The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition.

Sulfur is an indispensable element for bacterial proliferation. Prior studies demonstrated that the human pathogen Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a five-gene locus comprising a putative ABC-transporter and predicted γ-glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter operon the glutathione import system (gisABCD). Ggt is encoded within the gisBCD operon, and we show that the enzyme is capable of liberating glutamate using either GSH or GSSG as substrates, demonstrating it is a bona fide γ-glutamyl transpeptidase. We also determine that Ggt is expressed in the cytoplasm, representing only the second example of cytoplasmic Ggt localization, the other being Neisseria meningitidis. Bioinformatic analyses revealed that Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologs. However, homologous systems were not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH- and GSSG-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSSG in addition to GSH and promotes competition against other staphylococci commonly associated with the human microbiota.

A Practical Guide to the Evaluation of Small Bowel Bleeding.

Gastrointestinal bleeding is a common clinical problem encountered in both the inpatient and outpatient settings. Although the evaluation of upper and lower gastrointestinal bleeding is often straightforward, bleeding from the small bowel may pose a clinical challenge. In this article, we review the indications, modalities, and differential diagnoses of small bowel bleeding. On completion of the article, clinicians should be able to identify common causes of small bowel bleeding, understand the advantages and disadvantages of the modalities used to evaluate small bowel bleeding, and enact a stepwise management approach to the patient with presumed small bowel bleeding.

Crohn's Disease in a Patient With Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by inflammatory flares of soft tissues, leading to heterotopic ossification and significant cumulative morbidity and early mortality. FOP minor trauma, including intramuscular medication administration, can induce ossification and should be avoided. We present a case of known FOP in a patient who presented with fevers of unknown origin and was found to have biopsy-proven ileal Crohn's disease. Crohn's disease management was complicated by concerns that intramuscular therapies would induce ossification, and oral monotherapy with methotrexate was initiated with excellent results.

Eosinophilic Gastroenteritis: Using Presenting Findings to Predict Disease Course.

INTRODUCTION: Studies on eosinophilic gastroenteritis have identified broad spectrums of disease. We aimed to characterize subtypes of disease and ascertain outcomes of each group. METHODS: This is a retrospective cohort study from a large tertiary medical center including 35 patients diagnosed with eosinophilic gastroenteritis from 2007 to 2018. We defined 2 groups of patients based on clinical and laboratory findings at presentation. Severe disease was defined as having weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis. The remaining patients were labeled as mild disease group. We collected and compared demographic data, clinical features, laboratory findings, an allergy history, and disease course of both cohorts. RESULTS: Among 35 patients with eosinophilic gastroenteritis, 18 patients met the criteria for severe disease and 17 patients for mild disease. Of the patients with severe eosinophilic gastroenteritis, 6 (38%) had remission without chronic symptoms, whereas 10 (63%) had chronic symptoms requiring chronic medical therapy. Of the mild group, 12 patients (80%) had disease remission without chronic medications. An allergy history was more common in the severe disease group (83%) compared with the mild disease group (45%). Prednisone and open capsule budesonide were the most commonly used treatment medications in both groups. DISCUSSION: Patients with eosinophilic gastroenteritis may be characterized into 2 forms. Patients with weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis were associated with a chronic disease course requiring chronic medications.

Long-Acting Lipoglycopeptides for the Treatment of Bone and Joint Infections.

Background: The long-acting lipoglycopeptides dalbavancin and oritavancin possess excellent microbiologic activity against gram-positive bacteria and provide prolonged tissue exposure at sites of infection. Moreover, these antibiotics are well tolerated and do not require therapeutic drug monitoring. Methods: Pharmacokinetic/pharmacodynamic experiments ascertained that one to two doses of these long-acting agents can provide an extended period (≥6 weeks) of antimicrobial therapy. Results: Clinical studies subsequently found that microbiologic and clinical response rates with these agents were comparable to standard antibiotic agents used in the treatment of bone and joint infections. In addition, pharmacoeconomic analyses have discovered cost savings with the use of these antimicrobial agents in the treatment of serious deep-seated bacterial infections. Conclusions: Thus, these long-acting lipoglycopeptides offer potential for cost-effective outpatient parenteral antibiotic therapy of difficult to treat infections, such as osteomyelitis.

Evaluation of a multifaceted approach to antimicrobial stewardship education methods for medical residents.

