Transcriptomic responses to antibiotic exposure in Mycobacterium tuberculosis.

Transcriptional responses in bacteria following antibiotic exposure offer insights into antibiotic mechanism of action, bacterial responses, and characterization of antimicrobial resistance. We aimed to define the transcriptional antibiotic response (TAR) in Mycobacterium tuberculosis (Mtb) isolates for clinically relevant drugs by pooling and analyzing Mtb microarray and RNA-seq data sets. We generated 99 antibiotic transcription profiles across 17 antibiotics, with 76% of profiles generated using 3-24 hours of antibiotic exposure and 49% within one doubling of the WHO antibiotic critical concentration. TAR genes were time-dependent, and largely specific to the antibiotic mechanism of action. TAR signatures performed well at predicting antibiotic exposure, with the area under the receiver operating curve (AUC) ranging from 0.84-1.00 (TAR <6 hours of antibiotic exposure) and 0.76-1.00 (>6 hours of antibiotic exposure) for upregulated genes and 0.57-0.90 and 0.87-1.00, respectfully, for downregulated genes. This work desmonstrates that transcriptomics allows for the assessment of antibiotic activity in Mtb within 6 hours of exposure.

Novel Synergies and Isolate Specificities in the Drug Interaction Landscape of Mycobacterium abscessus.

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.

Acute Versus Delayed Surgical Intervention in Multiligament Knee Injuries: A Systematic Review.

BACKGROUND: The optimal timing of surgical intervention for multiligament knee injuries remains controversial. PURPOSE: To review the clinical and functional outcomes after acute and delayed surgical intervention for multiligament knee injuries. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We performed a search of the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to September 2020. Eligible studies reported on knee dislocations, multiligament knee injuries, or bicruciate ligament injuries in adult patients (age, ≥18 years). In addition to comparing outcomes between acute and delayed surgical intervention groups, we conducted 3 subgroup analyses for outcomes within isolated knee injuries, knee injuries with concomitant polytrauma/fractures, and high-level (level 2) studies. RESULTS: Included in the analysis were 31 studies, designated as evidence level 2 (n = 3), level 3 (n = 8), and level 4 (n = 20). These studies reported on 2594 multiligament knee injuries sustained by 2585 patients (mean age, 25.1-65.3 years; mean follow-up, 12-157.2 months). At the latest follow-up timepoint, the mean Lysholm (n = 375), International Knee Documentation Committee (IKDC) (n = 286), and Tegner (n = 129) scores for the acute surgical intervention group were 73.60, 67.61, and 5.06, respectively. For the delayed surgical intervention group, the mean Lysholm (n = 196), IKDC (n = 172), and Tegner (n = 74) scores were 85.23, 72.32, and 4.85, respectively. The mean Lysholm (n = 323), IKDC (n = 236), and Tegner (n = 143) scores for our isolated subgroup were 83.7, 74.8, and 5.0, respectively. By comparison, the mean Lysholm (n = 270), IKDC (n = 236), and Tegner (n = 206) scores for the polytrauma/fractures subgroup were 83.3, 64.5, and 5.0, respectively. CONCLUSION: The results of our systematic review did not elucidate whether acute or delayed surgical intervention produced superior clinical and functional outcomes. Although previous evidence has supported acute surgical intervention, future prospective randomized controlled trials and matched cohort studies must be completed to confirm these findings.

Canned Comments in the Hospital Laboratory Information System Can Decrease Microbiology Requests.

OBJECTIVES: Phone calls to the microbiology laboratory can be to clarify culture results and provide education, but those calls also interrupt laboratory workflow. We characterized calls that the laboratory received and developed targeted comments to educate providers. METHODS: Calls were logged and characterized, and we developed comments to address common call subjects. We applied the new comments to cultures and logged calls over the same interval the subsequent year. Data before and after implementation were analyzed. RESULTS: Call volume decreased from 496 calls to 419 calls after implementation. There was a significant difference in level of training among callers (P < .005), but the nature of the calls did not change. Laboratory response showed an increase in release of previously generated data (eg, suppressed susceptibility results). Comments specifically developed to address intrinsic antibiotic resistance and common susceptibility patterns did not decrease call volume. CONCLUSIONS: Implementation of comments in the laboratory information system decreased call volume, but targeted comments were less effective than anticipated.

Draft Genome Sequence of Escherichia coli Strain UMD142.

Escherichia coli can be a harmless commensal organism or cause a range of diseases in humans, including diarrhea, urinary tract infections, meningitis, sepsis, and skin and soft tissue infections. Here, we describe the genome of an isolate that was associated with necrotizing fasciitis and the decompensation of previously undiagnosed cirrhosis.

A review of published spoligotype data indicates the diversity of Mycobacterium tuberculosis from India is under-represented in global databases.

BACKGROUND: Mycobacterium tuberculosis (MTBC) lineages differ in clinical presentation, virulence, transmission, drug resistance and immunological responses. Despite having the largest burden of tuberculosis (TB) in the world, strains from India are underrepresented in international databases. We reviewed published spoligotype data to determine the distribution and diversity of MTBC lineages in India. METHODS: A Pubmed/MEDLINE search identified 34 M. tuberculosis spoligotyping studies from India. Spoligotype patterns were extracted and the Spoligotype International Type (SIT) number, sub-lineage and lineage determined. Minimum Spanning Trees were used to determine relationships between patterns. RESULTS: We identified 1528 spoligotype patterns distributed across 8300 isolates; 6733 isolates belonged to 472 SITs, with 53% of all isolates belonging to 12 SITs with at least 100 isolates each. Lineage 1 and Lineage 3 made up 67% of all isolates, although a lineage could not be assigned for 16% of isolates. Lineage 1 isolates were most common in Southern, Western and Eastern India, and Lineage 3 was most common in Northern and Central India. The RULE, CBN and KBBN lineage prediction algorithms from the TB-lineage tools performed variably, with the correct lineage predicted correctly for only 64% of patterns with known lineage. Using a consensus definition, 64% of the 1359 isolates with unknown lineage were assigned to Lineage 1, and 14% each were assigned to Lineages 3 and 4. With these lineage assignments, 80% of all isolates belonged to either Lineage 1 or Lineage 3. CONCLUSION: Our findings indicate significant M. tuberculosis diversity in India. The documentation of 1056 orphan and unreported patterns indicate that this diversity is under-represented in global databases.

