scholarly journals Experimental therapies of Mycobacterium abscessus infections

2020 ◽  
Author(s):  
Michal Meir ◽  
Daniel Barkan
Keyword(s):  
Acquired Resistance ◽  
Severe Case ◽  
Experimental Models ◽  
Mycobacterium Abscessus ◽  
Multiple Drug ◽  
Beta Lactam ◽  
Chronic Infections ◽  
Drug Regimens ◽  
Therapy Treatment

Mycobacterium abscessus is a non-tuberculous mycobacteria notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations e.g. vancomycin-clarithromycin and dual beta-lactam therapy have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as intracellular and/or animal models, most have little if any evidence of effect in humans infections. Clinical studies of M. abscesssus treatments are needed in order to reliably determine the value of their incorporation in therapeutic regimens.

scholarly journals Alternative and Experimental Therapies of Mycobacterium abscessus Infections

2020 ◽  
Vol 21 (18) ◽  
pp. 6793
Author(s):  
Michal Meir ◽  
Daniel Barkan
Keyword(s):  
Acquired Resistance ◽  
Severe Case ◽  
Experimental Models ◽  
Mycobacterium Abscessus ◽  
Multiple Drug ◽  
Beta Lactam ◽  
Chronic Infections ◽  
Drug Regimens ◽  
Human Infections

Mycobacterium abscessus is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of M. abscessus to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of M. abscessus infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for M. abscessus. Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against M. abscessus. Novel antimicrobials active against M. abscessus include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations, e.g. vancomycin–clarithromycin and dual beta-lactam therapy, have been shown to have synergistic effect against M. abscessus in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated M. abscessus infection. While many of these experimental therapeutics have shown activity against M. abscessus in vitro, as well as in intracellular and/or animal models, most have little if any evidence of effect in human infections. Clinical studies of M. abscesssus treatments are needed to reliably determine the value of their incorporation in therapeutic regimens.

scholarly journals Phage Therapy for Mycobacterium Abscessus and Strategies to Improve Outcomes

2021 ◽  
Vol 9 (3) ◽  
pp. 596
Author(s):  
Abdolrazagh Hashemi Shahraki ◽  
Mehdi Mirsaeidi
Keyword(s):  
Host Range ◽  
Phage Therapy ◽  
Acquired Resistance ◽  
Severe Case ◽  
Chemotherapeutic Agents ◽  
Mycobacterium Abscessus ◽  
Resistant Bacteria ◽  
Lytic Phage ◽  
Broad Host Range ◽  
Chronic Infections

Members of Mycobacterium abscessus complex are known for causing severe, chronic infections. Members of M. abscessus are a new “antibiotic nightmare” as one of the most resistant organisms to chemotherapeutic agents. Treatment of these infections is challenging due to the either intrinsic or acquired resistance of the M. abscessus complex to the available antibiotics. Recently, successful phage therapy with a cocktail of three phages (one natural lytic phage and two engineered phages) every 12 h for at least 32 weeks has been reported against a severe case of the disseminated M. abscessus subsp. massiliense infection, which underlines the high value of phages against drug-resistant superbugs. This report also highlighted the limitations of phage therapy, such as the absence of lytic phages with a broad host-range against all strains and subspecies of the M. abscessus complex and also the risk of phage resistant bacteria over treatment. Cutting-edge genomic technologies have facilitated the development of engineered phages for therapeutic purposes by introducing new desirable properties, changing host-range and arming the phages with additional killing genes. Here, we review the available literature and suggest new potential solutions based on the progress in phage engineering that can help to overcome the present limitations of M. abscessus treatment.

scholarly journals Dual β-Lactam Combinations Highly Active against Mycobacterium abscessus Complex In Vitro

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
R. Pandey ◽  
L. Chen ◽  
C. Manca ◽  
S. Jenkins ◽  
L. Glaser ◽  
...  
Keyword(s):  
Antibiotic Therapy ◽  
Patient Care ◽  
Laboratory Finding ◽  
Acquired Resistance ◽  
Large Family ◽  
Mycobacterium Abscessus ◽  
Chronic Infections ◽  
Content Type ◽  
Human Macrophages

ABSTRACT As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study’s finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen. IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.

scholarly journals Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Shuyi Ma ◽  
Suraj Jaipalli ◽  
Jonah Larkins-Ford ◽  
Jenny Lohmiller ◽  
Bree B. Aldridge ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Computational Model ◽  
Drug Combinations ◽  
Broth Culture ◽  
Multiple Drug ◽  
Content Type ◽  
Drug Synergy ◽  
Drug Regimens

