bluuebunny/crossref_metadata_2025 huggingface dataset:
764. Impact of Diabetes Mellitus on the Presentation and Response to Treatment of Adults With Pulmonary Tuberculosis in Qatar
Authors: Dousa Khalid M , Hamad Abdelrahman , Alsoub Hussam , Elzouki Abdel-Naser , Alwakeel Mahmoud I , Thiel Bonnie A , Johnson John L
Published: November 2018

Background

Persons with diabetes mellitus (DM) have a 3-fold increased risk of TB. Vitamin D deficiency also is associated with a 4-fold increase in risk of progression of TB from latent TB infection to active TB. Qatar is an oil rich country with high prevalence of diabetes, obesity, and vitamin D deficiency. We aimed to evaluate the effect of diabetes mellitus on manifestations and response to treatment in adults with DM and TB.

Methods

Retrospective national hospital-based study of adult from January 2007 to December 2011, comparing TB-infected patients with and without DM.

Results

Of 134 adults with DM and TB, 62 (47%) became culture negative after 8 weeks of anti-TB treatment compared with 84 (72%) patients without DM. Patients with DM had more frequent lower lobe disease (28% vs. 17%, P = 0.03). Week 8 sputum culture conversion did not differ between patients by the degree of dysglyemia at time of diagnosis and onset of anti-TB treatment (70% vs. 46%, P = 0.09).

Conclusion

Diabetes mellitus was associated with delayed sputum culture conversion at two month and atypical radiological findings in adults with pulmonary TB in Qatar. Glycemic control had no effect on week-8 sputum culture conversion.

Disclosures

All authors: No reported disclosures.
774. Extrapulmonary Tuberculosis: Impact of Early Diagnosis and Treatment on Mortality
Authors: Walayat Saqib , Awwal Talha , Ren Jimna , Farrell John
Published: November 2018

Background

Pakistan has a high burden of endemic Mycobacterium tuberculos is complex (MTC) disease. Extrapulmonary tuberculosis (EPT) is defined as MTC infection involving any part of the body other than the lung. Extrapulmonary tuberculosis (EPT) is seen 20% of MTC infection in Pakistan, diagnosis is often delayed, and timeliness of initiation of treatment is extremely varied. We conducted a retrospective review of all cases of EPT presenting to a large public hospital in Islamabad, Pakistan to identify the role of early diagnosis and clinical treatment on patients with extra pulmonary tuberculosis.

Methods

Retrospective review of EPT diagnosed at Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan. All cases diagnosed and treated as EPT from January to June 2016 were included. Demographic, clinical and laboratory data were extracted from PIMS Medical records and TB01 cards from the National TB Control Program Pakistan. All patients were contacted to determine outcome status. Study was approved from National TB control Program.

Results

Two hundred seventy-five patients were identified who received a diagnosis of EPT. Mean age was 34.4 years; ratio of men to woman was 1.3:1. Pleural tuberculosis was the most common site involved (28.7%). The next most frequent site involved was lymphatic disease (20.3%). 47.6 percent of patients (113/275) were diagnosed by clinical criteria alone (i.e., symptoms and radiographic imaging). There were only three cases of culture confirmed EPT in the cohort. The overall cure rate was 82.9%. There was no difference of cure rates between the cure rates of males and females. Diagnosis based on clinical criteria was associated with significantly higher cure rate (87.6% vs. 79.6%, P = 0.038) and lower mortality (5.3% vs. 9.3%, P = 0.041) compared with laboratory-based diagnosis (5.3% vs. 9.3%, respectively). Improved outcomes and mortality benefit was seen in patients who were treated based on clinical criteria as compared with those in whom treatment was delayed due to biochemical confirmation (Odds ratio 0.28, 95% CI: 0.086–0.95). Sixteen cases were lost to follow-up.

Conclusion

Early initiation of treatment based on clinical criteria was associated with lower mortality and overall outcome benefit in our study cohort. However, further larger studies of patients with EPT are required to validate our observations.

Disclosures

All authors: No reported disclosures.
777. Ten-Year Experience of Tertiary Hospital Regarding Epidemiology, Diagnostic Method, and Drug Resistance of Tuberculosis—Jeddah, Saudi Arabia
Authors: Qutub Mohammed , Aldabbagh Yasser , Govindan Prasanth , Alamoudi Ebtihal
Published: November 2018

Background

The prevalence of tuberculosis across Saudi Arabia is variable with western provinces have the highest incidence. This study aimed to determine the epidemiology of tuberculosis in Jeddah, the age and gender distribution and the accuracy of conventional diagnostic method, for better understanding of tuberculosis-resistant pattern in the country.

