A Clinical Case of Extensive Drug Resistant Pulmonary Tuberculosis Using an Endobronchial Valve. Analysis of Errors in the Choice of Chemotherapy Regimen

The article describes a clinical case of a female patient with respiratory tuberculosis exposed to several cases of extensive drug resistance in their family. Tuberculosis progressed in this patient due to the late initiation of adequate treatment. Therefore, the total duration of chemotherapy made 5 years till cure was achieved and an endobronchial valve was used to heal persisting (for 3 years) lung destruction.

Genomic Characterization of a Proteus sp. Strain of Animal Origin Co-Carrying blaNDM-1 and lnu(G)

The emergence of carbapenem-resistant Proteus represents a serious threat to global public health due to limited antibiotic treatment options. Here, we characterize a Proteus isolate NMG38-2 of swine origin that exhibits extensive drug resistance, including carbapenems. Whole-genome sequencing based on Illumina and MinION platforms showed that NMG38-2 contains 24 acquired antibiotic resistance genes and three plasmids, among which, pNDM_NMG38-2, a pPvSC3-like plasmid, is transferable and co-carries blaNDM-1 and lnu(G). Sequence analysis of pPvSC3-like plasmids showed that they share a conserved backbone but have a diverse accessory module with complex chimera structures bearing abundant resistance genes, which are facilitated by transposons and/or homologous recombination. The acquisition of blaNDM-1 in pNDM_NMG38-2 was due to the ISCR1-mediated integration event. Comprehensive analysis of the lnu(G)-bearing cassettes carried by bacterial plasmids or chromosomes revealed a diversification of its genetic contexts, with Tn6260 and ISPst2 elements being the leading contributors to the dissemination of lnu(G) in Enterococcus and Enterobacteriaceae, respectively. In conclusion, this study provides a better understanding of the genetic features of pPvSC3-like plasmids, which represent a novel plasmid group as a vehicle mediating the dissemination of blaNDM-1 among bacteria species. Moreover, our results highlight the central roles of Tn6260 and ISPst2 in the spread of lnu(G).

Multiple-Replicon Resistance Plasmids of Klebsiella Mediate Extensive Dissemination of Antimicrobial Genes

Multiple-replicon resistance plasmids have become important carriers of resistance genes in Gram-negative bacteria, and the evolution of multiple-replicon plasmids is still not clear. Here, 56 isolates of Klebsiella isolated from different wild animals and environments between 2018 and 2020 were identified by phenotyping via the micro-broth dilution method and were sequenced and analyzed for bacterial genome-wide association study. Our results revealed that the isolates from non-human sources showed more extensive drug resistance and especially strong resistance to ampicillin (up to 80.36%). The isolates from Malayan pangolin were particularly highly resistant to cephalosporins, chloramphenicol, levofloxacin, and sulfamethoxazole. Genomic analysis showed that the resistance plasmids in these isolates carried many antibiotic resistance genes. Further analysis of 69 plasmids demonstrated that 28 plasmids were multiple-replicon plasmids, mainly carrying beta-lactamase genes such as blaCTX–M–15, blaCTX–M–14, blaCTX–M–55, blaOXA–1, and blaTEM–1. The analysis of plasmids carried by different isolates showed that Klebsiella pneumoniae might be an important multiple-replicon plasmid host. Plasmid skeleton and structure analyses showed that a multiple-replicon plasmid was formed by the fusion of two or more single plasmids, conferring strong adaptability to the antibiotic environment and continuously increasing the ability of drug-resistant isolates to spread around the world. In conclusion, multiple-replicon plasmids are better able to carry resistance genes than non-multiple-replicon plasmids, which may be an important mechanism underlying bacterial responses to environments with high-antibiotic pressure. This phenomenon will be highly significant for exploring bacterial resistance gene transmission and diffusion mechanisms in the future.

Potential sources and characteristic occurrence of mobile colistin resistance (mcr) gene-harbouring bacteria recovered from the poultry sector: a literature synthesis specific to high-income countries