ABSTRACT The rapid spread of multidrug-resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen Mycobacterium tuberculosis (MTB), coupled with the large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico more than 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c upregulation reduces the antagonism of the bedaquiline-streptomycin combination. A retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (P value = 1 × 10−4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens. IMPORTANCE Multidrug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.

scholarly journals Synergistic Efficacy of β-Lactam Combinations againstMycobacterium abscessusPulmonary Infection in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Acquired Resistance ◽  
Mycobacterium Abscessus ◽  
The Novel ◽  
Content Type ◽  
Treatment Regimens ◽  
Chronic Lung Diseases ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Inhibitor Combination

ABSTRACTMycobacterium abscessusis an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinicalM. abscessusisolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several β-lactams againstM. abscessusin vitro; however, these combinations have never been tested in an animal model ofM. abscessuspulmonary disease. We utilized a recently developed murine system of sustainedM. abscessuslung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual β-lactam combinations and one β-lactam/β-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log10reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).

scholarly journals FATE OF MYCOBACTERIUM TUBERCULOSIS IN MOUSE TISSUES AS DETERMINED BY THE MICROBIAL ENUMERATION TECHNIQUE

1956 ◽  
Vol 104 (5) ◽  
pp. 737-762 ◽  
Author(s):  
Robert M. McCune ◽  
Ralph Tompsett
Keyword(s):  
Fatal Outcome ◽  
Multiple Drug ◽  
Uniform Persistence ◽  
Antimicrobial Drugs ◽  
Mouse Tissues ◽  
Drug Regimens ◽  
The Subject ◽  
Drug Influence ◽  
Microbial Enumeration

Observations are presented on the behavior of populations of tubercle bacilli in the tissues of mice during the administration of antimicrobial drugs. The behavior of the populations during therapy with any particular drug was different depending upon whether the tubercle bacilli were subsisting in the lung or in the spleen. Moreover, the pattern of microbial behavior was distinctive and predictable for each drug studied. Changes in the size of the populations of tubercle bacilli in the tissues appeared to be a more sensitive reflection of drug influence than microscopic study of the number and character of the tuberculous lesions. Nevertheless, in untreated animals, pulmonary lesions evolved and progressed steadily to a fatal outcome despite the fact that the populations of tubercle bacilli had stabilized at a relatively high census early in the course of therapy. The uniform persistence of tubercle bacilli in the spleen throughout prolonged drug administration was demonstrated with every drug or multiple drug regimens except for pyrazinamide when accompanied by isoniazid. Cultures of the bacilli which survived in the tissues despite antimicrobial therapy were highly susceptible to the drugs employed when tested in vitro. Thus the survival of the tubercle bacilli in the tissues represented microbial persistence rather than drug resistance. When pyrazinamide and isoniazid were administered together, it was not possible to detect the microorganisms in the spleen or lungs of treated animals. A detailed investigation of this apparent abolition of microbial persistence forms the subject of an accompanying report.

scholarly journals Transcriptomic signatures predict regulators of drug synergy and clinical regimen efficacy against Tuberculosis

2019 ◽  
Author(s):  
Shuyi Ma ◽  
Suraj Jaipalli ◽  
Jonah Larkins-Ford ◽  
Jenny Lohmiller ◽  
Bree B. Aldridge ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Computational Model ◽  
Drug Combinations ◽  
Broth Culture ◽  
Multiple Drug ◽  
P Value ◽  
Drug Synergy ◽  
Drug Regimens

ABSTRACTThe rapid spread of multi-drug resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen M. tuberculosis (MTB), coupled with large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico over 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c up-regulation reduces the antagonism of the bedaquiline-streptomycin combination. Retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (p-value = 1 × 10−4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens.IMPORTANCEMulti-drug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB, which identifies synergistic drug regimens from an immense set of possible drug combinations using pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.

scholarly journals Imipenem for Treatment of Tuberculosis in Mice and Humans

2005 ◽  
Vol 49 (7) ◽  
pp. 2816-2821 ◽  
Author(s):  
Henry F. Chambers ◽  
Joan Turner ◽  
Gisela F. Schecter ◽  
Masae Kawamura ◽  
Philip C. Hopewell
Keyword(s):  
Mouse Model ◽  
Antimycobacterial Activity ◽  
Multiple Drug ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Development Of Resistance ◽  
Multiple Drug Resistant ◽  
Poor Outcomes ◽  
Toxic Drugs

ABSTRACT Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.

