Jeffrey Tornheim | Johns Hopkins University School of Medicine (original) (raw)

Papers by Jeffrey Tornheim

Microbiology spectrum, Feb 24, 2017

Tuberculosis and human immunodeficiency virus (HIV) infection are two important linked public hea... more Tuberculosis and human immunodeficiency virus (HIV) infection are two important linked public health problems in the world of today. Tuberculosis in HIV infected patients is frequently atypical in its clinical and radiological findings and commonly has an extrapulmonary dissemination. Atypical mycobacteriosis have also been reported in patients with HIV infection. We review here all the patients admitted from 1986 to 1991 with definitive diagnosis of tuberculosis and HIV infection at the National Institute of Respiratory Diseases in Mexico City. Out of 220 patients with HIV infection and pulmonary complications, 19 had proven tuberculosis. Their mean age was 34 +/- 8 years and seven were homosexual males. In 16 patients (84%), respiratory symptoms (cough with sputum) and fever were the first manifestations of the HIV infection. Only two patients had the typical cavitary lesions but also coexisting with miliary tuberculosis. The rest had several types of non cavitated pulmonary opacities or other thoracic or pleural alterations. Eleven patients (58%) had, in addition, extrapulmonary tuberculosis. Mycobacterium tuberculosis was cultured in 11 of 12 patients but no atypical mycobacteria were isolated. Only seven of the 19 patients completed at least six months of treatment and two of them relapsed. Three patients died in their first admission; the rest were lost in the follow up. Our results show that the clinical features of tuberculosis associated to HIV infection are similar to those described in other countries.

Tuberculosis, Sep 7, 2020

Background: Multidrug-resistant tuberculosis (MDR-TB) is an increasing problem worldwide, and 24%... more Background: Multidrug-resistant tuberculosis (MDR-TB) is an increasing problem worldwide, and 24% occurs in India. Linezolid is associated with improved MDR-TB treatment outcomes but causes significant side-effects and drug susceptibility testing (DST) is rarely available. This study assessed whether clinical factors could predict linezolid resistance. Methods: An observational cohort of adults and adolescents with MDR-TB at a tertiary care hospital in Mumbai, India was analyzed for clinical, laboratory, and radiographic findings associated with linezolid resistance. Results: In total, 343 MDR-TB patients had linezolid DST performed, and 23 (6.7%) had linezolid-resistant MDR-TB. Univariable analysis associated linezolid resistance with underweight (odds ratio (OR)-1.07, 95% con

Indian Journal of Medical Research, 2021

Background & objectives Linezolid (LZD) is increasingly being used in tuberculosis (TB) treat... more Background & objectives Linezolid (LZD) is increasingly being used in tuberculosis (TB) treatment. However, LZD resistance has already been reported, which is highly alarming, given its critical therapeutic role. This study was aimed to phenotypically and genotypically assess LZD resistance in Mycobacterium tuberculosis (MTB) isolates at a laboratory in a tertiary care centre in Mumbai, India. Methods A sample of 32 consecutive LZD-resistant MTB isolates identified by liquid culture susceptibility testing was subjected to whole-genome sequencing (WGS) on the Illumina NextSeq platform. Sequences were analyzed using BioNumerics software to predict resistance for 12 antibiotics within 15 min. Results Sixty eight of the 2179 isolates tested for LZD resistance by MGIT-based susceptibility testing (June 2015 to June 2016) were LZD-resistant. Thirty two consecutive LZD-resistant isolates were analyzed by WGS to screen for known mutations conferring LZD resistance. WGS of 32 phenotypically LZD-resistant isolates showed that C154R in the rplC gene and G2814T in the rrl gene were the major resistance determinants. Interpretation & conclusions LZD resistance poses an important risk to the success of treatment regimens, especially those designed for resistant isolates; such regimens are extensively used in India. As LZD-containing regimens increase in prominence, it is important to support clinical decision-making with an improved understanding of the common mutations conferring LZD resistance and their frequency in different settings.

