Clinical Outcomes of Drug-resistant Shigellosis Treated With Azithromycin in Bangladesh

2020 ◽  
Author(s):  
Eric R Houpt ◽  
Tahsin Ferdous ◽  
Rifat Ara ◽  
Momena Ibrahim ◽  
Md Masud Alam ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Susceptibility Testing ◽  
Shigella Flexneri ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Primary Analysis ◽  
In Vitro Susceptibility ◽  
Culture Positivity ◽  
Clinical Breakpoints

Abstract Background Azithromycin is frequently used to treat shigellosis; however, clinical outcomes are uncertain. Methods We performed an observational cohort study in Bangladesh of patients with invasive diarrhea treated empirically with azithromycin. Susceptibility testing was performed by broth microdilution and disk diffusion post hoc on all Shigella isolates and clinical response was correlated with in vitro susceptibility. Results There were 149 Shigella culture-positive patients in the primary analysis. Infection with Shigella with decreased susceptibility to azithromycin was significantly associated with persistence of diarrhea at day 5 (31% vs 12%; relative risk [RR], 2.66; 95% confidence interval [CI], 1.34–5.28), culture positivity at day 5 or 6 (35% vs 5%; RR, 5.26; 95% CI, 1.84–14.85), and a higher rate of overnight hospitalization (58% vs 39%; RR, 1.49; 95% CI, 1.06–2.09). Shigella flexneri was more common than Shigella sonnei (58% vs 36%); however, S. sonnei constituted most of the isolates with decreased susceptibility to azithromycin (67%) and most of the multidrug-resistant strains (54%); thus, poor clinical outcomes were associated with S. sonnei. The current epidemiological cutoff for S. flexneri of ≥16 µg/mL to define decreased susceptibility to azithromycin was clinically predictive of poor outcome. Patients with S. sonnei and a low MIC (4 µg/mL) still had elevated rates of persistent diarrhea and culture positivity. Conclusions This study documents worse clinical outcomes for S. flexneri with decreased susceptibility to azithromycin, as well as S. sonnei, and supports the utility of susceptibility testing and clinical breakpoints for azithromycin. S. sonnei is an emerging drug-resistant threat. Clinical Trials Registration NCT03778125.

scholarly journals 1594. Ceftolozane–Tazobactam Demonstrates Higher In Vitro Susceptibility than Ceftazidime–Avibactam Against Pseudomonas aeruginosa Isolated from Respiratory Tract of Adult Cystic Fibrosis Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S581-S582
Author(s):  
Patrick James Nolan ◽  
Tiffeny Smith ◽  
James D Finklea ◽  
Leah Cohen ◽  
Raksha Jain
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Susceptibility Testing ◽  
Clinical Laboratory ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
In Vitro Susceptibility

Abstract Background Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane–tazobactam (C/T) and ceftazidime–avibactam (CZA) exhibit promising activity against antimicrobial-resistant organisms, including P. aeruginosa. In this study, we compared in vitro activity of C/T and CZA against P. aeruginosa isolated from respiratory cultures obtained from adult patients with CF. Methods This is a retrospective study of respiratory cultures positive for P. aeruginosa collected from adult CF patients between January 1, 2015 to November 30, 2018. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin were included in the study. All isolates underwent in-house susceptibility testing for 9 anti-pseudomonal agents according to the methodology established by the Clinical Laboratory Standards Institute (CLSI). Susceptibility testing of C/T, CZA, and colistin were performed by a reference lab. Isolates were classified into 3 drug-resistant categories using the following definition: multidrug-resistant (MDR) non-susceptible (NS) to ≥1 agent in ≥3 different antimicrobial classes, extensive drug-resistant (XDR) NS to 4 or 5 different classes, and pan drug-resistant (PDR) NS to all 6 classes except colistin. Results Forty-two P. aeruginosa respiratory isolates from 32 patients with CF were included. The overall susceptibility to C/T and CZA was 59.5% and 42.9%, respectively. Thirty-eight (90%) isolates were considered MDR with susceptibility of 55.3% to C/T and 44.7% to CZA. Among the 11 XDR isolates, susceptibility to C/T was 81.8% vs. CZA 72.7%. Susceptibility to C/T vs. CZA was also higher (37.5% vs. 25%) among the 24 PDR isolates. Conclusion Among P. aeruginosa isolated from CF respiratory cultures, C/T appears to have better in vitro activity compared with CZA, and remained true among isolates considered XDR and PDR. These results suggest using C/T while awaiting susceptibilities when standard anti-pseudomonal agents cannot be used. Future studies evaluating clinical outcomes for the treatment of pulmonary CF exacerbations are needed to assess the applicability of in vitro susceptibility data. Disclosures All authors: No reported disclosures.

scholarly journals Discovery of beta-lactamase CMY-10 inhibitors for combination therapy against multi-drug resistant Enterobacteriaceae

