Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Usefulness of previous methicillin-resistant Staphylococcus aureus screening results in guiding empirical therapy for S aureus bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is an important infection. Methicillin-resistant S aureus (MRSA) screening is performed on hospitalized patients for infection control purposes. OBJECTIVE: To assess the usefulness of past MRSA screening for guiding empirical antibiotic therapy for SAB. METHODS: A retrospective cohort study examined consecutive patients with confirmed SAB and previous MRSA screening swab from six academic and community hospitals between 2007 and 2010. Diagnostic test properties were calculated for MRSA screening swab for predicting methicillin resistance of SAB. RESULTS: A total of 799 patients underwent MRSA screening swabs before SAB. Of the 799 patients, 95 (12%) had a positive and 704 (88%) had a negative previous MRSA screening swab. There were 150 (19%) patients with MRSA bacteremia. Overall, previous MRSA screening swabs had a positive likelihood ratio of 33 (95% CI 18 to 60) and a negative likelihood ratio of 0.45 (95% CI 0.37 to 0.54). Diagnostic accuracy differed depending on mode of acquisition (ie, community-acquired, nosocomial or health care-associated infection) (P<0.0001) and hospital (P=0.0002). At best, for health care-associated infection, prior MRSA screening swab had a positive likelihood ratio of 16 (95% CI 9 to 28) and a negative likelihood ratio of 0.27 (95% CI 0.17 to 0.41). CONCLUSIONS: A negative prior MRSA screening swab cannot reliably rule out MRSA bacteremia and should not be used to guide empirical antibiotic therapy for SAB. A positive prior MRSA screening swab greatly increases likelihood of MRSA, necessitating MRSA coverage in empirical antibiotic therapy for SAB.

HISTORIQUE: La bactériémie à Staphylococcus aureus (BSA) est une infection grave. Les patients hospitalisés subissent un dépistage du S. aureus résistant à la méthicilline (SARM) afin de prévenir les infections. OBJECTIF: Évaluer l'utilité d'un dépistage antérieur du SARM pour orienter l'antibiothérapie empirique de la BSA. MÉTHODOLOGIE: Les chercheurs ont effectué une étude de cohorte rétrospective dans six hôpitaux universitaires et hôpitaux généraux entre 2007 et 2010 auprès de patients consécutifs atteints d'une BSA confirmée ayant déjà subi un prélèvement de dépistage du SARM. Ils ont calculé les propriétés des tests diagnostiques par prélèvement pour diagnostiquer le SARM et prédire la résistance de la BSA à la méthicilline. RÉSULTATS: Au total, 799 patients avaient déjà subi des prélèvements pour dépister le SARM avant une BSA. De ce nombre, 95 (12 %) ont présenté un résultat positif et 704 (88 %) avaient déjà subi un prélèvement pour dépister le SARM. Cent cinquante patients (19 %) avaient une bactériémie à SARM. Dans l'ensemble, les prélèvements antérieurs pour dépister le SARM avaient un ratio de probabilité positif de 33 (95 % IC 18 à 60) et négatif de 0,45 (95 % IC 0,37 à 0,54). La précision diagnostique différait en fonction du mode d'acquisition (origine non nosocomiale, origine nosocomiale ou association aux soins de santé) (P<0,0001) et de l'hôpital (P=0,0002). Dans le meilleur des cas, en présence d'une infection associée aux soins de santé, un prélèvement antérieur pour dépister un SARM s'associait à un ratio de probabilité positif de 16 (95 % IC 9 à 28) et négatif de 0,27 (95 % IC 0,17 à 0,41). CONCLUSIONS: Un prélèvement antérieur négatif au SARM ne permet pas d'écarter une bactériémie par le SARM avec fiabilité et ne devrait pas orienter l'antibiothérapie empirique de la BSA. Un prélèvement antérieur positif au SARM accroît considérablement la probabilité de SARM, ce qui oblige à en tenir compte pour l'antibiothérapie empirique de la BSA.

Use of Transthoracic Echocardiography in the Management of Low-Risk Staphylococcus aureus Bacteremia: Results From a Retrospective Multicenter Cohort Study.

OBJECTIVES: The aim of this study was to develop a prediction model to identify patients with low-risk Staphylococcus aureus bacteremia (SAB), in whom infective endocarditis (IE) can be ruled out based on transthoracic echocardiogram (TTE). BACKGROUND: S. aureus is a major cause of bacteremia and often leads to IE. Current guidelines recommend performing transesophageal echocardiography on all patients or treating all patients empirically with prolonged intravenous antibiotics; however, this approach is resource intensive, many physicians do not adhere to guidelines, and recent studies suggest that low-risk patients may not require transesophageal echocardiography. METHODS: We conducted a retrospective cohort study of 833 consecutive hospitalized patients with SAB from 7 academic and community hospitals in Toronto, Canada, over a 3-year period (2007 to 2010). Patients who received a TTE within 28 days of bacteremia (n = 536) were randomly divided into derivation and validation cohorts. Multivariable logistic regression analysis was used to determine high-risk criteria for IE in the derivation cohort, and criteria were then applied to the validation cohort to determine diagnostic properties. RESULTS: Four high-risk criteria predicted IE: indeterminate or positive TTE (p < 0.001), community-acquired bacteremia (p = 0.034), intravenous drug use (p < 0.001), and high-risk cardiac condition (p < 0.004). In the validation cohort, the presence of any 1 of the high-risk criteria had 97% sensitivity (95% confidence interval [CI]: 87% to 100%) and 99% negative predictive value (95% CI: 96% to 100%) for IE. The negative likelihood ratio was 0.05 (95% CI: 0.007 to 0.35). CONCLUSIONS: A normal TTE ruled out IE in patients without community-acquired SAB, high-risk cardiac conditions, and intravenous drug use. This study provides evidence that clinical risk stratification combined with a normal TTE may be adequate to rule out IE in most patients with SAB.