Topics in antiviral medicine, 2021

PLOS Neglected Tropical Diseases, Sep 19, 2013

Background: Chagas disease treatment is limited by drug availability, adverse side effect profile... more Background: Chagas disease treatment is limited by drug availability, adverse side effect profiles of available medications, and poor adherence. Methods: Adult Chagas disease patients initiating 60-days of benznidazole were randomized to weekly or twice-weekly evaluations of medication adherence and screening for adverse drug events (ADEs). Midweek evaluations employed phone-based evaluations. Adherence was measured by self-report, pill counts with intentional over-distribution, and Medication Event Monitoring Systems (MEMS). Prospective data were compared to historical controls treated with benznidazole at the same hospital. Results: 162 prospective patients were compared to 172 historical patients. Pill counts correlated well with MEMS data (R = 0.498 for 7-day intervals, R = 0.872 for intervals .7 days). Treatment completion rates were higher among prospective than historical patients (82.1% vs. 65.1%), primarily due to lower abandonment rates. Rates of ADEs were lower among prospective than historical patients (56.8% vs. 66.9%). Twice-weekly evaluations increased identification of mild ADEs, prompting higher suspension rates than weekly evaluations. While twice-weekly evaluations identified ADEs earlier, they did not reduce incidence of moderate or severe ADEs. Many dermatologic ADEs were moderately severe upon presentation (35.6%), were not reduced by use of antihistamines, occurred among adult patients of all ages, and occurred throughout treatment, rather than the first few weeks alone. Conclusions: Intensive management improved completion and identified more ADEs, but did not reduce moderate or severe ADEs. Risk of dermatologic ADEs cannot be reduced by selecting younger adults or monitoring only during the first few weeks of treatment. Pill counts and phone-based encounters are reliable tools for treatment programming in rural Bolivia.

Current Opinion in Hiv and Aids, Nov 1, 2018

Purpose of review In the past few years, tuberculosis (TB) has overtaken HIV as the infectious di... more Purpose of review In the past few years, tuberculosis (TB) has overtaken HIV as the infectious disease with the highest global mortality. Successful management of this syndemic will require improved diagnostic tests, shorter preventive therapies, and more effective treatments, particularly in light of drug-resistant TB. Recent findings Results from several major studies have been published or presented recently, including the development of a more sensitive rapid, molecular assay for TB; several new symptom-based screening tools; use of a 1month regimen for TB prevention; the results of early vs. delayed TB preventive therapy for pregnant women; newer drugs and regimens for multidrug-resistant tuberculosis; and pharmacokinetic, safety, and efficacy studies of new HIV drugs in combination with TB treatment. We reviewed each of these topic areas and summarize relevant findings for the management of TB and HIV co-infection. Summary Moving forward, as new treatment regimes for HIV or TB are developed, consideration of the HIV-TB coinfected patient must figure prominently, both when determining the diagnostic tests employed and to assess properly the drug-drug and drug-disease interactions that influence dosing, safety, and response.

Open Forum Infectious Diseases, Dec 23, 2021

Background. Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidr... more Background. Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. Methods. We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. Results. Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]). Conclusions. In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

The European respiratory journal, Dec 23, 2021

In 2018 cycloserine was elevated to World Health Organization (WHO) group B status for multidrug-... more In 2018 cycloserine was elevated to World Health Organization (WHO) group B status for multidrug-resistant tuberculosis (MDR-TB), and is recommended in longer MDR-TB treatment regimens [1]. Inclusion of cycloserine is associated with improved MDR-TB treatment success and reduced mortality, but is limited by treatment-associated depression, psychosis and neuropathy, forcing 9% of patients to stop therapy [1-3]. Cycloserine also demonstrates wide interindividual pharmacokinetic variation, with significant food and drug interactions, leaving nearly half of patients with inappropriate drug levels [4, 5]. Optimal dosing is unknown [6], but modelling studies suggest doses from 250 mg to 750 mg twice daily, with 500 mg twice daily for paucibacillary disease and 750 mg twice daily for cavitary pulmonary disease [7]. Therefore, clinicians must balance the known benefits of cycloserine with the dearth of susceptibility-and drug-monitoring capacity and the spectre of treatment-limiting side-effects. To evaluate the impact of cycloserine prescription and dose on incident depression during MDR-TB treatment, we analysed longitudinal cohort data from India. Outpatients aged ⩾15 years seeking MDR-TB care at a private hospital in Mumbai, India were recruited for a prospective observational cohort study approved by the institutional review boards of the