OBJECTIVE: Medical residents are an important group for antimicrobial stewardship programs (ASPs) to target with interventions aimed at improving antibiotic prescribing. In this study, we compared antimicrobial prescribing practices of 2 academic medical teams receiving different ASP training approaches along with a hospitalist control group. DESIGN: Retrospective cohort study comparing guideline-concordant antibiotic prescribing for 3 common infections among a family medicine (FM) resident service, an internal medicine (IM) resident service, and hospitalists. SETTING: Community teaching hospital. PARTICIPANTS: Adult patients admitted between July 1, 2016, and June 30, 2017, with a discharge diagnosis of pneumonia, cellulitis, and urinary tract infections were reviewed. METHODS: All 3 medical teams received identical baseline ASP education and daily antibiotic prescribing audit with feedback via clinical pharmacists. The FM resident service received an additional layer of targeted ASP intervention that included biweekly stewardship-focused rounds with an ASP physician and clinical pharmacist leadership. Guideline-concordant prescribing was assessed based on the institution's ASP guidelines. RESULTS: Of 1,572 patients, 295 (18.8%) were eligible for inclusion (FM, 96; IM, 69; hospitalist, 130). The percentage of patients receiving guideline-concordant antibiotic selection empirically was similar between groups for all diagnoses (FM, 87.5%; IM, 87%; hospitalist, 83.8%; P = .702). No differences were observed in appropriate definitive antibiotic selection among groups (FM, 92.4%; IM, 89.1%; hospitalist, 89.9%; P = .746). The FM resident service was more likely to prescribe a guideline-concordant duration of therapy across all diagnoses (FM, 74%; IM, 56.5%; hospitalist, 44.6%; P < .001). CONCLUSIONS: Adding dedicated stewardship-focused rounds into the graduate medical curriculum demonstrated increased guideline adherence specifically to duration of therapy recommendations.

Native joint septic arthritis with Veillonella species.

Septic arthritis usually presents as subacute monoarticular inflammation. Majority of the cases in healthy adults are caused by methicillin-resistant Staphylococcus aureus, streptococci and certain gram-negative organisms, mostly in the setting of extremes of ages, trauma or immunosuppression. This is a case of a healthy adult with a sudden onset of inflammation of the knee joint, being diagnosed with septic arthritis of the left knee with Veillonella sp. growing from the joint aspirate on two successive cultures. The patient was treated with 6 weeks of oral metronidazole and 4 weeks of intravenous ceftriaxone in addition to arthroscopic drainage and irrigation. Rare causes of septic arthritis should be considered even in healthy adults with native joints. Closer follow-up might be needed to ensure successful treatment.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

Cytomegalovirus infection in immunocompetent adults: Is observation still the best strategy?

Cytomegalovirus (CMV) infection in immunocompetent patients generally resolves with few sequelae. However, it can cause severe and relapsing symptoms that can last for several weeks. Due to the self-limiting nature of CMV disease in immunocompetent individuals, criteria for specific antiviral therapy in this cohort are not well established. Additionally the adverse effect profile of currently available anti-CMV therapy limits its use in specific patient populations .We describe 3 immunocompetent adults who developed symptomatic CMV infection and were ill for several weeks. All patients had positive CMV viral assays and ultimately received anti-CMV therapy with significant improvement in symptoms within a few days of starting therapy. Choosing appropriate candidates for anti-CMV therapy, among mmunocompetent individuals, requires further research.

Lemierre's syndrome and 2016 American College of Physician guidelines for pharyngitis: no to empiric coverage for bacterial pharyngitis. While no role for routine Fusobacterium PCR, keep suspicion for this pathogen.

An 18-year-old woman presented to clinic with acute pharyngitis with 4/4 Centor criteria. Rapid streptococcal antigen test was negative. The patient, who was allergic to penicillin, was prescribed azithromycin. Ultimately, after 5 days and without any corticosteroids, she presented to the emergency department with 10/10 chest pain and was admitted to the intensive care unit. CT showed nodular lung disease and blood cultures on admission grew Fusobacterium, likely Fusobacterium nucleatum. She sustained two cardiac arrests, three tube thoracostomies, acute kidney injury requiring dialysis and ventilatory failure requiring tracheostomy. After 16 days in hospital and 18 days in long-term acute care, the patient was discharged home. It is unclear how much of this could have been prevented by prescribing an antimicrobial that had activity against Fusobacterium When severe pharyngitis occurs, Fusobacterium needs to be considered as an underlying cause. In vitro macrolides have marginal activity against most anaerobes, such as this pathogen, and should be avoided.

Sleep Apnea Screening Practices During Department of Transportation Medical Examinations.

OBJECTIVE: The aim of this study was to examine the practices of Michigan Occupational and Environmental Medicine Association (MOEMA) members regarding screening for sleep apnea during required driver medical examinations. METHODS: A 13-question survey on sleep apnea screening practices was emailed to the MOEMA member. Nonresponders received additional E-mails and calls. RESULTS: The survey response rate was 66%. Fifty-five percent of respondents performed driver examinations and 94% screened for sleep apnea. Variations in practice included differences in how many risk factors were used to determine the need for polysomnography, 13% never ordered polysomnography and 42% never denied medical certification because of sleep apnea. CONCLUSION: Although there was significant consensus that sleep apnea screening was important, there was a large variation in the indication for and frequency in which sleep studies were ordered and drivers were denied approval because of concern about sleep apnea.

Immunogenicity of 13-Valent Conjugate Pneumococcal Vaccine in Patients 50 Years and Older with End-Stage Renal Disease and on Dialysis.

