 mL/minute), and 3.9% had bacteremia. The bacterial causes of ABSSSI among IVDU are shown in the Table. Conclusion IVDU, a growing population, are vulnerable to ABSSSI. S. aureus, including MRSA, and S. anginosus group were the most commonly identified bacterial causes of ABSSSI in patients who are IVDU. Therefore, antibiotic selection should cover these bacteria among IVDU who present with an ABSSSI. Disclosures All authors: No reported disclosures.

An improved protocol for the formal elimination of propene from organic substrates is reported. This process entails the ozonolytic conversion of an alkene to a methoxy hydroperoxide which undergoes fragmentation mediated by copper and iron. The use of soluble Cu(BF4)2 and Fe(BF4)2 results in reproducible results up to a 100 gram scale.

Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC 0–24ss ), AUC/MIC, and time above the MIC during the dosing interval ( T > MIC), while QTc prolongation was associated with the maximal concentration at steady state ( C maxss ) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC 0–24ss , AUC/MIC, and T > MIC while minimizing the probability of a C maxss of ≥800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC 0–24ss , AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a C maxss of ≥800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials.

We report a total synthesis of the pyridine-containing limonoid alkaloid (−)-xylogranatopyridine B in 11 steps from commercially available dihydrocarvone. The central pyridine ring was assembled by a late-stage fragment coupling approach employing a modified Liebeskind pyridine synthesis. One fragment was prepared by an allyl-palladium catalyzed oxidative enone β-stannylation, in which the key bimetallic β-stannyl palladium enolate intermediate undergoes a β-hydride elimination. This methodology also allowed introduction of alkyl and silyl groups to the β-position of enones.

New antibiotics are needed because of the increased morbidity and mortality associated with multidrug-resistant bacteria. Iclaprim, a bacterial dihydrofolate reductase inhibitor, not currently approved, is being studied for the treatment of skin infections and nosocomial pneumonia caused by Gram-positve bacteria, including multidrug-resistant bacteria. Iclaprim showed noninferiority at –10% to linezolid in 1 of 2 phase 3 studies for the treatment of complicated skin and skin structure infections with a weight-based dose (0.8 mg/kg) but did not show noninferiority at –10% to linezolid in a second phase 3 study. More recently, iclaprim has shown noninferiority at –10% to vancomycin in 2 phase 3 studies for the treatment of acute bacterial skin and skin structure infections with an optimized fixed dose (80 mg). A phase 3 study for the treatment of hospital-acquired bacterial and ventilator-associated bacterial pneumonia is upcoming. If, as anticipated, iclaprim becomes available for the treatment of skin and skin structure infections, it will serve as an alternative to current antibiotics for treatment of severe infections. This article will provide an update to the chemistry, preclinical, pharmacology, microbiology, clinical and regulatory status of iclaprim.

Iclaprim is a bacterial dihydrofolate reductase inhibitor in Phase 3 clinical development for the treatment of acute bacterial skin and skin structure infections and hospital-acquired bacterial pneumonia caused by Gram-positive bacteria. Daptomycin, linezolid, and vancomycin are commonly used antibiotics for these indications. With increased selective pressure to these antibiotics, outbreaks of bacterial resistance to these antibiotics have been reported. This in vitro pilot study evaluated the activity of iclaprim against methicillin-resistant Staphylococcus aureus (MRSA) isolates, which were also not susceptible to daptomycin, linezolid, or vancomycin. Iclaprim had an MIC ≤ 1 µg/ml to the majority of MRSA isolates that were nonsusceptible to daptomycin (5 of 7 (71.4%)), linezolid (26 of 26 (100%)), or vancomycin (19 of 28 (66.7%)). In the analysis of time-kill curves, iclaprim demonstrated ≥ 3 log10 reduction in CFU/mL at 4–8 hours for tested strains and isolates nonsusceptible to daptomycin, linezolid, or vancomycin. Together, these data support the use of iclaprim in serious infections caused by MRSA nonsusceptible to daptomycin, linezolid, or vancomycin.

The neutropenic murine thigh infection model was used to define the pharmacokinetic/pharmacodynamic index linked to efficacy of iclaprim against Staphylococcus aureus ATCC 29213 and Staphylococcus pneumoniae ATCC 10813. The 24-h area under the curve (AUC)/MIC index was most closely linked to efficacy for S. aureus (R2, 0.65), while both the 24-h AUC/MIC and the percentage of time that drug concentrations remain above the MIC (%T>MIC) were strongly associated with effect (R2, 0.86 for both parameters) for S. pneumoniae.

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and surveillance data prior to 2006 suggested that iclaprim was active against Gram-positive pathogens including emerging drug-resistant pathogens. In an era of increasing antimicrobial resistance, we undertook testing iclaprim and comparators against 931 Gram-positive clinical isolates from the United States and Europe collected between 2015 and 2016. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing criteria. MIC50/MIC90 was 0.03/0.12 for all Staphylococcus aureus, 0.06/0.06 for methicillin-susceptible S. aureus, 0.03/0.12 for methicillin-resistant S. aureus, 0.12/0.5 for Streptococcus agalactiae, ≤0.015/≤0.015 for Streptococcus anginosus, 0.03/0.06 for Streptococcus dysgalactiae, and ≤0.015 /0.03 μg/mL for Streptococcus pyogenes. Iclaprim was active against a contemporary collection (2015–2016) of Gram-positive bacteria isolated from the skin or soft tissue from patients with SSSI from the United States and Europe.

Pneumocystis pneumonia is a serious complication that may affect immunosuppressed patients. The absence of reliable and safe therapeutic alternatives to trimethoprim–sulfamethoxazole (TMP/SMX) justifies the search for more effective and less toxic agents. In this study, the in vitro and in vivo anti-Pneumocystis jirovecii activity of iclaprim, a diaminopyrimidine compound that exerts its antimicrobial activity through the inhibition of dihydrofolate reductase (DHFR), as does TMP, was evaluated alone or in combination with SMX. The antimicrobial activity of iclaprim was tested in vitro using an efficient axenic culture system, and in vivo using P. carinii endotracheally inoculated corticosteroid-treated rats. Animals were orally administered iclaprim (5, 25, 50 mg/kg/day), iclaprim/SMX (5/25, 25/125, 50/250 mg/kg/day), TMP (50 mg/kg/day), or TMP/SMX (50/250 mg/kg/day) once a day for ten consecutive days. The in vitro maximum effect (Emax) and the drug concentrations needed to reach 50% of Emax (EC50) were determined, and the slope of the dose–response curve was estimated by the Hill equation (Emax sigmoid model). The iclaprim EC50 value was 20.3 μg/mL. This effect was enhanced when iclaprim was combined with SMX (EC50: 13.2/66 μg/mL) (p = 0.002). The TMP/SMX EC50 value was 51.4/257 μg/mL. In vivo, the iclaprim/SMX combination resulted in 98.1% of inhibition compared to TMP/SMX, which resulted in 86.6% of inhibition (p = 0.048). Thus, overall, the iclaprim/SMX combination was more effective than TMP/SMX both in vitro and in vivo, suggesting that it could be an alternative therapy to the TMP/SMX combination for the treatment of Pneumocystis pneumonia.