Methods

Three hundred forty-four culture proven tuberculosis where collected from November 2006 to November 2016 in KFSHRC. AFB smear and nucleic acid amplification test (NAAT) were conducted in all positive cultures, and all data were analyzed using SPSS. Mean days number to culture positivity was 12.79.

Results

TB showed young age predominant (59.5%) compared with older population (37.0%) and pediatrics (3.5%), with 55.4% males and 44.6% females, 54.8% of samples were taken from pulmonary and 45.2% from extra pulmonary site of infection. 68.3% and 5.9% of the tuberculosis proven culture were negative by using AFB smear and NAAT, respectively, and only 68.8% were positive for mycobacterium tuberculosis complex by using NAAT. Resistant level to first-line anti tuberculosis of 12.5%, 10.3%, 5.2%, 2.6%, 1.3%, 2.6% to Streptomycin, isoniazid, pyrazinamide, Rifampicin, Ethambutol and multidrug-resistant, respectively, was observed in our study.

Conclusion

Young age predominance, high values of negative smear and NAAT increased incidence of extra pulmonary site of infection and Re-emergence of tuberculosis resistant which was observed in our study compared with previous national surveys (Illustrated in Figure 1), all should alter physicians’ Attention when investigating patients in Saudi Arabia and high clinical suspicion should be considered.

Disclosures

All authors: No reported disclosures.
778. Trend of Tuberculosis Meningitis and Associated Mortality in Texas, 2010–2017, A Large Population-Based Analysis
Authors: Nguyen Duc T , Agarwal Saroochi , Graviss Edward A
Published: November 2018

Background

As the most severe form of tuberculosis (TB), TB meningitis (TBM) is still associated with high mortality even in developed countries. In certain US states more than 50% of the TBM patients eventually die or have neurological complications despite having advanced healthcare settings. This population-based analysis aimed to determine the risk factors and trends associated with TBM morbidity and mortality using state-wide surveillance data.

Methods

De-identified surveillance data of all confirmed TB patients from the state of Texas reported between January 2010 and December 2017 to the National TB Surveillance System was analyzed. Spatial distribution of TBM cases was presented by Stata’s Geographic Information Systems mapping. Univariate and multiple logistic regression were used to identify risk factors associated with meningitis morbidity and mortality. Non-parametric trend testing was used for the morbidity and mortality trends.

Results

Among 10,103 TB patients reported from Texas between 2010 and 2017, 192 (1.9%) had TBM. Over the 8-year period, TBM proportion fluctuated between 1.5% and 2.7% with peaks in 2011 (2.7%) and 2016 (2.1%) and an overall trend z = −1.32, P = 0.19. TBM had higher mortality at diagnosis (8.9%), during treatment (20.3%) and overall (22.9%) than non-TBM (1.9%, 6.8%, and 7.2%, respectively, P < 0.001). While the mortality during treatment was unchanged overtime in non-TBM patients (z=0.5, P = 0.62), it has consistently increased in TBM patients since 2013 (z=3.09, P = 0.002). TBM patients had more than 7 times the odds for overall death in multivariate analysis [OR 7.25 (95% CI 4.64, 11.33), P < 0.001]. TBM patients were younger, more likely to present with miliary TB or HIV(+). Age ≥45 years, resident of a long-term care facility, IDU, diabetes, chronic kidney disease, abnormal chest radiograph, positive AFB smear or culture, culture not converted from positive to negative, and HIV(+) were independently associated with a higher mortality.

Conclusion

TBM remains a challenge in Texas with significantly higher mortality. Risk factors determined by multivariate modeling will inform health professionals and lay a foundation for the development of more effective strategies for TBM prevention and management.

Disclosures

All authors: No reported disclosures.
785. Treatment of Mycobacterium immunogenum Skin and Soft-Tissue Infections: A Case in a Peritoneal Dialysis Patient
Authors: El-Nahal Walid , Shenoy Abhishek , Walker McCall , Chopra Tushar , Townsend Greg , Heysell Scott , Eby Joshua
Published: November 2018

Background

Mycobacterium immunogenum is a somewhat recently identified species of rapidly growing nontuberculous mycobacteria, genetically related to M. abscessus and M. chelonae. Resistance patterns of rapidly growing nontuberculous mycobacterium species can make them difficult to treat. This is particularly true of M. immunogenum, in part due to the infrequency of reported cases of human infection and limited data to guide therapy.

Methods

We present here a case of M. immunogenum skin and soft-tissue infection at the site of insertion of a peritoneal dialysis catheter in a patient with end-stage renal disease. He initially presented with nodular subcutaneous lesions around his catheter site that progressed through oral antibiotics. This led to sampling which confirmed the diagnosis of M. immunogenum. We conducted a review of the literature to identify previously reported cases of M. immunogenum, including skin and soft-tissue infections, and used these data to guide management.

