Posts filed under ‘Resistencia bacteriana’

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

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

CIM City: the Game Continues for a Better Carbapenemase Test

Clin. Microbiol. July 2019 V.57 N.7 P.1-5

The Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing agree that carbapenemase testing is not necessary for clinical care, provided that the laboratory is up to date with current breakpoints. Nonetheless, publication on the development and modification of carbapenemase tests continues, as is the case in this issue of the Journal of Clinical Microbiology (R. W. Beresford and M. Maley, J Clin Microbiol 57:e01852-18, 2019, https://doi.org/10.1128/JCM.01852-18). This commentary explores modifications to the carbapenem inactivation method—but is this the right focus for clinical laboratories?

PDF

https://jcm.asm.org/content/jcm/57/7/e00353-19.full.pdf

June 26, 2019 at 4:19 pm

Gentamicin as an alternative treatment for gonorrhoea

LANCET June 22, 2019 V.393 N.10190 P.2474-2475

COMMENT

A high gonorrhoea disease burden, increasing rates, and growing antimicrobial resistance portend a developing global public health crisis.1 Gonorrhoea can cause reproductive complications such as pelvic inflammatory disease and infertility, blindness in infants born to infected mothers, and can facilitate HIV acquisition and transmission. Effective treatment prevents sequelae and transmission. Yet Neisseria gonorrhoeae has developed resistance to each antimicrobial used for treatment.2 Development of new antimicrobials has not kept pace…..

FULL TEXT

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30244-2/fulltext?dgcid=raven_jbs_etoc_email

PDF

https://www.thelancet.com/action/showPdf?pii=S0140-6736%2819%2930244-2

 

LANCET June 22, 2019 V.393 N.10190 P.2511-2520

Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial

Background

Gonorrhoea is a common sexually transmitted infection for which ceftriaxone is the current first-line treatment, but antimicrobial resistance is emerging. The objective of this study was to assess the effectiveness of gentamicin as an alternative to ceftriaxone (both combined with azithromycin) for treatment of gonorrhoea.

Methods

G-ToG was a multicentre, parallel-group, pragmatic, randomised, non-inferiority trial comparing treatment with gentamicin to treatment with ceftriaxone for patients with gonorrhoea. The patients, treating physician, and assessing physician were masked to treatment but the treating nurse was not. The trial took place at 14 sexual health clinics in England. Adults aged 16–70 years were eligible for participation if they had a diagnosis of uncomplicated genital, pharyngeal, or rectal gonorrhoea. Participants were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (gentamicin group) or ceftriaxone 500 mg (ceftriaxone group). All participants also received a single 1 g dose of oral azithromycin. Randomisation (1:1) was stratified by clinic and performed using a secure web-based system. The primary outcome was clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post treatment. Primary outcome analyses included only participants who had follow-up data, irrespective of the baseline visit N gonorrhoeae test result. The margin used to establish non-inferiority was a lower confidence limit of 5% for the risk difference. This trial is registered with ISRCTN, number ISRCTN51783227.

Findings

Of 1762 patients assessed, we enrolled 720 participants between Oct 7, 2014, and Nov 14, 2016, and randomly assigned 358 to gentamicin and 362 to ceftriaxone. Primary outcome data were available for 306 (85%) of 362 participants allocated to ceftriaxone and 292 (82%) of 358 participants allocated to gentamicin. At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6·4%, 95% CI −10·4% to −2·4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference −4·4%, −8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15·3%, −24·0 to −6·5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7·8%, −13·6 to −2·0). Thus, we did not find that a single dose of gentamicin 240 mg was non-inferior to a single dose of ceftriaxone 500 mg for the treatment of gonorrhoea, when both drugs were combined with a 1 g dose of oral azithromycin. The side-effect profiles were similar between groups, although severity of pain at the injection site was higher for gentamicin (mean visual analogue pain score 36 of 100 in the gentamicin group vs 21 of 100 in the ceftriaxone group).

Interpretation

Gentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea.

Funding

UK National Institute for Health Research.

FULL TEXT

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32817-4/fulltext?dgcid=raven_jbs_etoc_email

PDF

https://www.thelancet.com/action/showPdf?pii=S0140-6736%2818%2932817-4

 

 

June 22, 2019 at 7:59 pm

Reduced rate of intensive care unit acquired gram-negative bacilli after removal of sinks and introduction of ‘water-free’ patient care.

Antimicrob Resist Infect Control. June 2017 V.6 P.59.

Hopman J#1, Tostmann A#1, Wertheim H1, Bos M1, Kolwijck E1, Akkermans R2, Sturm P1,3, Voss A1,4, Pickkers P5, Vd Hoeven H5.

Abstract

BACKGROUND:

Sinks in patient rooms are associated with hospital-acquired infections. The aim of this study was to evaluate the effect of removal of sinks from the Intensive Care Unit (ICU) patient rooms and the introduction of ‘water-free’ patient care on gram-negative bacilli colonization rates.

METHODS:

We conducted a 2-year pre/post quasi-experimental study that compared monthly gram-negative bacilli colonization rates pre- and post-intervention using segmented regression analysis of interrupted time series data. Five ICUs of a tertiary care medical center were included. Participants were all patients of 18 years and older admitted to our ICUs for at least 48 h who also received selective digestive tract decontamination during the twelve month pre-intervention or the twelve month post-intervention period. The effect of sink removal and the introduction of ‘water-free’ patient care on colonization rates with gram-negative bacilli was evaluated. The main outcome of this study was the monthly colonization rate with gram-negative bacilli (GNB). Yeast colonization rates were used as a ‘negative control’. In addition, colonization rates were calculated for first positive culture results from cultures taken ≥3, ≥5, ≥7, ≥10 and ≥14 days after ICU-admission, rate ratios (RR) were calculated and differences tested with chi-squared tests.

RESULTS:

In the pre-intervention period, 1496 patients (9153 admission days) and in the post-intervention period 1444 patients (9044 admission days) were included. Segmented regression analysis showed that the intervention was followed by a statistically significant immediate reduction in GNB colonization in absence of a pre or post intervention trend in GNB colonization. The overall GNB colonization rate dropped from 26.3 to 21.6 GNB/1000 ICU admission days (colonization rate ratio 0.82; 95%CI 0.67-0.99; P = 0.02). The reduction in GNB colonization rate became more pronounced in patients with a longer ICU-Length of Stay (LOS): from a 1.22-fold reduction (≥2 days), to a 1.6-fold (≥5 days; P = 0.002), 2.5-fold (for ≥10 days; P < 0.001) to a 3.6-fold (≥14 days; P < 0.001) reduction.

CONCLUSIONS:

Removal of sinks from patient rooms and introduction of a method of ‘water-free’ patient care is associated with a significant reduction of patient colonization with GNB, especially in patients with a longer ICU length of stay.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466749/pdf/13756_2017_Article_213.pdf

June 3, 2019 at 6:20 pm

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