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244967
Author(s):  
Nousheen Parvaiz ◽  
Faisal Ahmad ◽  
Wenbo Yu ◽  
Alexander D. MacKerell ◽  
Syed Sikander Azam
Keyword(s):  
Combination Therapy ◽  
Antimicrobial Agents ◽  
Susceptibility Testing ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Activity Assay ◽  
Primary Resistance ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing

β-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving β-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the strategy of combination therapeutics and aims at identifying novel β-lactamase inhibitors that can inactivate the β-lactamase enzyme of the pathogen while allowing the β-lactam antibiotic to act against its penicillin-binding protein target. Inhibitor discovery applied the Site-Identification by Ligand Competitive Saturation (SILCS) technology to map the functional group requirements of the β-lactamase CMY-10 and generate pharmacophore models of active site. SILCS-MC, Ligand-grid Free Energy (LGFE) analysis and Machine-learning based random-forest (RF) scoring methods were then used to screen and filter a library of 700,000 compounds. From the computational screens 74 compounds were subjected to experimental validation in which β-lactamase activity assay, in vitro susceptibility testing, and Scanning Electron Microscope (SEM) analysis were conducted to explore their antibacterial potential. Eleven compounds were identified as enhancers while 7 compounds were recognized as inhibitors of CMY-10. Of these, compound 11 showed promising activity in β-lactamase activity assay, in vitro susceptibility testing against ATCC strains (E. coli, E. cloacae, E. agglomerans, E. alvei) and MDR clinical isolates (E. cloacae, E. alvei and E. agglomerans), with synergistic assay indicating its potential as a β-lactam enhancer and β-lactamase inhibitor. Structural similarity search against the active compound 11 yielded 28 more compounds. The majority of these compounds also exhibited β-lactamase inhibition potential and antibacterial activity. The non-β-lactam-based β-lactamase inhibitors identified in the current study have the potential to be used in combination therapy with lactam-based antibiotics against MDR clinical isolates that have been found resistant against last-line antibiotics.

Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing Position Statements on Polymyxin B and Colistin Clinical Breakpoints

2020 ◽  
Author(s):  
Michael J Satlin ◽  
James S Lewis ◽  
Melvin P Weinstein ◽  
Jean Patel ◽  
Romney M Humphries ◽  
...  
Keyword(s):  
Antimicrobial Susceptibility ◽  
Susceptibility Testing ◽  
Polymyxin B ◽  
Antimicrobial Susceptibility Testing ◽  
In Vitro Susceptibility ◽  
Susceptibility Data ◽  
European Committee ◽  
Clinical Breakpoints ◽  
State Concentration

Abstract Recent data on polymyxin pharmacokinetics, pharmacodynamics, toxicity, and clinical outcomes suggest these agents have limited clinical utility. Pharmacokinetics-pharmacodynamics data show a steady-state concentration of 2 μg/mL is required for killing bacteria with colistin minimum inhibitory concentrations of 2 μg/mL. Less than 50% of patients with normal renal function achieve this exposure, and it is associated with high risk of nephrotoxicity. This exposure does not achieve bacterial stasis in pneumonia models. Randomized and observational studies consistently demonstrate increased mortality for polymyxins compared with alternative agents. The Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) are 2 global organizations that establish interpretive criteria for in vitro susceptibility data. CLSI has recently taken the step to eliminate the “susceptible” interpretive category for the polymyxins, whereas EUCAST maintains this interpretive category. This viewpoint describes the opinions of these organizations and the data that were used to inform their perspectives.

scholarly journals In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

2017 ◽  
Vol 55 (6) ◽  
pp. 1747-1754 ◽  
Author(s):  
Barbara A. Brown-Elliott ◽  
Richard J. Wallace
Keyword(s):  
Susceptibility Testing ◽  
Nontuberculous Mycobacteria ◽  
Multidrug Resistant ◽  
In Vitro Susceptibility ◽  
Content Type ◽  
Treatment Agent ◽  
In Vitro Susceptibility Testing ◽  
Resistant Strains ◽  
Isolated Species

ABSTRACT Tedizolid is a new oxazolidinone with improved in vitro and intracellular potency against Mycobacterium tuberculosis , including multidrug-resistant strains, and some species of nontuberculous mycobacteria (NTM) compared with that of linezolid. Using the current Clinical and Laboratory Standards Institute (CLSI)-recommended method of broth microdilution, susceptibility testing of 170 isolates of rapidly growing mycobacteria showed equivalent or lower (1- to 8-fold) MIC 50 and/or MIC 90 values for tedizolid compared with that for linezolid. The tedizolid MIC 90 values for 81 isolates of M. abscessus subsp. abscessus and 12 isolates of M. abscessus subsp. massiliense were 8 μg/ml and 4 μg/ml, respectively, compared with linezolid MIC 90 values of 32 μg/ml for both. The MIC 90 values for 20 isolates of M. fortuitum were 2 μg/ml for tedizolid and 4 μg/ml for linezolid. Twenty-two isolates of M. chelonae had tedizolid and linezolid MIC 90 s of 2 μg/ml and 16 μg/ml, respectively. One hundred forty-two slowly growing NTM, including 7/7 M. marinum , 7/7 M. kansasii , and 7/11 of other less commonly isolated species, had tedizolid MICs of ≤1 μg/ml and linezolid MICs of ≤4 μg/ml. One hundred isolates of Mycobacterium avium complex and eight M. simiae isolates had tedizolid MIC 50 s of 8 μg/ml and linezolid MIC 50 s 32 and 64 μg/ml, respectively. Nine M. arupense isolates had MIC 50 s of 4 μg/ml and 16 μg/ml for tedizolid and linezolid, respectively. These findings demonstrate a greater in vitro potency of tedizolid than linezolid against NTM and suggest that an evaluation of tedizolid as a potential treatment agent for infections caused by selected NTM is warranted.