Understanding the sources, prevalence, phenotypic and genotypic characteristics of mcr gene-harbouring bacteria (MGHB) in the poultry sector is crucial to supplement existing information. Through this, the plasmid-mediated colistin resistance (PMCR) could be tackled to improve food safety and reduce public health risks. Therefore, we conducted a literature synthesis of potential sources and characteristic occurrence of MGHB recovered from the poultry sector specific to the high-income countries (HICs). Colistin (COL) is a last-resort antibiotic used for treating deadly infections. For more than 60 years, COL has been used in the poultry sector globally, including the HICs. The emergence and rapid spread of mobile COL resistance (mcr) genes threaten the clinical use of COL. Currently, ten mcr genes (mcr-1 to mcr-10) have been described. By horizontal and vertical transfer, the mcr-1, mcr-2, mcr-3, mcr-4, mcr-5, and mcr-9 genes have disseminated in the poultry sector in HICs, thus posing a grave danger to animal and human health, as harboured by Escherichia coli, Klebsiella pneumoniae, Salmonella species, and Aeromonas isolates. Conjugative and non-conjugative plasmids are the major backbones for mcr in poultry isolates from HICs. The mcr-1, mcr-3 and mcr-9 have been integrated into the chromosome, making them persist among the clones. Transposons, insertion sequences (IS), especially ISApl1 located downstream and upstream of mcr, and integrons also drive the COL resistance in isolates recovered from the poultry sector in HICs. Genes coding multi-and extensive-drug resistance and virulence factors are often co-carried with mcr on chromosome and plasmids in poultry isolates. Transmission of mcr to/among poultry strains in HICs is clonally unrestricted. Additionally, the contact with poultry birds, manure, meat/egg, farmer’s wears/farm equipment, consumption of contaminated poultry meat/egg and associated products, and trade of poultry-related products continue to serve as transmission routes of MGHB in HICs. Indeed, the policymakers, especially those involved in antimicrobial resistance and agricultural and poultry sector stakeholders-clinical microbiologists, farmers, veterinarians, occupational health clinicians and related specialists, consumers, and the general public will find this current literature synthesis very useful.

Beta-lactam antibiotics as reserve medications for the treatment of drug-resistant tuberculosis

The review article presents an analysis of literature data on the necessity to expand the range of medications possessing anti-tuberculosis activity for the treatment of the most severe forms of drug-resistant tuberculosis through the use of beta-lactam antibiotics in chemotherapy regimens. The mechanism of action of beta- lactam antibiotics on mycobacterium tuberculosis is shown, and the results of in vitro studies to assess their anti-tuberculosis activity are presented. Clinical studies on the use of carbapenems prove the feasibility of their use for the treatment of patients with tuberculosis with multiple and extensive drug resistance of the pathogen.

Study of Biofilm Formation and Antibiotic Resistant Profile in Multidrug Resistant and Extensive Drug Resistance Pseudomonas Aeruginosa Isolated from Burn Wound Infections in Southwest Iran

The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of Sulbactam-Durlobactam holds promise for therapeutic intervention

Acinetobacter baumannii is an emerging nosocomial strain expressing extensive drug resistance (XDR). Whole-genome sequencing and molecular characterisation analysis revealed the presence of carbapenemase in 92.86% of studied Indian isolates having blaOXA-51, blaOXA-23, blaOXA-58, and blaNDM genes, with a few evidences of dual carbapenemase genes. As per the MLST scheme, IC2Oxf/CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of β-lactamases has rendered sulbactam (SUL) resistance (MIC: 16-256μg/ml) in all the studied isolates. The efficacy of novel durlobactam (DUR) in inhibiting β-lactamases and PBP2 was assessed through in-silico inter-molecular interaction analysis. Several non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein-backbone dynamics in active-site motifs of wild-type (WT) and mutants (MT), which correlated with the negligible binding energy fluctuations for PBP3-SUL (-5.85±.04Kcal/mol) and PBP2-DUR (-5.16±0.66Kcal/mol) complexes. Furthermore, stronger binding affinities and low inhibition constants were noted in DUR complexed with OXA23 (-7.36Kcal/mol; 4.01 μM), OXA58 (-6.44Kcal/mol; 19.07 μM) and NDM (-6.82Kcal/mol; 10.01 μM) when compared with conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR, can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of novel SUL-DUR combination as a successful treatment strategy to combat emerging XDR strains.

Study of Biofilm Formation and Antibiotic Resistant Profile in Multidrug Resistant and Extensive Drug Resistance Pseudomonas Aeruginosa Isolated from Burn Wound Infections in Southwest Iran

Background: Pseudomonas aeruginosa is an opportunistic pathogen that has remained on the ‘top 10’ common hospital ‘superbugs’ worldwide for more than a decade. Study of biofilm formation and antibiotic resistant profile in multidrug resistant and extensive drug resistance P. aeruginosa isolated from burn wound infections in southwest IranMethods and Results: This study, which was performed in 110 P. aeruginosa isolates culture-positive reports. Assessment of biofilm formation via microtiteplate and congo red agar. Overall, 110 clinical P. aeruginosa isolates were confirmed from wound burn infections. The maximum resistance rate among P. aeruginosa isolates to antibiotics tested was as follow Piperacillin, ceftazidime, and minimum resistance rate among P. aeruginosa isolates to antibiotics tested such as ticarcillin-clavulanic acid. The isolates were then evaluating the MICs by using the E-test. only 7 isolates were confirmed as colistin-resistant. Colistin reference MICs for the The prevalence of MDR P. aeruginosa was 38% and XDR- P. aeruginosa was 22% respectively. One of P. aeruginosa isolates were PDR. In microtiteplate assay,76% of the isolates have ability for biofilm, formation, 40% were categorized as strong biofilm-formers; 32% were moderate; 21% were weak biofilm formers and 43% could not form any detectable biofilm. Conclusion: in our study development of resistance by P. aeruginosa to many antimicrobial agents is a great challenge in controlling its infections. Therefore, the transmission of these isolates to patients leads to higher resistance. Therefore, the necessary hygiene measurements should be taken for the prevention of transferring the P. aeruginosa isolates to hospitalized patients.

