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Antimicrobial Agents and Chemotherapy May 2024Treatment of infection presents significant challenges, exacerbated by the emergence of macrolide-resistant strains that necessitate the use of multiple antimicrobials...
Treatment of infection presents significant challenges, exacerbated by the emergence of macrolide-resistant strains that necessitate the use of multiple antimicrobials in combination and carry the potential for significant toxic effects. Select dual beta-lactam combinations, with or without beta-lactamase inhibitors, have been shown to be highly active . Herein, we describe a 6-year-old child with underlying mild bilateral lower lobe cylindrical bronchiectatic lung disease who developed pulmonary infection and was treated with a multi-drug regimen including two β-lactam antibiotics, achieving both early clinical and microbiological cure. This case highlights the potential benefit of dual β-lactam therapy for the treatment of drug-resistant infection.
PubMed: 38757973
DOI: 10.1128/aac.00319-24 -
Scientific Reports May 2024Mycobacteroides (Mycobacterium) abscessus, which causes a variety of infectious diseases in humans, is becoming detected more frequently in clinical specimens as cases...
Mycobacteroides (Mycobacterium) abscessus, which causes a variety of infectious diseases in humans, is becoming detected more frequently in clinical specimens as cases are spreading worldwide. Taxonomically, M. abscessus is composed of three subspecies of M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense, with different susceptibilities to macrolides. In order to identify rapidly these three subspecies, we determined useful biomarker proteins, including ribosomal protein L29, L30, and hemophore-related protein, for distinguishing the subspecies of M. abscessus using the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) profiles. Thirty-three clinical strains of M. abscessus were correctly identified at the subspecies-level by the three biomarker protein peaks. This study ultimately demonstrates the potential of routine MALDI-MS-based laboratory methods for early identification and treatment for M. abscessus infections.
Topics: Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Ribosomal Proteins; Mycobacterium abscessus; Bacterial Proteins; Humans; Mycobacterium Infections, Nontuberculous; Biomarkers
PubMed: 38755267
DOI: 10.1038/s41598-024-61549-7 -
Tuberculosis (Edinburgh, Scotland) Jul 2024Drug susceptibility testing (DST) protocol of omadacycline against non-tuberculous mycobacteria has not yet been established. We developed a method to accurately...
BACKGROUND
Drug susceptibility testing (DST) protocol of omadacycline against non-tuberculous mycobacteria has not yet been established. We developed a method to accurately determine MIC omadacycline MIC against Mycobacterium abscessus (Mab), Mycobacterium avium-complex (MAC), and Mycobacterium kansasii (Mkn).
METHODS
First, we identified the oxyrase concentration not affecting Mab, MAC, and Mkn growth followed by omadacycline MIC experiments with and without oxyrase using reference and clinical strains.
RESULTS
Oxyrase 0.5 % (v/v) stabilized omadacycline in the culture medium. The median omadacycline MIC was 1 mg/L for Mab and 8 mg/L for Mkn. For MAC, the median omadacycline MIC was 2 mg/L for M. avium, 256 mg/L for M. intracellulare, and 4 mg/L for M. chimaera (p < 0.0001). Wilcoxon matched-pairs signed rank test revealed statistically lower MICs with oxyrase for all MAC subspecies (p < 0.0001), all Mab subspecies (p < 0.0001), and Mkn (p = 0.0002). The decrease in MICs with oxyrase was 17/18 of Mab, 14/19 of Mkn, 8/8 of M. avium, 4/5 M. chimera, but only 11/18 of M. intracellulare (p < 0.013).
CONCLUSION
Use of 0.5 % oxyrase could be a potential solution to reliable and reproducible omadacycline MIC of Mab. However, oxyrase demonstrated a variable effect in reducing MICs against MAC and Mkn.
Topics: Microbial Sensitivity Tests; Humans; Antitubercular Agents; Tetracyclines; Mycobacterium abscessus; Mycobacterium kansasii; Mycobacterium avium Complex; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous
PubMed: 38754247
DOI: 10.1016/j.tube.2024.102519 -
Open Forum Infectious Diseases May 2024Lung transplant recipients are at increased risk of complex (MABC) acquisition and invasive infection. We analyzed risk factors and outcomes of early post-lung...