scholarly journals In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium avium Complex

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Barbara A. Brown-Elliott ◽  
Julie V. Philley ◽  
David E. Griffith ◽  
Foram Thakkar ◽  
Richard J. Wallace
Keyword(s):  
Cytochrome P450 ◽  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Susceptibility Testing ◽  
Multidrug Resistant ◽  
Broth Microdilution ◽  
In Vitro Susceptibility ◽  
Content Type ◽  
In Vitro Susceptibility Testing

ABSTRACT We performed bedaquiline broth microdilution susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) guidelines on 103 respiratory isolates of Mycobacterium avium complex (MAC), including multidrug-resistant isolates. Approximately 90% of isolates had bedaquiline MICs of ≤0.008 μg/ml, and 102/103 isolates had MICs of ≤0.015 μg/ml. Bedaquiline has excellent potential for use in patients with MAC infections, although for reasons of its metabolism by the cytochrome P450 system, it should not be given with rifampin.

scholarly journals 1463. Activity of Delafloxacin against Multi-Drug-Resistant Fastidious Respiratory Pathogens from European Medical Centers (2014-2019)

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S733-S733
Author(s):  
Dee Shorttidge ◽  
Jennifer M Streit ◽  
Michael D Huband ◽  
Robert K Flamm
Keyword(s):  
Active Agent ◽  
The United States ◽  
Multidrug Resistant ◽  
Respiratory Pathogens ◽  
Services Research ◽  
In Vitro Susceptibility ◽  
Amoxicillin Clavulanate ◽  
Tract Infections ◽  
Research Grant

Abstract Background Delafloxacin (DLX) is an anionic fluoroquinolone (FQ) that has been approved in the United States and in Europe for the treatment of acute bacterial skin and skin structure infections and was recently approved in the US for treatment of community-acquired bacterial pneumonia (CABP). In the present study, in vitro susceptibility (S) results for DLX and comparator agents were determined for CABP pathogens including Streptococcus pneumoniae (SPN), Haemophilus influenzae (HI), H. parainfluenzae (HP) and Moraxella catarrhalis (MC) clinical isolates from European hospitals participating in the SENTRY Program during 2014-2019. Methods A total of 2,835 SPN, 1,484 HI, 959 MC, and 20 HP isolates were collected from community-acquired respiratory tract infections (CARTI) during 2014-2019 from European hospitals. Sites included only 1 isolate/patient/infection episode. Isolate identifications were confirmed at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology, and EUCAST (2020) breakpoints were applied where applicable. Other antimicrobials tested included levofloxacin (LEV) and moxifloxacin (MOX; not tested in 2015). Multidrug-resistant (MDR) SPN isolates were categorized as being nonsusceptible (NS) to amoxicillin-clavulanate, erythromycin (ERY), and tetracycline; other SPN phenotypes were ERY-NS, or penicillin (PEN)-NS. β-lactamase (BL) presence was determined for HI, HP, and MC. Results The activities of the 3 FQs are shown in the table. The most active agent against SPN was DLX, with the lowest MIC50/90 values of 0.015/0.03 mg/L. DLX activities were the same when tested against the MDR or PEN-NS for SPN phenotypes. ERY-NS isolates had DLX MIC50/90 results of 0.015/0.03 mg/L. DLX was the most active FQ against HI, HP, and MC. BL presence did not affect FQ MIC values for HI or MC; only 1 HP isolate was BL-positive. Conclusion DLX demonstrated potent in vitro antibacterial activity against SPN, HI, HP, and MC. DLX was active against MDR SPN that were NS to the agents commonly used as treatments for CABP. These data support the utility of DLX in CABP including when caused by antibiotic resistant strains. Table 1 Disclosures Jennifer M. Streit, BS, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Robert K. Flamm, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)

scholarly journals Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Zhaojing Zong ◽  
Wei Jing ◽  
Jin Shi ◽  
Shu'an Wen ◽  
Tingting Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
23S Rrna ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Significant Difference ◽  
Mdr Tb

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.

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