Apramycin overcomes the inherent lack of antimicrobial bactericidal activity in Mycobacterium abscessus

2021 ◽  
Author(s):  
Petra Selchow ◽  
Diane J. Ordway ◽  
Deepshikha Verma ◽  
Nicholas Whittel ◽  
Aline Petrig ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Lung Infection ◽  
Resistance Mechanisms ◽  
Mycobacterium Abscessus ◽  
Multi Drug Resistance ◽  
Emerging Pathogen ◽  
Aminoglycoside Resistance ◽  
Treatment Regimens ◽  
Distinct Structure ◽  
Poor Therapeutic Outcome

Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism’s inherent resistance towards clinically available antimicrobials. The low bactericidal potency of currently available treatment regimens is of concern and testifies to the poor therapeutic outcome in pulmonary M. abscessus infections. Mechanistically, we here demonstrate that the acetyltransferase Eis2 is responsible for the lack of bactericidal activity of amikacin, the standard aminoglycoside used in combination treatment. In contrast, the distinct structure aminoglycoside apramycin is not modified by any of the pathogen’s innate aminoglycoside resistance mechanisms nor is it affected by the multi-drug resistance regulator WhiB7. As a consequence, apramycin uniquely shows potent bactericidal activity against M. abscessus . This favourable feature of apramycin is reflected in a mouse model of M. abscessus lung infection, which demonstrates superior activity over amikacin. These findings encourage the development of apramycin for the treatment of M. abscessus infections and suggest that M. abscessus eradication in lung pulmonary disease may be within therapeutic reach.

scholarly journals Development and Persistence of Antimicrobial Resistance in Pseudomonas aeruginosa: a Longitudinal Observation in Mechanically Ventilated Patients

2007 ◽  
Vol 51 (4) ◽  
pp. 1341-1350 ◽  
Author(s):  
Anita Reinhardt ◽  
Thilo Köhler ◽  
Paul Wood ◽  
Peter Rohner ◽  
Jean-Luc Dumas ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Selective Pressure ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Antimicrobial Treatment ◽  
Aminoglycoside Resistance ◽  
Prolonged Intubation ◽  
Treatment Regimens ◽  
Underlying Mechanisms

ABSTRACT Intubated patients frequently become colonized by Pseudomonas aeruginosa, which is subsequently responsible for ventilator-associated pneumonia. This pathogen readily acquires resistance against available antimicrobials. Depending on the resistance mechanism selected for, resistance might either be lost or persist after removal of the selective pressure. We investigated the rapidity of selection, as well as the persistence, of antimicrobial resistance and determined the underlying mechanisms. We selected 109 prospectively collected P. aeruginosa tracheal isolates from two patients based on their prolonged intubation and colonization periods, during which they had received carbapenem, fluoroquinolone (FQ), or combined β-lactam-aminoglycoside therapies. We determined antimicrobial resistance phenotypes by susceptibility testing and used quantitative real-time PCR to measure the expression of resistance determinants. Within 10 days after the initiation of therapy, all treatment regimens selected resistant isolates. Resistance to β-lactam and FQ was correlated with ampC and mexC gene expression levels, respectively, whereas imipenem resistance was attributable to decreased oprD expression. Combined β-lactam-aminoglycoside resistance was associated with the appearance of small-colony variants. Imipenem and FQ resistance persisted for prolonged times once the selecting antimicrobial treatment had been discontinued. In contrast, resistance to β-lactams disappeared rapidly after removal of the selective pressure, to reappear promptly upon renewed exposure. Our results suggest that resistant P. aeruginosa is selected in less than 10 days independently of the antimicrobial class. Different resistance mechanisms lead to the loss or persistence of resistance after the removal of the selecting agent. Even if resistant isolates are not evident upon culture, they may persist in the lung and can be rapidly reselected.

scholarly journals Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Maria Carla Martini ◽  
Tianbi Zhang ◽  
John T. Williams ◽  
Robert B. Abramovitch ◽  
Pamela J. Weathers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bactericidal Activity ◽  
Artemisia Annua ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Major Barrier ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Emergence Of Resistance