Results

We reviewed 11 reports (cases and case series) of Mycobacterium immunogenum in the literature. Susceptibilities often take weeks to return, and so empiric therapy is based on case series, and then later adjusted based on susceptibilities. Patients received combined antimicrobial regimens with durations of 2 weeks to 12 months, with variable outcomes. Several required surgical debridement, as was the case with our patient. His PD catheter was removed and he was treated empirically with amikacin, azithromycin, and tigecycline intravenous induction. His ultimate long-term regimen was later switched to azithromycin, clofazimine, and tedizolid due to side effects and the eventually available susceptibility profile.

Conclusion

The treatment of M. immunogenum remains a challenge due to the relative scarcity of data to guide treatment, and consequent lack of systemic approach to therapy. Most reported cases involve the use of a macrolide, often in combination with an aminoglycoside or a fluoroquinolone. Several started with intravenous induction, followed by transition to oral therapy on the order of weeks to months. Others also require surgical debridement. More data are required to develop a standardized approach to the treatment of M. immunogenum.

Disclosures

All authors: No reported disclosures.
788. Therapeutic Drug Monitoring for Pyrazinamide During Tuberculosis Treatment: What Is the Diagnostic Accuracy?
Authors: Anderson Ginger , Vinnard Christopher
Published: November 2018

Background

Pyrazinamide (PZA) is a key drug for both drug-sensitive and drug-resistant tuberculosis (TB). Patients co-infected with TB and human immunodeficiency virus (HIV) are more likely to have low blood levels of PZA, associated with inferior outcomes. Therapeutic drug monitoring (TDM) with sparse blood sampling is recommended for high-risk groups, including HIV/TB patients, but the accuracy is uncertain. We performed a pharmacokinetic (PK) simulation study to estimate the diagnostic accuracy of TDM for PZA among HIV/TB patients.

Methods

We recently performed a population PK study among HIV/TB patients in Botswana, identifying a 1-compartment model with first-order elimination. In the current work, we performed an intensive PK simulation (n = 10,000 patients) to determine the accuracy of sparse blood sampling in identifying HIV/TB patients with low PZA blood levels, as defined by the AUC in a dosing interval (AUC0-24) predictive of successful outcome (363 mg*hr/L). PZA dosing followed WHO guidelines with weight-based dosing bands. In secondary analysis, we examined the peak concentration (Cmax) target predictive of 2-month sputum conversion (58 mg/L). To determine the accuracy of sparse sampling (2- and 6-hours), we performed receiver-operating-characteristic (ROC) analysis, with bootstrapping (n = 1,000) for 95% confidence intervals (CI), and defined accuracy as the area under the ROC curve.

Results

In this simulation PK study of PZA among HIV/TB patients, the PZA AUC0-24 fell below the target in 29% of patients, while in 71% of patients the PZA Cmax was below the target. For the AUC0-24 target, the area under the ROC curve was 0.69 (95% CI 0.68–0.70) for a single 2-hour sample, increasing to 0.75 (95% CI 0.74–0.76) for 2- and 6-hour samples. For the Cmax target, diagnostic accuracy was similar for a 2-hour sample (0.87, 95% CI 0.86–0.87) and 2- and 6-hour samples (0.88, 95% CI 0.88–0.89).

Conclusion

We observed modest diagnostic accuracy of TDM for identifying in silico HIV/TB patients with low PZA AUC0-24, and higher accuracy for low Cmax. By identifying diagnostic performance characteristics of sparse sampling strategies, including optimal cut-offs, the ROC framework can support wider implementation of TDM in high-risk TB populations.

Disclosures

All authors: No reported disclosures.
794. Infectivity of Smear-Positive Pulmonary TB After 2 Weeks of Rifampicin-based Anti-Tuberculous Therapy
Authors: Alhowady Faraj , Elmaki Nada , Ali Maisa , Husain Ahmad , Al-Maslamani Muna , Alsuwaidi Zubaida , Mohamed Mahmoud , Alsoub Hussam
Published: November 2018

Background

Pulmonary tuberculosis (TB) remains one of the leading infectious causes of morbidity and mortality worldwide. Most data showed that infectiousness of pulmonary TB diminishes rapidly after 2 weeks of effective anti-tuberculous therapy and the bacilli seen in the smear after 2 weeks are most likely nonviable. We aim to assess this hypothesis by doing sputum culture after 2 weeks of therapy to assess the viability of the bacilli in the smear.

