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Microbiology Spectrum Feb 2024pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate...
pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate of resistance. Amikacin is critical to treatment, but the development of toxicity, amikacin resistance, and treatment failure are significant challenges. Amikacin has been characterized previously as peak-dependent and extended-interval dosing is commonly used. In our hollow fiber infection model of , amikacin exhibited time-dependent rather than the expected peak-dependent pharmacodynamics. Humanized amikacin exposures with more frequent, short-interval dosing (continuous infusion or every 12 hours) yielded improved microbiological response compared to extended-interval dosing (every 24 hours or 1-3 times per week). Short-interval dosing inhibited growth with a mean (SD) maximum Δlog colony forming units of -4.06 (0.52), significantly more than extended-interval dosing ( = 0.0013) every 24 hours, -2.40 (0.58), or 1-3 times per week, -2.39 (0.38). Growth recovery, an indicator of resistance emergence, occurred at 6.56 (0.70) days with short-interval dosing but was significantly earlier with extended-interval dosing ( = 0.0032) every 24 hours, 3.88 (0.85) days, and 1-3 times per week, 3.27 (1.72) days. Microbiological response correlated best with the pharmacodynamic index of %T > minimum inhibitory concentration (MIC), with an EC for growth inhibition of ~40%T > MIC. We used a previously published population model of amikacin to determine the probability of achieving 40%T > MIC and show that current dosing strategies are far below this target, which may partially explain why treatment failure remains so high for these infections. These data support a cautious approach to infrequent amikacin dosing for the treatment of .IMPORTANCEPulmonary disease caused by complex (MABSC) is increasing worldwide, particularly in patients with cystic fibrosis. MABSC is challenging to treat due to high levels of antibiotic resistance. Treatment requires 2-4 antibiotics over more than 12 months and has a significant risk of toxicity but still fails to eradicate infection in over 50% of patients with cystic fibrosis. Antibiotic dosing strategies have been largely informed by common bacteria such as . The "pharmacodynamic" effects of amikacin, a backbone of MABSC treatment, were thought to be related to maximum "peak" drug concentration, leading to daily or three times weekly dosing. However, we found that amikacin MABSC kill and growth recovery, an indicator of antibiotic resistance, are dependent on how long amikacin concentrations are above the minimum inhibitory concentration, not how high the peak concentration is. Therefore, we recommend a re-evaluation of amikacin dosing to determine if increased frequency can improve efficacy.
Topics: Humans; Amikacin; Mycobacterium abscessus; Cystic Fibrosis; Anti-Bacterial Agents; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous
PubMed: 38236037
DOI: 10.1128/spectrum.03222-23 -
Antimicrobial Agents and Chemotherapy Jul 2023Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of...
Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
Topics: Humans; Mycobacterium abscessus; Azithromycin; Anti-Bacterial Agents; Amikacin; Mycobacterium Infections, Nontuberculous; Drug Interactions; Microbial Sensitivity Tests
PubMed: 37278639
DOI: 10.1128/aac.00090-23 -
Biofilm Dec 2023Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose...
OBJECTIVES
Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose people to lung infection by inhaled bacteria that form biofilm aggregates. Nontuberculous mycobacteria (NTM), primarily and are the growing cause of these lung infections and are extremely challenging to treat due to antibiotic recalcitrance. Better therapeutic approaches are urgently needed. We developed a humanized monoclonal antibody (HuTipMab) directed against a biofilm structural linchpin, the bacterial DNABII proteins, that rapidly disrupts biofilms and generates highly vulnerable newly released bacteria (NRel).
METHODS
HuTipMab's ability to recognize HupB, NTM's DNABII homologue was determined by ELISA. Relative ability of HuTipMab to disrupt biofilms formed by lab-passaged and clinical isolates of NTM was assessed by CLSM. Relative sensitivity of NTM NRel to antibiotic killing compared to when grown planktonically was evaluated by plate count.
