Posts filed under ‘Antimicrobianos’

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

Efficacy and accuracy of qSOFA and SOFA scores as prognostic tools for community-acquired and healthcare-associated pneumonia

International Journal of Infectious Diseases July 2019 V.84 P.89-96

Nobuhiro Asai, Hiroki Watanabe, Arufumi Shiota, Hideo Kato, Daisuke Sakanashi, Mao Hagihara, Yusuke Koizumi, Yuka Yamagishi, Hiroyuki Suematsu, Hiroshige Mikamo

Highlights

  • The Japanese Respiratory Society recently updated the prognostic guidelines for pneumonia in 2017.
  • The new guidelines recommend that pneumonia severity be evaluated using the sequential organ failure assessment (SOFA) and the quick SOFA (qSOFA) scoring systems in a therapeutic strategy flowchart.
  • The combination of qSOFA and SOFA score could be an independent prognostic factor for 30-day mortality among patients with community-onset pneumonia.

Background

The Japanese Respiratory Society recently updated its prognostic guidelines for pneumonia, recommending that pneumonia severity be evaluated using the sequential organ failure assessment (SOFA) and quick SOFA (qSOFA) scoring systems in a therapeutic strategy flowchart. However, the efficacy and accuracy of these tools are still unknown.

Methods

All patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) who were admitted to the study institution between 2014 and 2017 were enrolled in this study. Pneumonia severity on admission was evaluated by A-DROP, CURB-65, PSI, I-ROAD, qSOFA, and SOFA scoring systems. Prognostic factors for 30-day mortality were also analyzed.

Results

This study included 406 patients, 257 male (63%) and 149 female (37%). The median age was 79 years (range 19–103 years). The 30-day and in-hospital mortality rates were both 5%. With respect to the diagnostic value of the predictive assessments for 30-day mortality, the area under the receiver operating characteristic curve (AUROC) value for the SOFA score was 0.769 for CAP patients and 0.774 for HCAP patients. Further, the AUROC values for the SOFA score in CAP and HCAP patients with a qSOFA score ≥2 were 0.829 and 0.784, respectively, for 30-day mortality.

Conclusions

qSOFA and SOFA scores were able to correctly evaluate the severity of CAP and HCAP.

FULL TEXT

https://www.ijidonline.com/article/S1201-9712(19)30190-0/fulltext

PDF

https://www.ijidonline.com/article/S1201-9712(19)30190-0/pdf

June 30, 2019 at 9:25 pm

Antibiotic penetration into bone and joints: An updated review

International Journal of Infectious Diseases April 2019 V.81 N.4 P.128-136

Abrar K. Thabit, Dania F. Fatani, Maryam S. Bamakhrama, Ola A. Barnawi, Lana O. Basudan, Shahad F. Alhejaili

Highlights

  • Despite the rigid structure of bone, many antibiotics demonstrated a good penetration profile.
  • Diffusion into synovial fluid was exhibited by many antibiotics despite their variation in pharmacokinetic properties.
  • Only penicillin, flucloxacillin, and metronidazole showed lower than optimum penetration profiles.
  • Antibiotics with good penetration profiles in bone and joints represent potential options for the treatment of osteomyelitis and septic arthritis.

Treatment of bone and joint infections can be challenging as antibiotics should penetrate through the rigid bone structure and into the synovial space. Several pharmacokinetic studies measured the extent of penetration of different antibiotics into bone and joint tissues. This review discusses the results of these studies and compares them with minimum inhibitory concentrations (MIC) of common pathogens implicated in bone and joint infections in order to determine which antibiotics may have a greater potential in the treatment of such infections. Clinical outcomes were also evaluated as data were available. More than 30 antibiotics were evaluated. Overall, most antibiotics, including amoxicillin, piperacillin/tazobactam, cloxacillin, cephalosporins, carbapenems, aztreonam, aminoglycosides, fluoroquinolones, doxycycline, vancomycin, linezolid, daptomycin, clindamycin, trimethoprim/sulfamethoxazole, fosfomycin, rifampin, dalbavancin, and oritavancin, showed good penetration into bone and joint tissues reaching concentrations exceeding the MIC90 and/or MIC breakpoints of common bone and joint infections pathogens. Few exceptions include penicillin and metronidazole which showed a lower than optimum penetration into bones, and the latter as well as flucloxacillin had poor profiles in terms of joint space penetration. Of note, studies on joint space penetration were fewer than studies on bone tissue penetration. Although clinical studies in osteomyelitis and septic arthritis are not available for all of the evaluated antibiotics, these pharmacokinetic results indicate that agents with good penetration profiles would have a potential utilization in such infections.