Patients with end-stage renal disease (ESRD) and on dialysis are at increased risk of pneumococcal disease. We evaluated the immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) in this population. Eligible patients with ESRD and on dialysis were given a single dose of PCV13. The concentrations of serum antibodies against 13 pneumococcal capsular polysaccharides were measured at the baseline and at 2 and 12 months postvaccination. A response to the vaccine was defined as a ≥2-fold increase in antibody concentration from that at the baseline and an absolute postvaccination value of at least 1 µg/ml. Seventeen patients completed the study. Increases in the concentrations of antibodies to the vaccine serotype were demonstrated 2 months after vaccination. The geometric mean antibody concentrations at 12 months postvaccination declined by 38% to 72% compared to those measured at 2 months postvaccination. A response to at least 1 serotype in the vaccine was seen in all patients at both 2 and 12 months postvaccination. The overall rate of the response to each individual vaccine serotype varied between 23.5% and 94.1% at 2 months postvaccination and 23.5% and 65% at 12 months postvaccination. Pain at the injection site was the most common local reaction. Vaccination with PCV13 induces antibody responses to vaccine serotypes in patients with ESRD and on dialysis at 2 months postvaccination. However, the decline in antibody concentrations at 12 months postvaccination with a conjugate pneumococcal vaccine requires further study. (This study has been registered at ClinicalTrials.gov under registration no. NCT01974817.).

Profile of oritavancin and its potential in the treatment of acute bacterial skin structure infections.

Oritavancin, a semisynthetic derivative of the glycopeptide antibiotic chloroeremomycin, received the US Food and Drug Administration approval for the treatment of acute bacterial skin and skin structure infections caused by susceptible Gram-positive bacteria in adults in August 2014. This novel second-generation semisynthetic lipoglycopeptide antibiotic has activity against a broad spectrum of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant Enterococcus. Oritavancin inhibits bacterial cell wall synthesis and is rapidly bactericidal against many Gram-positive pathogens. The long half-life of this drug enables a single-dose administration. Oritavancin is not metabolized in the body, and the unchanged drug is slowly excreted by the kidneys. In two large Phase III randomized, double-blind, clinical trials, oritavancin was found to be non-inferior to vancomycin in achieving the primary composite end point in the treatment of acute Gram-positive skin and skin structure infections. Adverse effects noted were mostly mild with nausea, headache, and vomiting being the most common reported side effects. Oritavancin has emerged as another useful antimicrobial agent for treatment of acute Gram-positive skin and skin structure infections, including those caused by MRSA and VISA.

A pharmacokinetic/pharmacodynamic analysis of ceftaroline prophylaxis in patients with external ventricular drains.

BACKGROUND: Ceftaroline is a broad-spectrum cephalosporin antibiotic with activity against drug-resistant bacteria, including strains of methicillin-resistant Staphylococcus aureus (MRSA), and may be useful to prevent and treat ventriculostomy-related infections (VRIs). The purpose of this study was to analyze the pharmacokinetics and pharmacodynamics of prophylactic ceftaroline in neurosurgical patients with an external ventricular drain (EVD). METHODS: Adult patients in the neurosurgical intensive care unit with an EVD were given prolonged prophylaxis with ceftaroline. Serum and cerebral spinal fluid (CSF) were obtained simultaneously at 2, 6, and 12 h after initiation of the fourth dose of ceftaroline and concentrations were measured by a liquid chromatography tandem mass spectrometry assay. Time-kill curves against isolates of coagulase-negative S. aureus, methicillin-sensitive S. aureus, MRSA, and Streptococcus pneumoniae were determined in serum and CSF at each collection time point. RESULTS: A total of five patients with a mean age of 63 y and mean weight of 83 kg were enrolled. The mean CSF:serum penetration ratios of ceftaroline were 0.005 (0.5%), 0.021 (2.1%), and 0.043 (4.3%) at 2, 6, and 12 h, respectively. The mean ceftaroline exposure ratio area under the curve (AUC)csf/AUCserum) was 0.011 (1.1%). Bactericidal activity at each collection time point was observed against each strain of staphylococci from serum samples and a penicillin-sensitive strain of S. pneumoniae from CSF samples. CONCLUSION: This investigation suggests that ceftaroline could have clinical utility for the prevention of VRIs in patients with EVDs.

Infectious diseases subspecialty: declining demand challenges and opportunities.

Recent match results from the National Resident Matching Program for the subspecialty of infectious diseases show an ongoing decline in the number of fellowship positions filled, and, more important, in the number of applicants, particularly from the pool of international medical graduates. The main reasons for this declining application rate are unclear; in the absence of hard data, we present our viewpoint on this issue. Difficulties in securing visas for permanent residency in the United States, perception of a limited job market, and the explosive growth in the number of hospitalist positions may be important contributing factors. Infectious Diseases Society of America members need to focus on medical students and medical residents in their formative years. We present potential solutions to this problem of declining interest in the field of infectious diseases.