RESULTS
HuTipMab recognized HupB and significantly disrupted NTM biofilms in a time- and dose-dependent manner. Importantly, NTM NRel of lab-passaged and clinical isolates were now highly sensitive to killing by amikacin and azithromycin.
CONCLUSIONS
If successful, this combinatorial treatment strategy would empower existing antibiotics to more effectively kill NTM newly released from a biofilm by HuTipMab and thereby both improve clinical outcomes and perhaps decrease length of antibiotic treatment for people that are NTM culture-positive.
PubMed: 38078059
DOI: 10.1016/j.bioflm.2023.100166 -
BMC Medical Genomics Oct 2023The study of CCR7/CCL19 chemokine axis and breast cancer (BC) prognosis and metastasis is a current hot topic. We constructed a ceRNA network and risk-prognosis model...
BACKGROUND
The study of CCR7/CCL19 chemokine axis and breast cancer (BC) prognosis and metastasis is a current hot topic. We constructed a ceRNA network and risk-prognosis model based on CCR7/CCL19.
METHODS
Based on the lncRNA, miRNA and mRNA expression data downloaded from the TCGA database, we used the starbase website to find the lncRNA and miRNA of CCR7/CCL19 and established the ceRNA network. The 1008 BC samples containing survival data were divided into Train group (504 cases) and Test group (504 cases) using R "caret" package. Then we constructed a prognostic risk model using RNA screened by univariate Cox analysis in the Train group and validated it in the Test and All groups. In addition, we explored the correlation between riskScores and clinical trials and immune-related factors (22 immune-infiltrating cells, tumor microenvironment, 13 immune-related pathways and 24 HLA genes). After transfection with knockdown CCR7, we observed the activity and migration ability of MDA-MB-231 and MCF-7 cells using CCK8, scratch assays and angiogenesis assays. Finally, qPCR was used to detect the expression levels of five RNAs in the prognostic risk model in MDA-MB-231 and MCF-7 cell.
RESULTS
Patients with high expression of CCR7 and CCL19 had significantly higher overall survival times than those with low expression. The ceRNA network is constructed by 3 pairs of mRNA-miRNA pairs and 8 pairs of miRNA-lncRNA. After multivariate Cox analysis, we obtained a risk prognostic model: riskScore= -1.544 *`TRG-AS1`+ 0.936 * AC010327.5 + 0.553 *CCR7 -0.208 *CCL19 -0.315 *`hsa-let-7b-5p. Age, stage and riskScore can all be used as independent risk factors for BC prognosis. By drug sensitivity analysis, we found 5 drugs targeting CCR7 (convolamine, amikacin, AH-23,848, ondansetron, flucloxacillin). After transfection with knockdown CCR7, we found a significant reduction in cell activity and migration capacity in MDA-MB-231 cells.
CONCLUSION
We constructed the first prognostic model based on the CCR7/CCL19 chemokine axis in BC and explored its role in immune infiltration, tumor microenvironment, and HLA genes.
Topics: Humans; Female; Chemokine CCL19; Breast Neoplasms; Prognosis; Receptors, CCR7; RNA, Long Noncoding; MicroRNAs; Biomarkers, Tumor; RNA, Messenger; Tumor Microenvironment
PubMed: 37864213
DOI: 10.1186/s12920-023-01683-9 -
BMC Microbiology Oct 2023Hospital infections such as ventilator-associated pneumonia (VAP) due to multidrug-resistant Klebsiella pneumoniae (MDR-KP) strains have increased worldwide. In...
In Vitro antibiotic combinations of Colistin, Meropenem, Amikacin, and Amoxicillin/clavulanate against multidrug-resistant Klebsiella pneumonia isolated from patients with ventilator-associated pneumonia.
BACKGROUND
Hospital infections such as ventilator-associated pneumonia (VAP) due to multidrug-resistant Klebsiella pneumoniae (MDR-KP) strains have increased worldwide. In addition, biofilm production by these resistant isolates has confronted clinicians with higher treatment failure and infection recurrence. Given the paucity of new agents and limited data on combination therapy for MDR-KPs, the present study sought to evaluate the in vitro activity of several antibiotic combinations against planktonic and biofilm MDR-KPs isolated from patients with VAP.