ABSTRACTEthnopharmacological relevanceEmergence of drug-resistant and multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is a major barrier to tuberculosis (TB) eradication, as it leads to longer treatment regimens and in many cases treatment failure. Thus, there is an urgent need to explore new TB drugs and combinations, in order to shorten TB treatment and improve outcomes. Here, we evaluate the potential of two medicinal plants, Artemisia annua, a natural source of artemisinin (AN), and Artemisia afra, as sources of novel antitubercular agents.Aim of the studyOur goal was to measure the activity of A. annua and A. afra extracts against Mtb as potential natural and inexpensive therapies for TB treatment, or as sources of compounds that could be further developed into effective treatments.Materials and MethodsThe minimum inhibitory concentrations (MICs) of A. annua and A. afra dichloromethane extracts were determined, and concentrations above the MICs were used to evaluate their ability to kill Mtb and Mycobacterium abscessus in vitro.ResultsPrevious studies showed that A. annua and A. afra inhibit Mtb growth. Here, we show for the first time that Artemisia extracts have a strong bactericidal activity against Mtb. The killing effect of A. annua was much stronger than equivalent concentrations of pure AN, suggesting that A. annua extracts kill Mtb through a combination of AN and additional compounds. A. afra, which produces very little AN, displayed bactericidal activity against Mtb that was substantial but weaker than that of A. annua. In addition, we measured the activity of Artemisia extracts against Mycobacterium abscessus. Interestingly, we observed that while A. annua is not bactericidal, it inhibits growth of M. abscessus, highlighting the potential of this plant in combinatory therapies to treat M. abscessus infections.ConclusionOur results indicate that Artemisia extracts have an enormous potential for treatment of TB and M. abscessus infections, and that these plants contain bactericidal compounds in addition to AN. Combination of extracts with existing antibiotics may not only improve treatment outcomes but also reduce the emergence of resistance to other drugs.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

AbstractCurrent treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular Mycobacterium abscessus

2021 ◽  
Author(s):  
Olumide Martins ◽  
Nicole Ammerman ◽  
Jin Lee ◽  
Amit Kaushik ◽  
Kelly E Dooley ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Tween 80 ◽  
Standard Of Care ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Culture Conditions ◽  
Mycobacterium Abscessus ◽  
Infection Model ◽  
Treatment Regimens

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

scholarly journals Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus

2014 ◽  
Vol 58 (7) ◽  
pp. 3828-3836 ◽  
Author(s):  
Florian P. Maurer ◽  
Vera L. Bruderer ◽  
Claudia Ritter ◽  
Claudio Castelberg ◽  
Guido V. Bloemberg ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Mode Of Action ◽  
Model Organism ◽  
Mycobacterium Abscessus ◽  
Therapeutic Outcome ◽  
Natural Resistance ◽  
Content Type ◽  
The Poor ◽  
Poor Therapeutic Outcome ◽  
The Impact

ABSTRACTAntibiotic therapy of infections caused by the emerging pathogenMycobacterium abscessusis challenging due to the organism's natural resistance toward most clinically available antimicrobials. We investigated the bactericidal activity of antibiotics commonly administered inM. abscessusinfections in order to better understand the poor therapeutic outcome. Time-kill curves were generated for clinicalM. abscessusisolates,Mycobacterium smegmatis, andEscherichia coliby using antibiotics commonly categorized as bactericidal (amikacin and moxifloxacin) or bacteriostatic (tigecycline and linezolid). In addition, the impact of aminoglycoside-modifying enzymes on the mode of action of substrate and nonsubstrate aminoglycosides was studied by usingM. smegmatisas a model organism. While amikacin and moxifloxacin were bactericidal againstE. coli, none of the tested compounds showed bactericidal activity againstM. abscessus. Further mechanistic investigations of the mode of action of aminoglycosides inM. smegmatisrevealed that the bactericidal activity of tobramycin and gentamicin was restored by disruption of the chromosomalaac(2′) gene in the mycobacterial genome. The lack of bactericidal antibiotics in currently recommended treatment regimens provides a reasonable explanation for the poor therapeutic outcome inM. abscessusinfection. Our findings suggest that chromosomally encoded drug-modifying enzymes play an important role in the lack of aminoglycoside bactericidal activity against rapidly growing mycobacteria.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time- and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals Association between the Presence of Aminoglycoside-Modifying Enzymes andIn VitroActivity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-β-Lactamase-Producing Enterobacter Species