BACKGROUND
Lung transplant recipients are at increased risk of complex (MABC) acquisition and invasive infection. We analyzed risk factors and outcomes of early post-lung transplant MABC acquisition.
METHODS
We conducted a retrospective matched case-control study of patients who underwent lung transplant from 1/1/2012 to 12/31/2021 at a single large tertiary care facility. Cases had de novo MABC isolation within 90 days post-transplant. Controls had no positive MABC cultures and were matched 3:1 with cases based on age and transplant date. Recipient demographics and pre-/peri-operative characteristics were analyzed, and a regression model was used to determine independent risk factors for MABC acquisition. We also assessed 1-year post-transplant outcomes, including mortality.
RESULTS
Among 1145 lung transplants, we identified 79 cases and 237 matched controls. Post-transplant mechanical ventilation for >48 hours was independently associated with MABC acquisition (adjusted odds ratio, 2.46; 95% CI, 1.29-4.72; = .007). Compared with controls, cases required more days of hospitalization after the MABC index date (28 vs 12 days; = .01) and had decreased 1-year post-transplant survival (78% vs 89%; log-rank = .02). One-year mortality appeared highest for cases who acquired subsp. (31% mortality) or had extrapulmonary infections (43% mortality).
CONCLUSIONS
In this large case-control study, prolonged post-transplant ventilator duration was associated with early post-lung transplant MABC acquisition, which in turn was associated with increased hospital-days and mortality. Further studies are needed to determine the best strategies for MABC prevention, surveillance, and management.
PubMed: 38746951
DOI: 10.1093/ofid/ofae209 -
MBio Jun 2024() affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, poses clinical challenges due to its...
UNLABELLED
() affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs-avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical isolates and ATCC19977 (MIC and MIC ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log for sulopenem-CXM and AVI and ~4 Log for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; Ldt-Ldt), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with Ldt-Ldt, DDC, and PBP B and CXM with Ldt and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and Ldt after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the Ldt with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat .
IMPORTANCE
Treating infections from (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a "step down" to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.
Topics: Mycobacterium abscessus; Anti-Bacterial Agents; Drug Synergism; Microbial Sensitivity Tests; Humans; Cefuroxime; Mycobacterium Infections, Nontuberculous; beta-Lactamase Inhibitors; Molecular Docking Simulation; Prohibitins
PubMed: 38742824
DOI: 10.1128/mbio.00609-24 -
Frontiers in Neurology 2024Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with...
INTRODUCTION
Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature.
MATERIALS AND METHODS
Between January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival.
RESULTS
Six cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [ complex (MAC) = 4; = 1] and one due to RGM (). Underlying immune disorders were identified only in the SGM cases [genetic ( = 2), HIV ( = 1), sarcoidosis ( = 1), and anti-interferon-gamma antibodies ( = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM = 85, RGM = 38, non-identified = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection ( = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, = 0.04).
DISCUSSION
NTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder.
PubMed: 38742044
DOI: 10.3389/fneur.2024.1360128 -
International Journal of Infectious... May 2024Predicting progression of nontuberculous mycobacterial lung disease (NTM-LD) remains challenging. This study evaluated whether sputum bacterial microbiome diversity can...
OBJECTIVES
Predicting progression of nontuberculous mycobacterial lung disease (NTM-LD) remains challenging. This study evaluated whether sputum bacterial microbiome diversity can be the biomarker and provide novel insights into related phenotypes and treatment timing.
METHODS
We analyzed 126 sputum microbiomes of 126 patients with newly diagnosed NTM-LD due to Mycobacterium avium complex, M. abscessus complex, and M. kansasii between May 2020 and December 2021. Patients were followed for 2 years to determine their disease progression status. We identified consistently representative genera that differentiated the progressor and nonprogressor by using six methodologies. These genera were used to construct a prediction model using random forest with 5-fold cross validation.