Methods

A prospective cohort study was conducted on patients admitted to Communicable Disease Centre (CDC), Qatar with smear positive pulmonary tuberculosis during the period November 2013–November 2014. We repeated sputum smear and culture after 2 weeks of rifampicin based regimen to assess the infectivity. Demographic and clinical characteristics of patients was evaluated and compared with smear and culture conversion rate.

Results

Ninety-five cases were included in the study. All had sputum smear and culture after 2 weeks of supervised rifampicin based therapy (Table 1). Sputum culture at two weeks of treatment was positive in 91 cases (95.7%) and only four cases were culture negative after 2 weeks. Demographic and clinical characteristics were compared with the culture status after 2 weeks, found Patient from Indian subcontinent and symptoms duration more than 1 month are less likely to clear infection after 2 weeks with P-value 0.01 and 0.009, respectively (Table 2).

The calculated mean for sputum smear and culture conversion rate was 4 and 8 weeks, respectively. The presence of cough and the duration of symptoms were associated significantly with rapid sputum conversion (P < 0.05); however, the presence of cavity on CXR had no statistical significant effect (Table 3).

Conclusion

Majority of our patients in the study have positive TB culture after two weeks of rifampicin based anti-tuberculosis therapy. So, discontinuation of the isolation after 2 weeks of treatment assuming that bacilli in the smear are nonviable may not be safe.

Disclosures

All authors: No reported disclosures.
803. Overcoming β-Lactam Resistance in Mycobacterium abscessus
Authors: Story-Roller Elizabeth , Lamichhane Gyanu
Published: November 2018

Background

Mycobacterium abscessus (Mab) is an environmentally acquired nontuberculous mycobacterium (NTM) that causes severe pulmonary infections in patients with chronic lung disease, such as cystic fibrosis (CF). The incidence of drug-resistant Mab infections in CF patients in the United States is steadily rising, making it increasingly difficult to manage these often chronic and incurable infections. Mab requires two enzyme classes, l,d- and d,d-transpeptidases, to synthesize peptidoglycan (PG); an integral component of the bacterial cell wall. Each enzyme class is uniquely susceptible to different classes of β-lactam antibiotics. We hypothesize that a combination of two β-lactams, each specific for an enzyme class, will optimally inhibit PG synthesis and swiftly kill Mab, with potential to overcome drug-resistance.

Methods

Paired antibiotic combinations were tested in vitro for synergy against the Mab reference strain ATCC 19977 at 106 CFU/mL, per CLSI guidelines. Combinations included two β-lactams, a β-lactam and a β-lactamase inhibitor, or a β-lactam and a rifamycin. The minimum inhibitory concentration (MIC) of each drug was initially confirmed via broth microdilution assay. A validated checkerboard assay was used to determine the fractional inhibitory concentration index (FICI) for each combination to identify pairs that exhibit synergistic activity against Mab.

Results

Of the initial 227 combinations screened, 18 pairs exhibited a high level of synergy (FICI ≤ 0.5). Half of these were combinations of two β-lactams. The average reduction in MIC for each drug in combination was at least fourfold, with 8/18 combinations exhibiting reductions greater than eightfold. Although MIC breakpoints against Mab have not been established for all of the antibiotics tested in this study, the MICs of at least seven combinations were within the therapeutic range.

Conclusion

Comprehensive inhibition of essential enzymes involved in PG synthesis requires more than one β-lactam antibiotic, and this phenomenon is hypothesized to be the basis for observed synergy between β-lactams. Some of the combinations reduced MICs to within therapeutically achievable levels, potentially leading to vital new treatment options against drug-resistant Mab.

Disclosures

All authors: No reported disclosures.
811. A Randomized Controlled Trial of Prednisolone vs. Interleukin 17 A Inhibitor Secuinumab in the Management of Type 1 Lepra Reaction in Leprosy Patients
Authors: Mitra Debdeep
Published: November 2018

Background

Leprosy is a chronic granulomatous infectious disease caused by Mycobacterium leprae. Type 1 lepra reactions (T1R) are delayed hypersensitivity (Type IV) reactions which if not treated promptly leads to disability affecting eyes, hands and feet. IL-17 A which is produced mainly by inflammatory T helper 17 cells is up regulated in patients of Lepra reaction. Conventionally oral corticosteroids steroids have been the main stay in the management of Type 1 lepra reactions. This novel biologic drug is a targeted therapy which blocks the offending interleukin molecule without any serious adverse effects. We report the results of this randomized control study wherein an immuno-modulator biologic molecule has been safely used to treat an inflammatory reaction in a chronic infectious disease. Outcomes were measured using recurrence rate, a clinical severity score, quality of life, and adverse events.

Methods

Seventy-four patients with new T1R were randomized to receive Secukinumab (a human IgG1κ monoclonal antibody that binds to the protein interleukin (IL)-17A) or Prednisolone for 20 weeks. IL-17 A levels were correlated before and after the intervention.

