Association between body mass index and newly diagnosed drug-resistant pulmonary tuberculosis in Shandong, China from 2004 to 2019

Background Drug-resistant tuberculosis (DR-TB), obesity, and malnutrition are growing public health problems in the world. However, little has discussed the impact of different BMI status on the emergence of TB drug resistance. We aimed to explore the drug-resistant profiles of DR-TB and its clinical predictors among underweight, overweight or obesity population. Methods 8957 newly diagnosed TB cases with drug susceptibility results and BMI data in Shandong China, from 2004 to 2019 were enrolled. Multivariable and univariable logistic regression models were applied to investigate the impact of BMI on different drug-resistance. Clinical predicators and drug-resistant profiles of DR-TB among obesity, underweight, normal TB group were also described. Results Among 8957 TB cases, 6417 (71.64%) were normal weight, 2121 (23.68%) were underweight, 373 (4.16%) were overweight, and 46 (0.51%) were obese. The proportion of drug resistance and co-morbidity among normal weight, underweight, overweight, obese TB groups were 18.86%/18.25%/20.38%/23.91% (DR-TB), 11.19%/11.74%/9.65%/17.39% (mono-resistant tuberculosis, MR-TB), 3.41%/3.06%/5.36%/0.00% (multidrug resistant tuberculosis, MDR-TB), 4.21%/3.39%/5.36%/6.52% (polydrug resistant tuberculosis, PDR-TB), 10.57%/8.44%/19.57%/23.91% (co-morbidity), respectively. Compared with normal weight group, underweight were associated with lower risk of streptomycin-related resistance (OR 0.844, 95% CI 0.726–0.982), but contributed to a higher risk of MR-TB (isoniazid) (odds ratio (OR) 1.347, 95% CI 1.049–1.730; adjusted OR (aOR) 1.31, 95% CI 1.017–1.686), P < 0.05. In addition, overweight were positively associated with MDR-TB (OR 1.603, 95% CI 1.002–2.566; aOR 1.639, 95% CI 1.02–2.633), isoniazid + rifampicin + streptomycin resistance (OR 1.948, 95% confidence interval (CI): 1.061–3.577; aOR 2.113, 95% CI 1.141–3.912), Any isoniazid + streptomycin resistance (OR 1.472, 95% CI 1.013–2.14; aOR 1.483, 95% CI 1.017–2.164), P < 0.05. Conclusions The higher risk of MDR-TB, isoniazid + rifampicin + streptomycin resistance, Any isoniazid + streptomycin resistance, and co-morbidity among overweight population implies that routine screening for drug sensitivity and more attention on co-morbidity among overweight TB cases may be necessary. In addition, underweight TB cases have a higher risk of isoniazid resistance. Our study suggests that an in-depth study of the interaction between host metabolic activity and infection of DR-TB may contribute more to novel treatment options or preventive measures, and accelerate the implementation of the STOP TB strategy.

Identification of strA-strB Genes in Streptomycin-Resistant Pseudomonas syringae pv. actinidiae Biovar 2 Strains Isolated in Korea

Bacterial canker is a devastating disease of kiwifruit caused by the bacterium <i>Pseudomonas syringe</i> pv. <i>actinidiae</i>. Canker disease of kiwifruit in Korea has been controlled using streptomycin for more than two decades. Four streptomycin-resistant strains, belonging to biovar 2, which are found only in Korea, were collected between 2013 and 2014 from different orchards located in Jeju, Korea. The genetic background for streptomycin resistance among <i>P. syringe</i> pv. <i>actinidiae</i> strains were determined by examining the presence of <i>strA</i>-<i>strB</i> or <i>aadA</i>, which are genes frequently found in streptomycin-resistant bacteria, and a point mutation at codon 43 in the <i>rpsL</i> gene. All four streptomycin-resistant strains of <i>P. syringe</i> pv. <i>actinidiae</i> investigated in this study contained <i>strA</i>-<i>strB</i> as a resistant determinant. The presence of the <i>aadA</i> gene and a mutation in codon 43 of the <i>rpsL</i> gene was not identified.

Characterization of Mutations Associated with Streptomycin Resistance in Multidrug-Resistant Mycobacterium tuberculosis in Zambia

Streptomycin (STR) is recommended for the management of multidrug-resistant tuberculosis (MDR-TB). Streptomycin resistance-conferring mutation types and frequency are shown to be influenced by genotypes of circulating strains in a population. This study aimed to characterize the mutations in MDR-TB isolates and examine their relationship with the genotypes in Zambia. A total of 138 MDR-TB isolates stored at the University Teaching Hospital Tuberculosis Reference Laboratory in Zambia were analyzed using spoligotyping and sequencing of STR resistance-associated genes. Streptomycin resistance was observed in 65.9% (91/138) of MDR-TB isolates. Mutations in rpsL, rrs, and gidB accounted for 33%, 12.1%, and 49.5%, respectively. Amino acid substitution K43R in rpsL was strongly associated with the CAS1_Kili genotype (p < 0.0001). The combination of three genes could predict 91.2% of STR resistance. Clustering of isolates based on resistance-conferring mutations and spoligotyping was observed. The clustering of isolates suggests that the increase in STR-resistant MDR-TB in Zambia is largely due to the spread of resistant strains from inadequate treatment. Therefore, rapid detection of STR resistance genetically is recommended before its use in MDR-TB treatment in Zambia.