Use of a Single Xpert MTB/RIF Assay to Determine the Duration of Airborne Isolation in Hospitalized Patients With Suspected Pulmonary Tuberculosis.

BACKGROUNDHospitalized patients with suspected tuberculosis (TB) are placed in airborne isolation until 3 sputum smear samples are negative for acid-fast bacilli (AFB). The Xpert MTB/RIF assay ("Xpert") nucleic acid amplification test (NAAT) to identify Mycobacterium tuberculosis DNA and resistance to rifampicin is superior to AFB sputum smear microscopy for the diagnosis of TB.OBJECTIVETo compare the performance of a single Xpert to AFB smear microscopy for time to airborne infection isolation (AII) discontinuation.METHODSConsecutive patients over 17 years of age in AII for suspected pulmonary TB between October 1, 2014, and March 31, 2016, with leftover respiratory AFB samples were enrolled in this study. A single Xpert was performed on the first available sample. Demographic, clinical, and microbiological data were recorded for each patient. We compared the duration of AII using a single Xpert to AFB smear microscopy under multiple theoretical scenarios using Kaplan-Meier cumulative incidence curves and the log-rank test.RESULTSIn total, 131 samples were included in our performance analysis of the Xpert, and 114 samples were included in our AII analysis. Overall, 81 patients (65%) were immunosuppressed, of whom 46 (37%) were positive for human immunodeficiency virus (HIV). The sensitivity and specificity of Xpert for diagnosis of M. tuberculosis infection were 67% and 100%, respectively. Xpert was negative in all cases of nontuberculous mycobacteria. Use of a single Xpert reduced AII duration from a median of 67 hours per patient to 42 hours with usual reporting, to 26 hours with direct communication, and to 12 hours with immediate testing.CONCLUSIONSA single negative Xpert result can reduce AII duration compared to the AFB smear microscopy technique under multiple theoretical scenarios.Infect Control Hosp Epidemiol 2018;39:590-595.

Varicella-Zoster Virus Vasculopathy: A Case Report Demonstrating Vasculitis using Black-Blood MRI.

Infections are rare but important causes of stroke. Among these, varicella zoster virus has been known to cause ischemic stroke. During an attack of herpes zoster ophthalmicus, it has been hypothesized that the virus replicates in the trigeminal ganglion and travels via the trigeminal nerve centrally to cause cerebral vasculopathy. Here we present a case of a 69 year-old Caucasian immunocompromised woman who suffered recurrent ischemic infarcts within the same vascular distribution following an episode of zoster ophthalmicus three months prior. An imaging technique termed black-blood magnetic resonance imaging was utilized to aid in the diagnosis of cerebral vasculitis. The case is used to provide a literature review of the pathogenesis, diagnosis, and treatment of cerebral varicella zoster vasculopathy. In situations where an isolated unilateral cerebral vasculopathy is identified, neurologists are urged to consider varicella zoster as a treatable etiologic agent, as untreated vasculopathy can lead to further strokes.

Comparison of ultrasound and magnetic resonance urography for evaluation of contralateral kidney in patients with multicystic dysplastic kidney disease.

PURPOSE: The contralateral kidney is abnormal in up to 25% of patients with multicystic dysplastic kidney. Traditionally, anatomical and functional evaluation of the contralateral kidney has been performed with ultrasound and dimercapto-succinic acid renal scintigraphy, as indicated. Recently magnetic resonance urography has been used to evaluate renal anatomy and function in other urological abnormalities. We compared the results of magnetic resonance urography and ultrasound for evaluating the contralateral kidney in patients with multicystic dysplastic kidney and we describe the range of findings detected. MATERIALS AND METHODS: Patients with multicystic dysplastic kidney who underwent magnetic resonance urography were identified. Anatomical findings on magnetic resonance urography were analyzed and compared to those on renal ultrasound. Additional functional information derived from magnetic resonance urography was also recorded. RESULTS: We retrospectively identified 58 patients with a unilateral multicystic dysplastic kidney who had undergone magnetic resonance urography, of whom 54 also underwent ultrasound. Of the patients 19 (32.8%) had a contralateral abnormality. A discrepancy between magnetic resonance urography and ultrasound was seen in 9 patients (16.7%). Of these patients only 1 had a completely normal contralateral kidney by ultrasound on retrospective review. The incidence and range of parenchymal abnormalities was wider than previously reported. CONCLUSIONS: Contralateral abnormalities in children with multicystic dysplastic kidney are common and more definitively evaluated with magnetic resonance urography vs ultrasound. Renal ultrasound remains the most appropriate modality for the initial evaluation of children with multicystic dysplastic kidney, and magnetic resonance urography is recommended when a functional study is required either to confirm the diagnosis of multicystic dysplastic kidney or to evaluate suspected abnormalities of the contralateral kidney.