Results

Recovery rates in skin signs was similar in both groups (92% vs. 87%). Improvements in nerve function both, new and old, sensory (67% vs. 48%) and motor (73% vs. 76%) loss were higher (but not significantly so) in the patients on Secukinumab. Recurrences rates of lepra reaction (25%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients on Secukinumab, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were much lesser with Secukinumab as compared with Prednisolone alone. Both groups had a significant improvement in their quality of life after the study, measured by the Short form survey SF-36.

Conclusion

This is the first double-blind randomized control trial assessing Secukinumab, in the management of lepra reaction. It could be a safe alternative second-line drug for patients with leprosy reactions who are not improving with prednisolone or are experiencing adverse events related to prednisolone. IL-17A levels could be an important diagnostic marker to diagnose and prognosticate cases of Type 1 Lepra reaction, which if not treated in time can lead to irreversible nerve damage.

Disclosures

All authors: No reported disclosures.
994. AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Peripheral Blood Mononuclear Cells
Authors: Howard Leigh , Goll Johannes , Jensen Travis , Hill Heather , Gelber Casey , Creech C Buddy , Edwards Kathryn
Published: November 2018

Background

Influenza A/H5N1 vaccines have been poorly immunogenic. Addition of Adjuvant System 03 (AS03) markedly enhances immune responses, but the mechanisms of this enhancement are unclear.

Methods

We compared gene expression in peripheral blood mononuclear cells (PBMCs) between recipients of AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 vaccine on days 1, 3, 7, and 28 postvaccination. We used a systems vaccinology approach to assess functional classifications of differentially expressed (DE) genes between the two vaccine groups, identify DE genes that correlate with serologic responses, and compare these findings with previous cell-specific assessments.

Results

AS03-adjuvanted vaccine induced the strongest differential gene expression signals on day 1 after vaccination (Figure 1). Multiple innate immune signaling pathways were activated, including the interferon, JAK-STAT, and TNF pathways, and FC gamma receptor (Fc_R) mediated phagocytosis. Immune pathways specific for antigen processing and presentation and influenza A responses were also enriched. Early differential expression of several signal transduction (day 1) and immunoglobulin (day 7) genes were predictive of peak HAI titer (Figure 2). Compared with cell-specific responses, DE gene, and immunologic pathways of PBMCs were most similar to innate immune cell subsets. However, several pathways were unique to PBMCs, and several cell-type-specific pathways, particularly from neutrophils, were absent in PBMCs (Figure 3).

Conclusion

Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early differential regulation of multiple innate immune signaling pathways and enrichment of pathways involved in antigen presentation and influenza immune responses. Early expression of several genes was associated with peak HAI responses, suggesting a potential role for application of these signatures in earlier determination of vaccine responses. While PBMC and immune cell-specific results shared key innate immune signals, unique signals were identified by either approach.

Disclosures

L. Howard, Pfizer: Grant Investigator, Grant recipient. C. B. Creech, Pfizer: Grant Investigator, Research grant. Novartis: Grant Investigator, Research grant. K. Edwards, Novartis: Grant Investigator, Research grant. Novartis: Scientific Advisor, Consulting fee.
999. Ongoing Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjuguate Vaccines
Authors: Asner Sandra
Published: November 2018

Background

Recent population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on the burden of pneumococcal sepsis in children are lacking. We aimed to define the burden of pneumococcal sepsis in children and assess predictors for severe outcomes following the introduction of PCV-13 in 2011 in a nationwide cohort study.

Methods

The Swiss Paediatric Sepsis Study prospectively recruited children <17 years of age with blood culture-proven sepsis between September 2011 and December 2015 in Switzerland. We report on patients with Streptococcus pneumoniae sepsis stratified by the presence of meningitis vs. any other clinical focus. Admission to the paediatric intensive care unit (PICU) and length ofhospital stay (LOS) were defined as outcomes.

Results

From all 1,181 sepsis episodes recorded during the 4.3-year period, children with pneumococcal sepsis (n = 117) accounted for 10% of all sepsis episodes, and 25% of community-acquired sepsis episodes. Forty-two (36%) patients required PICU admission resulting in a mortality of 8%. Children presenting with meningitis (29; 25%) were more frequently admitted to PICU (69% vs. 25%; P < 0.001) and more likely infected by serotypes not included in vaccines (69% vs. 31%; P < 0.001) than those without meningitis. Pneumococcal serotypes 3, 19A, and 7F accounted for 49 (44%) pneumococcal sepsis episodes. From 62 children completely immunised with PCV, of whom 32 were infected with vaccine serotypes, 16 (50%) presented with vaccine failure, of whom 11 were infected with serotype 3. In multivariable analyses, children with meningitis (OR 6.8; 95% C.I 2.4–19.3; P < 0.001) and those infected with serotype 3 (OR 2.8; 95% C.I 1.1- 7.3; P = 0.04) were more likely admitted to PICU, and those infected with serotype 3 had a longer hospital stay (β-coefficient 0.2, 95% CI 0.1–1.1; P = 0.01).