2016 ◽  
Vol 60 (9) ◽  
pp. 5208-5214 ◽  
Author(s):  
Ghady Haidar ◽  
Ammar Alkroud ◽  
Shaoji Cheng ◽  
Travis M. Churilla ◽  
Bryce M. Churilla ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Treatment Options ◽  
Resistance Mechanisms ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Treatment Regimens ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Research Priority ◽  
Extended Spectrum

ABSTRACTWe compared thein vitroactivities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13Enterobacterisolates possessing bothKlebsiella pneumoniaecarbapenemase and extended-spectrum β-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL−, 6 KPC−/ESBL+, and 38 KPC−/ESBL− isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL− (25% and 38%, respectively), KPC−/ESBL+ (50% and 17%, respectively), and KPC−/ESBL− (0% and 3%, respectively) isolates. KPC+/ESBL+ isolates were more likely than others to possess an aminoglycoside-modifying enzyme (AME) (100% versus 38%, 67%, and 5%;P= 0.007, 0.06, and <0.0001, respectively) or multiple AMEs (100% versus 13%, 33%, and 0%, respectively;P< 0.01 for all). KPC+/ESBL+ isolates also had a greater number of AMEs (mean of 4.6 versus 1.5, 0.9, and 0.05, respectively;P< 0.01 for all). GEN and TOB MICs were higher against isolates with >1 AME than with ≤1 AME. The presence of at least 2/3 of KPC, SHV, and TEM predicted the presence of AMEs. PLZ MICs against all isolates were ≤4 μg/ml, regardless of KPC/ESBL pattern or the presence of AMEs. In conclusion, GEN and TOB are limited as treatment options against KPC+ and ESBL+Enterobacter. PLZ may represent a valuable addition to the antimicrobial armamentarium. A full understanding of AMEs and other aminoglycoside resistance mechanisms will allow clinicians to incorporate PLZ rationally into treatment regimens. The development of molecular assays that accurately and rapidly predict antimicrobial responses among KPC- and ESBL-producingEnterobacterspp. should be a top research priority.

scholarly journals In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular Mycobacterium abscessus

2021 ◽  
Author(s):  
Olumide Martins ◽  
Jin Lee ◽  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Kelly E. Dooley ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Tween 80 ◽  
Standard Of Care ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Culture Conditions ◽  
Mycobacterium Abscessus ◽  
Infection Model ◽  
Treatment Regimens

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus , where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

scholarly journals Selection of Resistance to Clarithromycin in Mycobacterium abscessus Subspecies