FULL TEXT

https://www.ijidonline.com/article/S1201-9712(19)30069-4/fulltext

PDF

https://www.ijidonline.com/article/S1201-9712(19)30069-4/pdf

June 30, 2019 at 12:23 pm

Group B Streptococcus in surgical site and non-invasive bacterial infections worldwide: A systematic review and meta-analysis

International Journal of Infectious Diseases June 2019 V.83 P.116-129

Simon M. Collin, Nandini Shetty, Rebecca Guy, Victoria N. Nyaga, Ann Bull, Michael J. Richards, Tjallie I.I. van der Kooi, Mayke B.G. Koek, Mary De Almeida, Sally A. Roberts, Theresa Lamagni

Highlights

  • This review obtained data on group B Streptococcus infection from 67 countries.
  • Group B Streptococcus is implicated in a small proportion of non-invasive infections.
  • Group B Streptococcus causes 10% of caesarean section invasive surgical infections.

Objectives

The epidemiology of disease caused by group B Streptococcus (GBS; Streptococcus agalactiae) outside pregnancy and the neonatal period is poorly characterized. The aim of this study was to quantify the role of GBS as a cause of surgical site and non-invasive infections at all ages.

Methods

A systematic review (PROSPERO CRD42017068914) and meta-analysis of GBS as a proportion (%) of bacterial isolates from surgical site infection (SSI), skin/soft tissue infection (SSTI), urinary tract infection (UTI), and respiratory tract infection (RTI) was conducted.

Results

Seventy-four studies and data sources were included, covering 67 countries. In orthopaedic surgery, GBS accounted for 0.37% (95% confidence interval (CI) 0.08–1.68%), 0.87% (95% CI 0.33–2.28%), and 1.46% (95% CI 0.49–4.29%) of superficial, deep, and organ/space SSI, respectively. GBS played a more significant role as a cause of post-caesarean section SSI, detected in 2.92% (95% CI 1.51–5.55%), 1.93% (95% CI 0.97–3.81%), and 9.69% (95% CI 6.72–13.8%) of superficial, deep, and organ/space SSI. Of the SSTI isolates, 1.89% (95% CI 1.16–3.05%) were GBS. The prevalence of GBS in community and hospital UTI isolates was 1.61% (1.13–2.30%) and 0.73% (0.43–1.23%), respectively. GBS was uncommonly associated with RTI, accounting for 0.35% (95% CI 0.19–0.63%) of community and 0.27% (95% CI 0.15–0.48%) of hospital RTI isolates.

Conclusions

GBS is implicated in a small proportion of surgical site and non-invasive infections, but a substantial proportion of invasive SSI post-caesarean section.

FULL TEXT

https://www.ijidonline.com/article/S1201-9712(19)30187-0/fulltext

PDF

https://www.ijidonline.com/article/S1201-9712(19)30187-0/pdf

 

 

June 30, 2019 at 12:21 pm

Pyoderma gangrenosum – a guide to diagnosis and management.

Clin Med (Lond). May 2019 V.19 N.3 P.224-228.       

George C1, Deroide F2, Rustin M2.

1 Royal Free Hospital, London, UK cgeorge2@nhs.net.

2 Royal Free Hospital, London, UK.

Abstract

Pyoderma gangrenosum (PG) is a reactive non-infectious inflammatory dermatosis falling under the spectrum of the neutrophilic dermatoses.

There are several subtypes, with ‘classical PG’ as the most common form in approximately 85% cases. This presents as an extremely painful erythematous lesion which rapidly progresses to a blistered or necrotic ulcer.

There is often a ragged undermined edge with a violaceous/erythematous border. The lower legs are most frequently affected although PG can present at any body site.

Other subtypes include bullous, vegetative, pustular, peristomal and superficial granulomatous variants.

The differential diagnosis includes all other causes of cutaneous ulceration as there are no definitive laboratory or histopathological criteria for PG.

Underlying systemic conditions are found in up to 50% of cases and thus clinicians should investigate thoroughly for such conditions once a diagnosis of PG has been made.

Treatment of PG remains largely anecdotal, with no national or international guidelines, and is selected according to severity and rate of progression.

Despite being a well-recognised condition, there is often a failure to make an early diagnosis of PG.

This diagnosis should be actively considered when assessing ulcers, as prompt treatment may avoid the complications of prolonged systemic therapy, delayed wound healing and scarring.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542232/pdf/clinmed-19-3-224.pdf

June 27, 2019 at 8:18 am

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