Conclusion

The burden of pneumococcal sepsis in swiss children shortly after the introduction of PCV-13 remains important. Meningitis and serotype 3 were significant predictors of severity.

Disclosures

All authors: No reported disclosures.
1000. Antimicrobial Susceptibility of Gram-Positive Bacteria Isolated From Patients Hospitalized With Bacteremia in United States and European Medical Centers: Results From the International Dalbavancin Evaluation of Activity (IDEA) Program
Authors: Sader Helio S , Flamm Robert K , Rappo Urania , Debabov Dmitri , Castanheira Mariana , Mendes Rodrigo E
Published: November 2018

Background

Gram-positive bacteria (GP), mainly S. aureus (SA), coagulase-negative staphylococci (CoNS), and Enterococcus spp., represent major causes of bacteremia in hospitalized patients. We evaluated the activity of dalbavancin (DALBA) and comparator agents against contemporary GP from patients with bacteremia.

Methods

A total of 8,296 GP unique isolates were consecutively collected from 33 United States (n = 4,409) and 39 European (EUR; n = 3,887) medical centers in 2015–2017 and susceptibility tested by reference broth microdilution methods.

Results

The most common organisms were SA (48.3% in United States, 44.3% in EUR), CoNS (14.3% in United States, 15.6% in EUR), and E. faecalis (EF; 11.5% in United States, 13.1% in EUR). All SA isolates were susceptible (S) to DALBA (MIC50/90, 0.03/0.03 mg/L), linezolid (LZD; MIC50/90, 1/2 mg/L), vancomycin (VAN; MIC50/90, 1/1 mg/L), and teicoplanin (TEI; MIC50/90, ≤0.5/≤0.5 mg/L); >99.9% were S to daptomycin (DAPTO; MIC50/90, 0.25/0.5 mg/L). Based on MIC50, DALBA was 8-fold more active than DAPTO and 32-fold more active than VAN against SA, and DALBA activity was not adversely affected by oxacillin (OXA) resistance (R). Among CoNS, 99.9% of isolates were inhibited at a DALBA MIC of ≤0.25 mg/L (MIC50/90, 0.03/0.06 mg/L); S to DAPTO (MIC50/90, 0.5/0.5 mg/L), LZD (MIC50/90, 0.5/1 mg/L), VAN (MIC50/90, 1/2 mg/L), and TEI (MIC50/90, 2/4 mg/L) were 99.9%, 97.6%, 100.0%, and 98.5%, respectively. Among EF, 97.7% were DALBA-S (96.4% in USA, 99.0% in EUR; MIC50/90, 0.03/0.06 mg/L), 97.5% were VAN-S (96.1% in United States, 99.0% in EUR; MIC50/90, 1/2 mg/L), and all isolates were S to ampicillin (MIC50/90, 1/1 mg/L), DAPTO (MIC50/90, 0.5/1 mg/L) and LZD (MIC50/90,1/2 mg/L). Among E. faecium isolates (n = 656; 7.9% overall), 63.9% were inhibited at ≤0.25 mg/L of DALBA (33.4% in United States, 87.5% in EUR) and 61.6% were VAN-S (32.8% in United States, 84.0% in EUR). DALBA was highly active against β-hemolytic streptococci (BHS; n = 686 [8.3%]; MIC50/90, 0.015/0.03 mg/L) and viridans group streptococci (VGS; n = 432 [5.2%]; MIC50/90, 0.015/0.03 mg/L).

Conclusion

DALBA was very active against SA, CoNS, VAN-S enterococci, BHS, and VGS isolated from patients with bacteremia. Based on MIC50, DALBA was generally 8- to 32-fold more active than DAPTO and VAN against these organisms.

Disclosures

H. S. Sader, Allergan: Research Contractor, Research support. R. K. Flamm, Allergan: Research Contractor, Research support. U. Rappo, Allergan: Employee, Salary. D. Debabov, Allergan: Employee, Salary. M. Castanheira, Allergan: Research Contractor, Research support. R. E. Mendes, Allergan: Research Contractor, Research support.
1001. Evaluation of the Clinical Efficacy and Safety of Oral Antibiotic Therapy for Streptococcus spp. Bloodstream Infections
Authors: Kang Amy , Bor Cynthia , Chen Jamie , Gandawidjaja Michelle , Minejima Emi
Published: November 2018

Background

Despite the severity and frequency of bloodstream infections (BSI), the effectiveness of oral definitive therapy remains unknown. The objective of this study was to evaluate the efficacy and safety of step down oral antibiotics for the treatment of Streptococcus spp. BSI.

