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      Characteristics of gram-negative urinary tract infections caused by extended spectrum beta lactamases: pivmecillinam as a treatment option within South Dublin, Ireland

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          Abstract

          Background

          The prevalence of urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae is increasing and the therapeutic options are limited, especially in primary care. Recent indications have suggested pivmecillinam to be a suitable option. This pilot study aimed to assess the viability of pivmecillinam as a therapeutic option in a Dublin cohort of mixed community and healthcare origin.

          Methods

          A prospective measurement of mean and fractional inhibitory concentrations of antibiotic use in 95 patients diagnosed with UTI caused by ESBL-producing Enterobacteriaceae was carried out. 36 % patients were from general practice, 40 % were admitted to hospital within south Dublin, and 25 % samples arose from nursing homes. EUCAST breakpoints were used to determine if an isolate was sensitive or resistant to antibiotic agents.

          Results

          Sixty-nine percent of patients ( N = 66) with urinary ESBL isolates were female. The mean age of females was 66 years compared with a mean age of 74 years for males. Thirty-six percent of isolates originated from primary care, hospital inpatients (26 %), and nursing homes (24 %). The vast majority of ESBL isolates were E. coli (80 %). The E tests for mecillinam and co-amoxiclav had concentration ranges from 0.16 mg/L up to 256 mg/L. The mean inhibitory concentration (MIC) of mecillinam ranged from 0.25 to 256 mg/L, while co-amoxiclav MICs ranged from 6 to 256 mg/L. The percentage of isolates resistant to mecillinam and co-amoxiclav was found to be 5.26 and 94.74 % respectively.

          Conclusions

          This is the first study exploring the use of pivmecillinam in an Irish cohort and has demonstrated that its use in conjunction with or without co-amoxiclav is an appropriate and useful treatment for urinary tract infections caused by ESBL-producing organisms.

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          Most cited references36

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          Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

          Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.
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            Carbapenems: past, present, and future.

            In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
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              Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test.

              An in vitro method of detecting synergy which is simple to perform, accurate, and reproducible and has the potential for clinical extrapolation is desirable. Time-kill and checkerboard methods are the most widely used techniques to assess synergy but are time-consuming and labor-intensive. The Epsilometer test (E test), a less technically demanding test, has not been well studied for synergy testing. We performed synergy testing of Escherichia coli ATCC 35218, Enterobacter cloacae ATCC 23355, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 29213 with various combinations of cefepime or ceftazidime with tobramycin or ciprofloxacin using time-kill, checkerboard, and E test techniques. Time-kill testing was performed against each organism alone and in combinations at one-fourth times the MIC (1/4 x MIC) and 2 x MIC. With checkerboard tests, the same combinations were studied at concentrations ranging from 1/32 x to 4 x MIC. Standard definitions for synergy, indifference, and antagonism were utilized. E test strips were crossed at a 90 degree angle so the scales met at the MIC of each drug alone, and the fractional inhibitory concentrations index was calculated on the basis of the resultant zone on inhibition. All antimicrobial combinations demonstrated some degree of synergy against the test organisms, and antagonism was infrequent. Agreement with time-kill testing ranged from 44 to 88% and 63 to 75% by the checkerboard and E test synergy methods, respectively. Despite each of these methods utilizing different conditions and endpoints, there was frequent agreement among the methods. Further comparisons of the E test synergy technique with the checkerboard and time-kill methods are warranted.
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                Author and article information

                Contributors
                fokelly@rcsi.ie
                siobhan.kavanagh@amnch.ie
                rustom.manecksha@amnch.ie
                marjorie.whiteflynn@amnch.ie
                +353-1-4143920 , jfennell@tcd.ie , jerome.fennell@amnch.ie
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                3 November 2016
                3 November 2016
                2016
                : 16
                : 620
                Affiliations
                [1 ]Department of Clinical Microbiology, AMNCH, Tallaght Hospital, Dublin 24, Ireland
                [2 ]Department of Urological Surgery, AMNCH, Tallaght Hospital, Dublin 24, Ireland
                Article
                1797
                10.1186/s12879-016-1797-3
                5093942
                27806687
                75e49420-3ebe-4a84-b621-a3c6fa599ac9
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 September 2015
                : 23 August 2016
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Infectious disease & Microbiology
                extended-spectrum beta lactamase,pivmecillinam,antibiotic resistance,urinary tract infection,mean inhibitory concentration,escherichia coli

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