Moxifloxacin (BAY12-8039), a New 8-Methoxyquinolone, Is Active in a Mouse Model of Tuberculosis

1999 ◽  
Vol 43 (1) ◽  
pp. 85-89 ◽  
Author(s):  
Eishi Miyazaki ◽  
Miki Miyazaki ◽  
Jong Min Chen ◽  
Richard E. Chaisson ◽  
William R. Bishai
Keyword(s):  
Combination Therapy ◽  
High Titer ◽  
Clinical Strain ◽  
Control Group ◽  
Multiple Drug ◽  
Time Curve ◽  
Highly Effective ◽  
Drug Regimens ◽  
Highly Virulent

ABSTRACT Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be active against Mycobacterium tuberculosis in vitro. We tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, recently isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain was 0.25 μg/ml. The serum moxifloxacin concentration after oral administration in mice peaked within 0.25 h, reaching 7.8 μg/ml with doses of 100 mg/kg of body weight; the maximum concentration and the analysis of the area under the concentration-time curve revealed dose dependency. When mice were infected with a sublethal inoculum of mycobacteria and then treated with moxifloxacin at 100 mg/kg per day for 8 weeks, the log10 CFU counts in the organs of treated mice were significantly lower than those for the control group (0.6 ± 0.2 versus 5.6 ± 0.3 in the lungs and 1.5 ± 0.7 versus 4.9 ± 0.5 in the spleens, respectively;P < 0.001 in both organs). The effectiveness of moxifloxacin monotherapy was comparable to that seen in mice receiving isoniazid alone. Combination therapy with moxifloxacin plus isoniazid was superior to that with moxifloxacin or with isoniazid alone in reducing bacillary counts in the organs studied. Using a sensitive broth-passage subculture method, we demonstrated that 8 weeks of treatment with moxifloxacin (100 mg/kg per day) or with moxifloxacin plus isoniazid (100 mg/kg and 25 mg/kg, respectively, per day) sterilized the lungs in seven of eight and in eight of eight mice, respectively. Among surviving bacilli isolated from animals infected with a high-titer inoculum and treated for 7 weeks with low-dose moxifloxacin (20 mg/kg per day), breakthrough resistance to moxifloxacin was not observed. These results indicate that moxifloxacin is highly effective in reducing M. tuberculosis infection in mice and has activity comparable to that of isoniazid. Combination therapy with moxifloxacin and isoniazid was highly effective, suggesting that moxifloxacin may be useful in multiple-drug regimens for human tuberculosis.

scholarly journals First Documented Case of Percutaneous Endoscopic Gastrostomy (PEG) Tube-Associated Bacterial Peritonitis due to Achromobacter Species with Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Nishant Tripathi ◽  
Niki Koirala ◽  
Hirotaka Kato ◽  
Tushi Singh ◽  
Kishore Karri ◽  
...  
Keyword(s):  
Literature Review ◽  
Percutaneous Endoscopic Gastrostomy ◽  
Spontaneous Bacterial Peritonitis ◽  
Acquired Resistance ◽  
Tube Placement ◽  
Chronic Infections ◽  
Bacterial Peritonitis ◽  
Endoscopic Gastrostomy ◽  
Peg Tube

Introduction. Achromobacter species (spp.) peritonitis has seldom been identified in medical literature. Scarce cases of Achromobacter peritonitis described previously have been correlated with peritoneal dialysis and more sparingly with spontaneous bacterial peritonitis. Achromobacter exhibits intrinsic and acquired resistance, especially in chronic infections, to most antibiotics. This article conducts a literature review of all previously reported Achromobacter spp. peritonitis and describes the first reported case of Achromobacter peritonitis as a complication of percutaneous endoscopic gastrostomy (PEG) tube placement. Discussion. Achromobacter peritonitis as a complication of PEG-tube placement has not been previously reported. In our patients’ case, the recently placed PEG-tube with ascitic fluid leakage was identified as the most plausible infection source. Although a rare bacterial peritonitis pathogen, Achromobacter may be associated with wide antimicrobial resistance and unfavorable outcomes. Conclusion. No current guidelines provide significant guidance on treatment of PEG-tube peritonitis regardless of microbial etiology. Infectious Disease Society of America identifies various broad-spectrum antibiotics targeting nosocomial intra-abdominal coverage; some of these antimicrobial selections (such as cefepime and metronidazole combination) may yet be inadequate for widely resistant Achromobacter spp. Recognizably, the common antibiotics utilized for spontaneous bacterial peritonitis, i.e., third generation cephalosporins and fluoroquinolones, to which Achromobacter is resistant and variably susceptible, respectively, would be extensively insufficient. Piperacillin/tazobactam (P/T) and carbapenem were identified to provide the most reliable coverage in vitro; clinically, 5 out of the 8 patients who received either P/T or a carbapenem, or both, eventually experienced clinical improvement.

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