Methods

This was a retrospective cohort study of adult, hospitalized patients with Streptococcus spp. BSI between June 2015 and June 2017. Patients were excluded if received <48 hours of antibiotic therapy or therapy was started >48 hours from first positive culture. Patients were grouped by receipt of step down oral antibiotic therapy (PO group) vs. full course IV therapy (IV group) and compared for demographics, clinical course, and outcomes. The primary outcome was 30-day mortality and hospital length of stay (LOS). The secondary outcomes included 30-day recurrence of BSI and adverse events (AEs).

Results

One hundred ninety-five patients met inclusion criteria; median age was 51 year old, 68% were male, 57% were Hispanic, and 71% had community-onset BSI. Sixty-four (33%) were treated with step down oral therapy. The most common source of bacteremia was pneumonia (21%); 8% had endocarditis. Comorbidities were similar between the groups, with diabetes being most common (IV 22% vs. PO 19%, P = 0.29). Severity of illness measured by need for ICU admission, initial lactate level, and SOFA score was similar between the two groups. S. viridans was the most frequent pathogen isolated (IV 28% vs. PO 27%, P = 0.87). Ceftriaxone (39%) for the IV group and levofloxacin (30%) for the PO group were the most common definitive therapy prescribed. PO group received 4 days of IV therapy prior to transition to orals. The IV group had significantly higher mortality rate (11% vs. 2%, P = 0.02) and longer LOS (median 9 days [IQR 5–18] vs. 5 days [4–7.75], P ≤ 0.01) compared with the PO group. 30-day recurrence (IV 2% vs. PO 5%, P = 0.40) and AEs (IV 2% vs. PO 3%, P = 0.60) were similar between the two groups.

Conclusion

In Streptococcus spp. BSI, step down oral antibiotic therapy was associated with a significantly shorter LOS compared with IV only therapy without compromise of clinical outcomes. Larger prospective trials evaluating step down oral therapy are warranted to confirm our results.

Disclosures

All authors: No reported disclosures.
1003. Clinical Implications of Emerging Nonvaccine-Serotype Invasive Pneumococcal Disease Among Adults in the Republic of Korea in the Era of Protein-Conjugated Pneumococcal Vaccine
Authors: Kim Jong Hun , Baik Seung Hee , Song Joon Young , Bae In-Gyu , Kim Hyo Youl , Kim Dong-Min , Choi Young Hwa , Choi Won Suk , Jeong Y H , Kwon Hyun Hee , Jeong Hye Won , Kim Yeon-Sook , Kim Jeong Yeon , Lee Jacob , Kee Sae Yoon , Chung Jin-Won , Nahm Moon H , Kim Min-Ja
Published: November 2018

Background

In the Republic of Korea (ROK), protein conjugated vaccines (PCV13 and PCV10) in replacement of PCV7 have been used in children since 2010, and then included in the childhood national immunization program (NIP) in 2014. This study investigated indirect effect of PVCs on serotypes in PCV-naïve adult invasive pneumococcal disease (IPD) and its clinical implications.

Methods

A prospective observational cohort study was conducted, through the serotype surveillance program following the NIP implementation of 23-valent pneumococcal polysaccharide vaccine (PPV23) for elderly population (≥65 years) from 2013 to 2015. Clinical data and pneumococcal isolates from adult IPD patients (≥18 years) were collected from 20 hospitals. Clinical characteristics were compared between vaccine-serotype (VT) and nonvaccine-serotype (NVT) groups.

Results

Of a total of 319 IPD patients enrolled, 189 cases (59.2%) were available for serotypes. Among them, the proportion of PCV-naïve cases was 99.5% (188/189) and 189 patients consisted of NVT (n = 64, 33.9%) and VT group (n = 125, 66.1%). Compared with the previous study in the ROK (2004–2010), the proportion of PCV13 serotypes was decreased (61.4% vs. 37.0%, P < 0.001) and PPV23 serotypes were stationary (71.5% vs. 65.6%), but NVT serotypes were increased (23.4% vs. 33.9%, P = 0.033) in our study. The most common serotype was 3 (20.8%) and 34 (23.4%) in VT and NVT group, respectively. VT group had more bacteremic pneumonia (72.0% vs. 48.4%, P = 0.002). There was no difference of the case fatality rate between NVT and VT groups (29.7% vs. 35.2%, P = 0.447). Multiple logistic regression analysis showed that chronic kidney disease (odds ratio [OR] 10.26, 95% confidence interval [CI] 1.94–54.44, P = 0.006), younger age of 18–49 years (OR 4.04, 95% CI 1.29–12.71, P = 0.017), deep-seated infection (OR 3.73, 95% CI 1.34–10.39, P = 0.012), meropenem resistance (OR 3.21, 95% CI 1.49–6.91, P = 0.003) were significantly associated with NVT-IPD cases.