Specific phenotypic, genomic, and fitness evolutionary trajectories toward streptomycin resistance induced by pesticide co-stressors in Escherichia coli

To explore how co-occurring non-antibiotic environmental stressors affect evolutionary trajectories toward antibiotic resistance, we exposed susceptible Escherichia coli K-12 populations to environmentally relevant levels of pesticides and streptomycin for 500 generations. The coexposure substantially changed the phenotypic, genotypic, and fitness evolutionary trajectories, resulting in much stronger streptomycin resistance (>15-fold increase) of the populations. Antibiotic target modification mutations in rpsL and rsmG, which emerged and dominated at late stages of evolution, conferred the strong resistance even with less than 1% abundance, while the off-target mutations in nuoG, nuoL, glnE, and yaiW dominated at early stages only led to mild resistance (2.5–6-fold increase). Moreover, the strongly resistant mutants exhibited lower fitness costs even without the selective pressure and had lower minimal selection concentrations than the mildly resistant ones. Removal of the selective pressure did not reverse the strong resistance of coexposed populations at a later evolutionary stage. The findings suggest higher risks of the selection and propagation of strong antibiotic resistance in environments potentially impacted by antibiotics and pesticides.

Heterogeneous Streptomycin Resistance Level Among Mycobacterium tuberculosis Strains From the Same Transmission Cluster

Widespread and frequent resistance to the second-line tuberculosis (TB) medicine streptomycin, suggests ongoing transmission of low fitness cost streptomycin resistance mutations. To investigate this hypothesis, we studied a cohort of 681 individuals from a TB epidemic in Portugal. Whole-genome sequencing (WGS) analyses were combined with phenotypic growth studies in culture media and in mouse bone marrow derived macrophages. Streptomycin resistance was the most frequent resistance in the cohort accounting for 82.7% (n = 67) of the resistant Mycobacterium tuberculosis isolates. WGS of 149 clinical isolates identified 13 transmission clusters, including three clusters containing only streptomycin resistant isolates. The biggest cluster was formed by eight streptomycin resistant isolates with a maximum of five pairwise single nucleotide polymorphisms of difference. Interestingly, despite their genetic similarity, these isolates displayed different resistance levels to streptomycin, as measured both in culture media and in infected mouse bone marrow derived macrophages. The genetic bases underlying this phenotype are a combination of mutations in gid and other genes. This study suggests that specific streptomycin resistance mutations were transmitted in the cohort, with the resistant isolates evolving at the cluster level to allow low-to-high streptomycin resistance levels without a significative fitness cost. This is relevant not only to better understand transmission of streptomycin resistance in a clinical setting dominated by Lineage 4 M. tuberculosis infections, but mainly because it opens new prospects for the investigation of selection and spread of drug resistance in general.

A novel mechanism of streptomycin resistance in Yersinia pestis: Mutation in the rpsL gene

Streptomycin is considered to be one of the effective antibiotics for the treatment of plague. In order to investigate the streptomycin resistance of Y. pestis in China, we evaluated streptomycin susceptibility of 536 Y. pestis strains in China in vitro using the minimal inhibitory concentration (MIC) and screened streptomycin resistance-associated genes (strA and strB) by PCR method. A clinical Y. pestis isolate (S19960127) exhibited high-level resistance to streptomycin (the MIC was 4,096 mg/L). The strain (biovar antiqua) was isolated from a pneumonic plague outbreak in 1996 in Tibet Autonomous Region, China, belonging to the Marmota himalayana Qinghai–Tibet Plateau plague focus. In contrast to previously reported streptomycin resistance mediated by conjugative plasmids, the genome sequencing and allelic replacement experiments demonstrated that an rpsL gene (ribosomal protein S12) mutation with substitution of amino-acid 43 (K43R) was responsible for the high-level resistance to streptomycin in strain S19960127, which is consistent with the mutation reported in some streptomycin-resistant Mycobacterium tuberculosis strains. Streptomycin is used as the first-line treatment against plague in many countries. The emergence of streptomycin resistance in Y. pestis represents a critical public health problem. So streptomycin susceptibility monitoring of Y. pestis isolates should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation, especially when treatment failure is suspected due to antibiotic resistance.

Investigating the distribution of strains of Erwinia amylovora and streptomycin resistance in apple orchards in New York using CRISPR profiles: a six-year follow-up

Fire blight, caused by the bacterium Erwinia amylovora, is one of the most important diseases of apple. The antibiotic streptomycin is routinely used in the commercial apple industries of New York and New England to manage the disease. In 2002, and again from 2011 to 2014, outbreaks of streptomycin resistance (SmR) were reported and investigated in NY. Motivated by new grower reports of control failures, we conducted a follow-up investigation of the distribution of SmR and E. amylovora strains for major apple production regions of NY over the last six years (2015-2020). Characterization of clustered regularly interspaced short palindromic repeat (CRISPR) profiles revealed that a few ‘cosmopolitan’ strains were widely prevalent across regions, while many other ‘resident’ strains were confined to one location. In addition, we uncovered novel CRISPR profile diversity in all investigated regions. SmR E. amylovora was detected only in a small area spanning two counties from 2017 to 2020, and always associated with one CRISPR profile (41:23:38), which matched the profile of SmR E. amylovora discovered in 2002. This suggests the original SmR E. amylovora was never fully eradicated and went undetected due to several seasons of low disease pressure in this region. Investigation of several representative isolates under controlled greenhouse conditions indicated significant differences in aggressiveness on ‘Gala’ apples. Potential implications of strain differences include the propensity of strains to become distributed across wide geographic regions and associated resistance management practices. Results from this work will directly influence sustainable fire blight management recommendations for commercial apple industries in NY State and other regions.