RESULTS
Disease progression occurred in 49 (38.6%) patients. Compared with nonprogressors, α-diversity was lower in the progressors. Significant compositional differences existed in the β-diversity between groups (p=0.001). The prediction model for NTM-LD progression constructed using seven genera (Burkholderia, Pseudomonas, Sphingomonas, Candidatus Saccharibacteria, Phocaeicola, Pelomonas, and Phascolarctobacterium) with significantly differential abundance achieved an area under curve of 0.871.
CONCLUSIONS
Identification of the composition of sputum bacterial microbiome facilitates prediction of the course of NTM-LD, and maybe used to develop precision treatment involving modulating the respiratory microbiome composition to ameliorate NTM-LD.
PubMed: 38740280
DOI: 10.1016/j.ijid.2024.107085 -
Tuberculosis (Edinburgh, Scotland) Jul 2024Mycobacterium abscessus, a rapidly growing nontuberculous mycobacterium, is increasingly recognized as an important pathogen of the human lung, disproportionally... (Review)
Review
Mycobacterium abscessus, a rapidly growing nontuberculous mycobacterium, is increasingly recognized as an important pathogen of the human lung, disproportionally affecting people with cystic fibrosis (CF) and other susceptible individuals with non-CF bronchiectasis and compromised immune functions. M. abscessus infections are extremely difficult to treat due to intrinsic resistance to many antibiotics, including most anti-tuberculous drugs. Current standard-of-care chemotherapy is long, includes multiple oral and parenteral repurposed drugs, and is associated with significant toxicity. The development of more effective oral antibiotics to treat M. abscessus infections has thus emerged as a high priority. While murine models have proven instrumental in predicting the efficacy of therapeutic treatments for M. tuberculosis infections, the preclinical evaluation of drugs against M. abscessus infections has proven more challenging due to the difficulty of establishing a progressive, sustained, pulmonary infection with this pathogen in mice. To address this issue, a series of three workshops were hosted in 2023 by the Cystic Fibrosis Foundation (CFF) and the National Institute of Allergy and Infectious Diseases (NIAID) to review the current murine models of M. abscessus infections, discuss current challenges and identify priorities toward establishing validated and globally harmonized preclinical models. This paper summarizes the key points from these workshops. The hope is that the recommendations that emerged from this exercise will facilitate the implementation of informative murine models of therapeutic efficacy testing across laboratories, improve reproducibility from lab-to-lab and accelerate preclinical-to-clinical translation.
Topics: Animals; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Disease Models, Animal; Mice; Anti-Bacterial Agents; Humans; Drug Evaluation, Preclinical; Lung
PubMed: 38729070
DOI: 10.1016/j.tube.2024.102503 -
PloS One 2024Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum...
Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro.
Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.
Topics: Succinates; Humans; Hydrogen-Ion Concentration; Nontuberculous Mycobacteria; THP-1 Cells; Mycobacterium Infections, Nontuberculous; Mycobacterium avium; Mycobacterium abscessus
PubMed: 38728330
DOI: 10.1371/journal.pone.0303516 -
Microbes and Infection May 2024Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex...
Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex that triggers IL-1β maturation and pyroptosis through the cleavage of caspase-1. In this study, we investigated the roles of NLRP3 and IL-1β in the host's defense against MAB. The IL-1β production by MAB was completely abolished in NLRP3, but not NLRC4, deficient macrophages. The NLRP3 inflammasome components, which are ASC and caspase-1 were also found to be essential for IL-1β production in response to MAB. NLRP3 and IL-1β deficiency did not affect the intracellular growth of MAB in macrophages, and the bacterial burden in lungs of NLRP3- and IL-1β-deficient mice was also comparable to the burden observed in WT mice. In contrast, IL-1β deficiency ameliorated lung pathology in MAB-infected mice. Notably, the lung homogenates of IL-1β-deficient mice had reduced levels of IL-17, but not IFN-γ and IL-4 when compared with WT counterparts. Furthermore, in vitro co-culture analysis showed that IL-1β signaling was essential for IL-17 production in response to MAB. Finally, we observed that the anti-IL-17 antibody administration moderately mitigated MAB-induced lung pathology. These findings indicated that IL-1β production contribute to MAB-induced lung pathology via the elevation of IL-17 production.
PubMed: 38724000
DOI: 10.1016/j.micinf.2024.105351