Determination of Duration of the Intensive Phase of Chemotherapy for Respiratory Tuberculosis in Children without Bacterial Excretion and at No Risk of Multiple and Extensive Drug Resistance

The objective of the study: to develop criteria to evaluate the duration of the intensive phase of chemotherapy for respiratory tuberculosis in children without bacterial excretion and at no risk of multiple and extensive drug resistance of tuberculous mycobacteria.Subjects and methods. Totally, 93 patients with newly diagnosed respiratory tuberculosis without bacterial excretion and at no risk of multiple and extensive drug resistance of tuberculous mycobacteria. Their age varied from 2 to 12 years old. Regimen III was used: the intensive phase – 4 drugs (isoniazid, rifampicin, pyrazinamide, ethambutol – HRZE).Results. The intensive phase lasted for 2 months in 39.8% of cases – the main criteria were achieved (relief of intoxication symptoms, normal blood rates, positive or stable CT changes) after 2 months and there was no indication to extend the duration of it. The intensive phase lasted for 3 months in 37.6% of cases – the main criteria were achieved after 2 months and there was at least one additional indication to extend it (17.2%); and the main criteria were achieved after 3 months and there was no indication to extend the duration of it (20.4%). The intensive phase lasted for more than 3 months (4 to 6 months) in 22.6% of cases – the main criteria were achieved after 3 months and there was at least one additional indication to extend it (12.9%), as well as in the case of failure to achieve the main criteria after 3 months regardless of the presence/absence of additional indications to extend its duration (9.7%).Conclusion. Various combinations of the main criteria and additional indications made the basis for differential approach to determining the duration of the intensive phase of chemotherapy in children with respiratory tuberculosis

Factors associated with unfavorable treatment outcomes in patients with rifampicin-resistant tuberculosis in Colombia 2013–2015: A retrospective cohort study

Background Multidrug- and rifampicin (RMP)-resistant tuberculosis (MDR/RR-TB) requires prolonged and expensive treatment, which is difficult to sustain in the Colombian health system. This requires the joint action of different providers to provide timely health services to people with TB. Identifying factors associated with unfavorable treatment outcomes in patients with MDR/RR-TB who received drug therapy between 2013 and 2015 in Colombia can help guide the strengthening of the national TB control program. Method A retrospective cohort study was conducted with all patients who received treatment for MDR/RR-TB between January 2013 and December 2015 in Colombia who were registered and followed up by the national TB control program. A multivariate logistic regression model was used to estimate the associations between the exposure variables with the response variable (treatment outcome). Results A total of 511 patients with MDR/RR-TB were registered and followed up by the national TB control program in Colombia, of whom 16 (3.1%) had extensive drug resistance, 364 (71.2%) had multidrug resistance, and 131 (25.6%) had RMP monoresistance. The mean age was 39.9 years (95% confidence interval (CI): 38.5–41.3), most patients were male 285 (64.6%), and 299 (67.8%) were eligible for subsidized health services. The rate of unfavorable treatment outcomes in the RR-TB cohort was 50.1%, with rates of 85.7% for patients with extensive drug resistance, 47.6% for patients with multidrug resistance, and 52.6% for patients with RMP monoresistance. The 511 MDR/RR-TB patients were included in bivariate and multivariate analyses, patients age ≥ 60 years (crude odds ratio (ORc) = 2.4, 95% CI 1.1–5.8; adjusted odds ratio (ORa) = 2.7, 95% CI 1.1–6.8) and subsidized health regime affiliation (ORc = 3.6, 95% CI 2.3–5.6; ORa = 3.4, 95% CI 2.0–6.0) were associated with unfavorable treatment outcomes. Conclusion More than 50% of the patients with MDR/RR-TB in Colombia experienced unfavorable treatment outcomes. The patients who were eligible for subsidized care were more likely to experience unfavorable treatment outcomes. Those who were older than 60 years were also more likely to experience unfavorable treatment outcomes.