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Faiza Mougari ◽  
Feriel Bouziane ◽  
Flora Crockett ◽  
Rachid Nessar ◽  
Françoise Chau ◽  
...  
Keyword(s):  
Ribosomal Subunit ◽  
Resistance Mechanisms ◽  
Mycobacterium Abscessus ◽  
23S Rrna ◽  
Emerging Pathogen ◽  
Content Type ◽  
Clarithromycin Resistance ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT Mycobacterium abscessus is an emerging pathogen against which clarithromycin is the main drug used. Clinical failures are commonly observed and were first attributed to acquired mutations in rrl encoding 23S rRNA but were then attributed to the intrinsic production of the erm(41) 23S RNA methylase. Since strains of M. abscessus were recently distributed into subspecies and erm(41) sequevars, we investigated acquired clarithromycin resistance mechanisms in mutants selected in vitro from four representative strains. Mutants were sequenced for rrl, erm(41), whiB, rpIV, and rplD and studied for seven antibiotic MICs. For mutants obtained from strain M. abscessus subsp. abscessus erm(41) T28 sequevar and strain M. abscessus subsp. bolletii, which are both known to produce effective methylase, rrl was mutated in only 19% (4/21) and 32.5% (13/40) of mutants, respectively, at position 2058 (A2058C, A2058G) or position 2059 (A2059C, A2059G). No mutations were observed in any of the other genes studied, and resistance to other antibiotics (amikacin, cefoxitin, imipenem, tigecycline, linezolid, and ciprofloxacin) was mainly unchanged. For M. abscessus subsp. abscessus erm(41) C28 sequevar and M. abscessus subsp. massiliense, not producing effective methylase, 100% (26/26) and 97.5% (39/40) of mutants had rrl mutations at position 2058 (A2058C, A2058G, A2058T) or position 2059 (A2059C, A2059G). The remaining M. abscessus subsp. massiliense mutant showed an 18-bp repeat insertion in rpIV, encoding the L22 protein. Our results showed that acquisition of clarithromycin resistance is 100% mediated by structural 50S ribosomal subunit mutations for M. abscessus subsp. abscessus erm(41) C28 and M. abscessus subsp. massiliense, whereas it is less common for M. abscessus subsp. abscessus erm(41) T28 sequevar and M. abscessus subsp. bolletii, where other mechanisms may be responsible for failure.

scholarly journals Healthcare-Associated Laboratory-Confirmed Bloodstream Infections—Species Diversity and Resistance Mechanisms, a Four-Year Retrospective Laboratory-Based Study in the South of Poland

2021 ◽  
Vol 18 (5) ◽  
pp. 2785
Author(s):  
Agnieszka Chmielarczyk ◽  
Monika Pomorska-Wesołowska ◽  
Dorota Romaniszyn ◽  
Jadwiga Wójkowska-Mach
Keyword(s):  
Bloodstream Infections ◽  
Diagnostic Techniques ◽  
Resistance Mechanisms ◽  
Infection Prevention And Control ◽  
The South ◽  
Coagulase Negative Staphylococci ◽  
Aminoglycoside Resistance ◽  
Gram Negative ◽  
Maldi Tof ◽  
Carbapenem Resistant

Introduction: Regardless of the country, advancements in medical care and infection prevention and control of bloodstream infections (BSIs) are an enormous burden of modern medicine. Objectives: The aim of our study was to describe the epidemiology and drug-resistance of laboratory-confirmed BSI (LC-BSIs) among adult patients of 16 hospitals in the south of Poland. Patients and methods: Data on 4218 LC-BSIs were collected between 2016–2019. The identification of the strains was performed using MALDI-TOF. Resistance mechanisms were investigated according to European Committee on Antimicrobial Susceptibility Testing, EUCAST recommendations. Results: Blood cultures were collected from 8899 patients, and LC-BSIs were confirmed in 47.4%. The prevalence of Gram-positive bacteria was 70.9%, Gram-negative 27.8% and yeast 1.4%. The most frequently isolated genus was Staphylococcus (50% of all LC-BSIs), with a domination of coagulase-negative staphylococci, while Escherichia coli (13.7%) was the most frequent Gram-negative bacterium. Over 4 years, 108 (2.6%) bacteria were isolated only once, including species from the human microbiota as well as environmental and zoonotic microorganisms. The highest methicillin resistant Staphylococcus aureus (MRSA) prevalence was in intensive care units (ICUs) (55.6%) but S. aureus with resistance to macrolides, lincosamides and streptogramins B (MLSB) in surgery was 66.7%. The highest prevalence of E. faecalis with a high-level aminoglycoside resistance (HLAR) mechanism was in ICUs, (84.6%), while E. faecium-HLAR in surgery was 83.3%. All cocci were fully glycopeptide-sensitive. Carbapenem-resistant Gram-negative bacilli were detected only in non-fermentative bacilli group, with prevalence 70% and more. Conclusions: The BSI microbiology in Polish hospitals was similar to those reported in other studies, but the prevalence of MRSA and enterococci-HLAR was higher than expected, as was the prevalence of carbapenem-resistant non-fermentative bacilli. Modern diagnostic techniques, such as MALDI-TOF, guarantee reliable diagnosis.

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