RESULTS
All 10 carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates demonstrated multidrug resistance against the tested antibiotics. At planktonic mode, combinations of colistin-meropenem and amoxicillin/clavulanate in combination with meropenem, colistin, or amikacin showed synergism against 60-70% isolates. On the other hand, in the biofilm state, colistin-based combinations exhibited synergism against 50-70% isolates and the most effective combination was colistin-amikacin with 70% synergy.
CONCLUSIONS
The results revealed that combinations of amoxicillin/clavulanate with colistin, meropenem, or amikacin in the planktonic mode and colistin with amoxicillin/clavulanate, meropenem, or amikacin in the biofilm mode could effectively inhibit CRKP isolates, and thus could be further explored for the treatment of CRKPs.
Topics: Humans; Meropenem; Colistin; Amikacin; Pneumonia, Ventilator-Associated; Klebsiella pneumoniae; Drug Synergism; Anti-Bacterial Agents; Klebsiella Infections; Amoxicillin-Potassium Clavulanate Combination; Microbial Sensitivity Tests
PubMed: 37864176
DOI: 10.1186/s12866-023-03039-w -
European Review For Medical and... Aug 2023The aim of our study is to determine the uropathogenic causing urinary tract infections (UTIs) and their incidences, assess their antibiotic resistance, and determine an...
OBJECTIVE
The aim of our study is to determine the uropathogenic causing urinary tract infections (UTIs) and their incidences, assess their antibiotic resistance, and determine an appropriate empirical antibiotic treatment strategy.
PATIENTS AND METHODS
We retrospectively analyzed the culture and antibiogram results of urine cultures of 49,706 patients aged 1 day to 18 years who applied to Diyarbakır Children's Hospital between March 2018 and October 2022.
RESULTS
A total of 4,064 cases meeting the study criteria were recorded. Girls comprised 76.7% of the study population. While reproduction in urine culture was more common in boys in the 0-1 age group, there was a decrease in the number of boys with increasing age, and the most common culture growth was seen in girls in the 5-10 age group (p<0.001). Escherichia coli (E. coli) infections were more common in girls, while non-E. coli infections were more common in boys (p<0.001). Gram-negative bacterial growth in urine cultures was the most common growth type. In descending order, E. coli was grown in 68.1% of all cultures, Klebsiella spp in 12.6%, and Proteus spp in 3.9%. Less commonly, Pseudomonas spp (2.8%), Enterobacter spp (1.5%), and fungi (1.1%) were grown. Antibiotic resistance/sensitivity tests revealed resistance patterns most commonly against ampicillin (73.2%), amoxicillin-clavulanate (57.9%), cefuroxime axetil (46.7%), cefixime (51%), and ceftriaxone (40.5%), and less commonly against meropenem (1.7%), amikacin (2.4%), and nitrofurantoin (9.8%). Escherichia coli showed resistance most commonly against ampicillin (69.8%), amoxicillin-clavulanate (59.7%), and cefixime (51.3%), while non-E.coli bacteria showed resistance most commonly against ampicillin (84.6%), amoxicillin (52.0%), and cefixime (50%). Resistance against nitrofurantoin was lower in E. coli infections than non-E. coli infections, although the difference did not reach statistical significance (3.7% and 27%, respectively; p=0.149). In contrast, resistance against trimethoprim-sulfamethoxazole was more common in E. coli infections than non-E. coli infections, although the difference was not statistically significant (42% and 29.7%, respectively; p=0.093).
CONCLUSIONS
Our study revealed that resistance has developed at very high rates against many oral and parenteral antibiotics that we use in the treatment of UTIs. If our rate of antibiotic use continues to increase this way, it is predicted that UTIs will, unfortunately, become untreatable with oral antibiotics. This upsetting point reached by our country, which is the state that uses antibiotics the most in Europe, exemplifies the importance of rational antibiotic use for the whole world.