The Lancet Respiratory Medicine, Apr 1, 2017

Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, Aug 1, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The Journal of Infectious Diseases, Dec 4, 2019

BackgroundGene expression profiling is emerging as a tool for tuberculosis diagnosis and treatmen... more BackgroundGene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist.MethodsSixteen pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for ribonucleic acid sequencing. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated.ResultsSeventy-one genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38–1.00, specificity 0.48–0.93) and treatment response (sensitivity 0.70–0.80, specificity 0.40–0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56–0.85, specificity 0.50–0.85) and treatment response (sensitivity 0.49– 0.86, specificity 0.50–0.84).ConclusionsGene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models.

PLOS Neglected Tropical Diseases, May 18, 2010

Background: Patients with Chagas disease have migrated to cities, where obesity, hypertension and... more Background: Patients with Chagas disease have migrated to cities, where obesity, hypertension and other cardiac risk factors are common. Methodology/Principal Findings: The study included adult patients evaluated by the cardiology service in a public hospital in Santa Cruz, Bolivia. Data included risk factors for T. cruzi infection, medical history, physical examination, electrocardiogram, echocardiogram, and contact 9 months after initial data collection to ascertain mortality. Serology and PCR for Trypanosoma cruzi were performed. Of 394 participants, 251 (64%) had confirmed T. cruzi infection by serology. Among seropositive participants, 109 (43%) had positive results by conventional PCR; of these, 89 (82%) also had positive results by real time PCR. There was a high prevalence of hypertension (64%) and overweight (body mass index [BMI] .25; 67%), with no difference by T. cruzi infection status. Nearly 60% of symptomatic congestive heart failure was attributed to Chagas cardiomyopathy; mortality was also higher for seropositive than seronegative patients (p = 0.05). In multivariable models, longer residence in an endemic province, residence in a rural area and poor housing conditions were associated with T. cruzi infection. Male sex, increasing age and poor housing were independent predictors of Chagas cardiomyopathy severity. Males and participants with BMI #25 had significantly higher likelihood of positive PCR results compared to females or overweight participants. Conclusions: Chagas cardiomyopathy remains an important cause of congestive heart failure in this hospital population, and should be evaluated in the context of the epidemiological transition that has increased risk of obesity, hypertension and chronic cardiovascular disease.

Microbiology, Feb 1, 2019

Drug-resistance due to AmpC β-lactamases represents a growing problem worldwide. In this study, a... more Drug-resistance due to AmpC β-lactamases represents a growing problem worldwide. In this study, a previously collected sample of 108 cefoxitin-resistant clinical isolates was assessed for AmpC β-lactamase production through routine phenotypic testing and double-disc cefoxitin/cloxcallin (DD-CC), cefoxitin/phenylboronic acid (CDT-PBA) and AmpC disc tests. The same isolates were characterized by a novel multiplex polymerase chain reaction molecular assay to detect the presence of blaACT, blaDHA, blaCIT, blaFOX, blaMIR and blaMOX. By phenotypic analysis, 56%, 55% and 48 % were detected as being AmpC β-lactamase producers by the CDT-PBA, DD-CC and AmpC disc tests, respectively. By molecular analysis, 57 % were determined to be AmpC β-lactamase producers, including 34 % blaFOX, 8 % blaCIT and 1.6 % blaDHAas mono-AmpC producers. The production of multiple AmpC molecular types was common, including 30 % with both blaCIT+FOX and 1.6 % each of blaCIT+DHA, blaACT+MIR, blaACT+FOX, blaACT+DHA and blaMIR+FOX. Molecular characterization of AmpC would help detect the prevalence of AmpC β-lactamase producers, facilitate proper patient management and implement infection control practices.

medRxiv (Cold Spring Harbor Laboratory), Sep 3, 2020

Background: Outpatient COVID-19 has been insufficiently characterized. Objective: To determine th... more Background: Outpatient COVID-19 has been insufficiently characterized. Objective: To determine the progression of disease and subsequent determinants of hospitalization.

