Intrapulmonary Pharmacokinetics of Relebactam, a Novel β-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects.

Antimicrob Agents Chemother. February 23, 2018 V.62 N.3

Rizk ML1, Rhee EG2, Jumes PA2, Gotfried MH3, Zhao T2, Mangin E2, Bi S2, Chavez-Eng CM2, Zhang Z2, Butterton JR2.

Abstract

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel β-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem-cilastatin, given intravenously every 6 h for 5 doses, and were randomized to bronchoscopy/bronchoalveolar lavage at 0.5, 1, 1.5, or 3 h after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem. The exposure (area under the concentration-time curve from time zero to infinity) in ELF relative to that in plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture its behavior in plasma, with a partitioning coefficient capturing its behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 55%, based on free drug levels. These results support the clinical evaluation of relebactam with imipenem-cilastatin for the treatment of bacterial pneumonia.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826112/pdf/e01411-17.pdf

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July 21, 2019 at 2:45 pm

REVIEW – New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?

Clin Microbiol Infect. October 2017 V.23 N.10 P.704-712.

Wright H1, Bonomo RA2, Paterson DL3.

Abstract

BACKGROUND:

Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made.

AIMS:

This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms.

SOURCES:

A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies.

CONTENT:

Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline.

IMPLICATIONS:

The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.

FULL TEXT

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30495-0/fulltext

PDF

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30495-0/pdf

July 21, 2019 at 2:43 pm

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics.

Antimicrob Agents Chemother. June 24, 2019 V.63 N.7  pii: e00496-19.

Ersoy SC1, Abdelhady W1, Li L1, Chambers HF2, Xiong YQ3,4, Bayer AS1,4.

1 Los Angeles Biomedical Research Institute, Torrance, California, USA.

2 Division of Infectious Diseases, Zuckerberg San Francisco General Department of Medicine, San Francisco School of Medicine, University of California, San Francisco, California, USA.

3 Los Angeles Biomedical Research Institute, Torrance, California, USA yxiong@ucla.edu .

4 Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Abstract

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE).

Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens.

In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied.

We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive).

These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam.

Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains.

Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media.

These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.

FULL TEXT

https://aac.asm.org/content/63/7/e00496-19.long

PDF

https://aac.asm.org/content/aac/63/7/e00496-19.full.pdf

July 18, 2019 at 8:59 am

Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype

J Virus Erad April 2019  5:73

Zaunders J et al.

Background

Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3′ long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual.

Methods

PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro.

Results

PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5.

Conclusions

Subject C135’s early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

FULL TEXT

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543488/pdf/jve-5-73.pdf

July 16, 2019 at 8:46 am

CLINICAL PRACTICE – Measles

New England J of Medicine July 11, 2019

P.M. Strebel and W.A. Orenstein

A 38-year-old man presents to his primary care physician with a 3-day history of fever and cough. He is a father of two children, his wife is pregnant, and he has a history of recent travel outside the United States. The physical examination is notable for a body temperature of 39°C, conjunctivitis, and rhonchi on chest auscultation. The physician suspects bronchitis and prescribes antibiotic agents. Two days later, the patient returns with a red blotchy rash over his face and trunk. The physician becomes concerned about the possibility of measles. How should this case be further evaluated and managed? How might measles have been prevented, and what can be done to prevent the spread of the disease within the patient’s family and community? …..

FULL TEXT

https://www.nejm.org/doi/full/10.1056/NEJMcp1905181?query=TOC

PDF

https://www.nejm.org/doi/pdf/10.1056/NEJMcp1905181?articleTools=true

July 11, 2019 at 3:54 pm

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice.

Nat Commun. July 2, 2019 V.10 N.1 P.2753.

Dash PK1, Kaminski R2, Bella R2, Su H1, Mathews S1, Ahooyi TM2, Chen C2, Mancuso P2, Sariyer R2, Ferrante P2, Donadoni M2, Robinson JA2, Sillman B1, Lin Z1, Hilaire JR1, Banoub M1, Elango M1, Gautam N3, Mosley RL1, Poluektova LY1, McMillan J1, Bade AN1, Gorantla S1, Sariyer IK2, Burdo TH2, Young WB2, Amini S2, Gordon J2, Jacobson JM2, Edagwa B1, Khalili K4, Gendelman HE5.

Author information

1 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

2 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA.

3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

4 Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19115, USA. kamel.khalili@temple.edu.

5 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA. hegendel@unmc.edu.

Abstract

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice.

HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests.

No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus.

In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606613/pdf/41467_2019_Article_10366.pdf

July 9, 2019 at 6:57 pm

Long-term outcomes in a large randomized trial of HIV-1 salvage therapy: 96-week results of AIDS Clinical Trials Group A5241 (OPTIONS).

Journal of Infectious Diseases May 28, 2019  [e-pub].

Gandhi RT et al

Background

Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain.

Methods

Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs.

Results

At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96.

Conclusions

HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression.

Clinical Trials Registration NCT00537394.

FULL TEXT

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz281/5499329

PDF (CLIC en PDF))

July 2, 2019 at 3:11 pm

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