Topics: Male; Female; Humans; Child; Infant, Newborn; Infant; Child, Preschool; Anti-Bacterial Agents; Cefixime; Nitrofurantoin; Retrospective Studies; Urinary Tract Infections; Ampicillin; Amoxicillin; Drug Resistance, Microbial; Amoxicillin-Potassium Clavulanate Combination; Escherichia coli
PubMed: 37667945
DOI: 10.26355/eurrev_202308_33421 -
Journal of Global Antimicrobial... Dec 2023Ceftazidime-avibactam (CAZ-AVI) combines ceftazidime and a reversible β-lactamase inhibitor that has shown activity against multidrug-resistant (MDR) Enterobacterales...
OBJECTIVES
Ceftazidime-avibactam (CAZ-AVI) combines ceftazidime and a reversible β-lactamase inhibitor that has shown activity against multidrug-resistant (MDR) Enterobacterales and P. aeruginosa. Using data from the Antimicrobial Testing Leadership and Surveillance program (ATLAS), this study examined the in vitro antimicrobial activity of CAZ-AVI and other antibiotics against Gram-negative bacteria collected from Chilean hospitals between 2015 and 2021.
METHODS
Clinical isolates of Enterobacterales and P. aeruginosa were collected from three medical centres in Chile. Blood, abdominal fluid, urine, soft tissues, and respiratory tract samples were obtained from infected patients. Minimum inhibitory concentrations using the broth microdilution method were determined for susceptibility testing, and the Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for interpreting the results. Extended-spectrum β-lactamases (ESBL) and carbapenemase genes were also detected through polymerase chain reaction.
RESULTS
A total of 2600 Enterobacterales and 836 P. aeruginosa were analysed. CAZ-AVI was the antibiotic with the highest in vitro activity against Enterobacterales (99.72%). The incidence of carbapenem-resistant Enterobacterales (CRE) was 1.5% (n = 39), and the antibiotics with the best in vitro activity were tigecycline (92.31%), CAZ-AVI (88.57%), and amikacin (79.49%). CAZ-AVI was the antibiotic with the best activity against ESBL-producing Enterobacterales (99.34%) and MDR Enterobacterales (99.31%). For KPC-producing Enterobacterales, susceptibility to amikacin was 100%, whereas susceptibility to CAZ-AVI was 91.67%. Regarding MDR and difficult-to-treat resistance P. aeruginosa, 44.83% and 38.99% were susceptible to CAZ-AVI, respectively.
CONCLUSION
CAZ-AVI shows excellent in vitro activity against Enterobacterales in general, CRE, ESBL-producing Enterobacterales, and KPC-producing Enterobacterales. CAZ-AVI is also an option against MDR P. aeruginosa.
Topics: Humans; Ceftazidime; Chile; Amikacin; Anti-Bacterial Agents; Carbapenems; Pseudomonas aeruginosa
PubMed: 37714380
DOI: 10.1016/j.jgar.2023.09.004 -
Frontiers in Medicine 2023Carbapenem-resistant (CRE) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections are associated with a high risk of morbidity, mortality, and treatment...
, and clinical studies comparing the efficacy of ceftazidime-avibactam monotherapy with ceftazidime-avibactam-containing combination regimens against carbapenem-resistant and multidrug-resistant isolates or infections: a scoping review.
INTRODUCTION
Carbapenem-resistant (CRE) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections are associated with a high risk of morbidity, mortality, and treatment costs. We aimed to evaluate , and clinical studies comparing the efficacy of ceftazidime-avibactam (CZA) combination regimens with CZA alone against CRE and/or MDR-PA isolates or infections.
METHODS
We systematically reviewed the relevant literature in CINAHL/MEDLINE, Pubmed, Cochrane, Web of Science, Embase, and Scopus until December 1, 2022. Review articles, grey literature, abstracts, comments, editorials, non-peer reviewed articles, non-English articles, and in vitro synergy studies conducted on single isolates were excluded.