Clinical Infectious Diseases, May 26, 2017

See the Editorial Commentary by Furin and Cox on pages 1212-3.) A novel, shorter-course regimen f... more See the Editorial Commentary by Furin and Cox on pages 1212-3.) A novel, shorter-course regimen for treating multidrug-resistant (MDR) tuberculosis was recently recommended by the World Health Organization. However, the most appropriate use of drug susceptibility testing (DST) to support this regimen is less clear. Implementing countries must therefore often choose between using a standardized regimen despite high levels of underlying drug resistance or require more stringent DST prior to treatment initiation. The former carries a high likelihood of exposing patients to de facto monotherapy with a critical drug class (fluoroquinolones), whereas the latter could exclude large groups of patients from their most effective treatment option. We discuss the implications of this dilemma and argue for an approach that will integrate DST into the delivery of any novel antimicrobial regimen, without excessively stringent requirements. Such guidance could make the novel MDR tuberculosis regimen available to most patients while reducing the risk of generating additional drug resistance.

Annual Review of Medicine, Jan 27, 2019

Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one in... more Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.

Journal of Community Health, Feb 6, 2011

Diagnosing and treating depression in a primary care practice is an important, yet difficult task... more Diagnosing and treating depression in a primary care practice is an important, yet difficult task, especially for safety-net practices serving the uninsured. In the United States healthcare system, there is a mismatch between the need for mental health care and access to services. This disparity is most striking among the uninsured. Mental health disorders are more prevalent among the uninsured, and even when diagnosed with mental illness, they are less likely to obtain necessary treatment than insured patients. Given the increasing burden of depression on society, growing numbers of uninsured and negative repercussions of untreated mental illness, improvements in screening and management protocols are becoming more important in primary care practices serving this population. The quality of depression treatment at commercial and public insurance plans in New York City (NYC) and New York State (NYS) were compared to that of the East Harlem Health Outreach Partnership (EHHOP), the student-run clinic of the Mount Sinai School of Medicine. Based on the comparison, the study made recommendations for an integrated, on-site mental health service program at the community health clinic. A cohort of 49 depressed patients were evaluated and treated at the EH-HOP clinic. The quality of the mental health care was evaluated according to variables from the Healthcare

Neuroimmunology and Neuroinflammation, Jun 13, 2016

Objective: To determine the feasibility of next-generation sequencing (NGS) microbiome approaches... more Objective: To determine the feasibility of next-generation sequencing (NGS) microbiome approaches in the diagnosis of infectious disorders in brain or spinal cord biopsies in patients with suspected CNS infections. Methods: In a prospective pilot study, we applied NGS in combination with a new computational analysis pipeline to detect the presence of pathogenic microbes in brain or spinal cord biopsies from 10 patients with neurologic problems indicating possible infection but for whom conventional clinical and microbiology studies yielded negative or inconclusive results. Results: Direct DNA and RNA sequencing of brain tissue biopsies generated 8.3 million to 29.1 million sequence reads per sample, which successfully identified with high confidence the infectious agent in 3 patients for whom validation techniques confirmed the pathogens identified by NGS. Although NGS was unable to identify with precision infectious agents in the remaining cases, it contributed to the understanding of neuropathologic processes in 5 others, demonstrating the power of large-scale unbiased sequencing as a novel diagnostic tool. Clinical outcomes were consistent with the findings yielded by NGS on the presence or absence of an infectious pathogenic process in 8 of 10 cases, and were noncontributory in the remaining 2. Conclusions: NGS-guided metagenomic studies of brain, spinal cord, or meningeal biopsies offer the possibility for dramatic improvements in our ability to detect (or rule out) a wide range of CNS pathogens, with potential benefits in speed, sensitivity, and cost. NGS-based microbiome approaches present a major new opportunity to investigate the potential role of infectious pathogens in the pathogenesis of neuroinflammatory disorders.

Frontiers in Pharmacology, Jan 4, 2023

Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including ... more Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either doseadjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300 mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21-35), weight 55.0 kg (IQR 45.6-65.8), and fatfree mass 38.7 kg (IQR 32.7-46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81 L/h. Simulations predicted that treatment with 300 mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA >90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%).