Impact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study.

BACKGROUND: We assessed the impact of infectious disease (ID) consultation on management and outcome in patients with Staphylococcus aureus bacteremia (SAB). METHODS: A retrospective cohort study examined consecutive SAB patients from 6 academic and community hospitals between 2007 and 2010. Quality measures of management including echocardiography, repeat blood culture, removal of infectious foci, and antibiotic therapy were compared between ID consultation (IDC) and no ID consultation (NIDC) groups. A competing risk model with propensity score adjustment was used to compare in-hospital mortality and time to discharge. RESULTS: Of 847 SAB patients, 506 (60%) patients received an ID consultation and 341 (40%) patients did not. Echocardiography was done for 371 (73%) IDC and 191 (56%) NIDC patients (P < .0001) in hospital. Blood cultures were repeated within 2-4 days of bacteremia in 207 (41%) IDC and 107 (31%) NIDC patients (P = .0058). The infectious foci removal rate was not statistically different between the 2 groups. For empiric therapy, 474 (94%) IDC and 297 (87%) NIDC patients received appropriate antibiotics (P = .0013). For patients who finished the planned course of antibiotics, 285 of 422 (68%) IDC and 141 of 262 (54%) NIDC patients received the appropriate duration of antibiotic therapy (P = .0004). In hospital, 204 (24%) patients died: 104 of 506 (21%) IDC and 100 of 341 (29%) NIDC patients. Matched by propensity score, ID consultation had a subdistribution hazard ratio of 0.72 (95% confidence interval [CI], .52-.99; P = .0451) for in-hospital mortality and 1.28 (95% CI, 1.06-1.56; P = .0109) for being discharged alive. CONCLUSIONS: ID consultation is associated with better adherence to quality measures, reduced in-hospital mortality, and earlier discharge in patients with SAB.

Comparative effectiveness of cefazolin versus cloxacillin as definitive antibiotic therapy for MSSA bacteraemia: results from a large multicentre cohort study.

OBJECTIVES: We compared the effectiveness of cefazolin versus cloxacillin in the treatment of MSSA bacteraemia in terms of mortality and relapse. METHODS: A retrospective cohort study examined consecutive patients with Staphylococcus aureus bacteraemia from six academic and community hospitals between 2007 and 2010. Patients with MSSA bacteraemia who received cefazolin or cloxacillin as the predominant definitive antibiotic therapy were included in the study. Ninety-day mortality was compared between the two groups matched by propensity scores. RESULTS: Of 354 patients included in the study, 105 (30%) received cefazolin and 249 (70%) received cloxacillin as the definitive antibiotic therapy. In 90 days, 96 (27%) patients died: 21/105 (20%) in the cefazolin group and 75/249 (30%) in the cloxacillin group. Within 90 days, 10 patients (3%) had a relapse of S. aureus infection: 6/105 (6%) in the cefazolin group and 4/249 (2%) in the cloxacillin group. All relapses in the cefazolin group were related to a deep-seated infection. Based on the estimated propensity score, 90 patients in the cefazolin group were matched with 90 patients in the cloxacillin group. In the propensity score-matched groups, cefazolin had an HR of 0.58 (95% CI 0.31-1.08, P = 0.0846) for 90 day mortality. CONCLUSIONS: There was no significant clinical difference between cefazolin and cloxacillin in the treatment of MSSA bacteraemia with respect to mortality. Cefazolin was associated with non-significantly more relapses compared with cloxacillin, especially in deep-seated S. aureus infections.

Effect of counterion structure on rates and diastereoselectivities in α,ß-unsaturated iminium-ion Diels-Alder reactions.

The use of cyclic α,ß-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

A case of remote asymmetric induction in the peptide-catalyzed desymmetrization of a bis(phenol).

We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.

Remote desymmetrization at near-nanometer group separation catalyzed by a miniaturized enzyme mimic.

The chirality of biological receptors often requires syntheses of therapeutic compounds in single enantiomer form. The field of asymmetric catalysis addresses enantioselective synthesis with chiral catalysts. Chemical differentiation of sites within molecules that are separated in space by long distances presents special challenges to chiral catalysts. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity for the catalyst. The extreme of catalyst complexity could be defined by macromolecular enzymes and their amazing capacity to effect stereospecific reactions over long distances between reactive sites and enzyme-substrate contacts. We report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a very long distance.