RESULTS
22 , 7 and 20 clinical studies were evaluated. studies showed reliable synergy between CZA and aztreonam against metallo-β-lactamase (MBL)-producing isolates. Some studies indicated good in vitro synergy between CZA and amikacin, meropenem, fosfomycin and polymyxins against CRE isolates. For MDR-PA isolates, there are comparatively fewer or studies. In observational clinical studies, mortality, clinical cure, adverse events, and development of CZA resistance after exposure were generally similar in monotherapy and combination therapy groups. However, antibiotic-related nephrotoxicity and infection relapses were higher in patients receiving CZA combination therapies.
DISCUSSION
The benefit, if any, of CZA combination regimens in MDR-PA infections is elusive, as very few clinical studies have included these infections. There is no currently documented clinical benefit for the use of CZA combination regimens rather than CZA monotherapy. CZA combined with aztreonam for serious infections due to MBL producers should be evaluated by randomized controlled trials.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278552, CRD42021278552.
PubMed: 37727767
DOI: 10.3389/fmed.2023.1249030 -
Microbiology Spectrum Aug 2023Tigecycline is an important antibacterial drug for treating infection by clinical multidrug-resistant bacteria, and tigecycline-resistant Staphylococcus aureus (TRSA)...
Tigecycline is an important antibacterial drug for treating infection by clinical multidrug-resistant bacteria, and tigecycline-resistant Staphylococcus aureus (TRSA) has been increasingly reported in recent years. Notably, only and are associated with the tigecycline resistance of S. aureus. The gene encodes MepA efflux pumps, and the overexpression of has been confirmed to be directly related to tigecycline resistance. Although the mutations of MepA widely occur, the associations between TRSA and mutations of MepA are still unclear. In this study, we explored mutations in the genes from various sources. Then, tigecycline resistance-associated mutations T29I, E287G, and T29I+E287G in MepA were identified, and their effects were evaluated through mutant deletion and complementation, tigecycline accumulation assay, and molecular docking experiments. Results showed that the MICs of tigecycline, gentamicin, and amikacin increased in special complementary transformants and recovered after the addition of the efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The tigecycline accumulation assay of the -deleted mutant strain and its complementary transformants showed that T29I, E287G, and T29I+E287G mutations promoted tigecycline efflux, and molecular docking showed that mutations T29I, E287G, and T29I+E287G decreased the binding energy and contributed to ligand binding. Moreover, we inferred the evolutionary trajectory of S. aureus under the selective pressure of tigecycline . Overall, our study indicated that mutations in MepA play important roles in tigecycline resistance in S. aureus. Previous analysis has shown that overexpression of MepA is an exact mechanism involved in tigecycline resistance apart from the mutation and is usually dependent on the mutant . However, no research has evaluated the effects of diverse mutations discovered in TRSA in MepA. This study demonstrates that the mutations in MepA confer resistance to tigecycline without overexpression and provides genotypic references for identifying TRSA. Although tigecycline resistance-associated mutations in MepA identified in this study have not been observed in clinical isolates, the mechanism should be explored given that S. aureus strains are prevalent in the environment. Measures should be implemented to contain TRSA within the time window before tigecycline resistance-associated mutations in MepA are prevalent.
Topics: Humans; Tigecycline; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Molecular Docking Simulation; Anti-Bacterial Agents; Staphylococcal Infections; Mutation; Microbial Sensitivity Tests; Bacterial Proteins
PubMed: 37432114
DOI: 10.1128/spectrum.00634-23 -
BMC Infectious Diseases Sep 2023Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing...
Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia.
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis.
METHODS
Here, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR-TB isolates. Overall, data for 12 anti-TB medications were analyzed.
RESULTS
In total, 63 MDR-TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR-TB cases in Latvia in 2012-2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates.
CONCLUSIONS
WGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Ethambutol; Isoniazid; Rifampin; Amikacin; Ethionamide; Capreomycin; Microbial Sensitivity Tests; Latvia; Moxifloxacin; Drug Resistance, Multiple, Bacterial; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing; Tuberculosis; Kanamycin
PubMed: 37770850
DOI: 10.1186/s12879-023-08629-7