Conclusion

Our study indicates that emerging and expanding NVT-IPD among adults, probably due to indirect herd effect of widespread use of pediatric PCV. Further changes of IPD serotypes might occur and IPD serotypes should be monitored for developing better pneumococcal vaccination policy.

Disclosures

All authors: No reported disclosures.
1004. Frequency of Occurrence and Antimicrobial Susceptibility of Bacteria Isolated From Patients Hospitalized With Bloodstream Infections in United States Medical Centers (2015–2017)
Authors: Sader Helio S , Flamm Robert K , Pfaller Michael A , Castanheira Mariana
Published: November 2018

Background

Bloodstream infections (BSIs) cause significant morbidity and mortality. We evaluated the frequency and antimicrobial susceptibility of bacteria causing BSIs in the United States.

Methods

A total of 9,210 bacterial isolates were consecutively collected (1/patient) from 33 US medical centers in 2015–2017 and tested for susceptibility by reference broth microdilution methods in a central laboratory (JMI Laboratories) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Whole-genome sequencing was performed on carbapenem-resistant Enterobacteriaceae (CRE).

Results

The most common organisms were S. aureus (SA; 24.3%), E. coli (EC; 20.8%), K. pneumoniae (KPN; 9.1%), coagulase-negative staphylococci (7.3%), E. faecalis (5.5%), P. aeruginosa (PSA; 4.7%), and β-hemolytic streptococci (4.7%). Overall, 50.0% of isolates were Gram-negative bacilli (GNB) and 41.4% were Enterobacteriaceae (ENT). All SA were susceptible (S) to dalbavancin (MIC90, 0.03 μg/mL), linezolid, tigecycline (TGC), and vancomycin; >99.9% S to daptomycin, 97.6% S to ceftaroline, and 57.8% S to oxacillin. The most active agents against ENT were CAZ-AVI (99.9% S; table), amikacin (AMK; 99.7% S), and the carbapenems meropenem (MEM) and doripenem (99.1% S). Ceftolozane-tazobactam (C-T; tested in 2017 only) was active against 96.9% of ENT. Ceftriaxone (CRO)-S rates were 83.0% and 86.5% among EC and KPN, respectively. CRO-non-S KPN exhibited low S rates to most agents, except CAZ-AVI (99.1% S), TGC (93.6%), AMK (93.8%), and colistin (COL; 93.4%). Among 28 CRE isolates (0.7% of ENT), 21 produced a KPC-like, 2 an NMD-like, and 1 a KPC-17 and an NDM-1. COL (100.0% S), C-T (98.7%S), CAZ-AVI (98.2% S), AMK (97.9% S), and tobramycin (95.6% S) were very active against PSA. CAZ-AVI and C-T remained active against most PSA isolates non-S to MEM (93.0 and 95.0% S, respectively) and/or piperacillin–tazobactam (P-T; 88.9 and 91.3% S) and/or CAZ (86.9 and 88.2% S).

Conclusion

GNB represented 50.0% of bacteria isolated from patients with BSIs and the most active agents against these organisms were CAZ-AVI and AMK. Various agents exhibited excellent overall coverage against Gram-positives, including dalbavancin, daptomycin, linezolid, and TGC.

Disclosures

H. S. Sader, Allergan: Research Contractor, Research support. R. K. Flamm, Allergan: Research Contractor, Research support. M. A. Pfaller, Allergan: Research Contractor, Research support. M. Castanheira, Allergan: Research Contractor, Research support.
1043. Evaluation of Early Clinical Failure Criteria for Gram-Negative Bloodstream Infections
Authors: Rac Hana , Gould Alyssa , Bookstaver P Brandon , Justo Julie Ann , Kohn Joseph , Al-Hasan Majdi N
Published: November 2018

Background

Early identification of patients at high risk of morbidity and mortality following Gram-negative bloodstream infections (GN-BSI) based on initial clinical course may prompt adjustments to optimize diagnostic and treatment plans. This retrospective cohort study aims to develop early clinical failure criteria (ECFC) to predict unfavorable outcomes in patients with GN-BSI.

Methods

Adults with community-onset GN-BSI who survived hospitalization for at least 96 hours at Palmetto Health hospitals in Columbia, SC, USA from January 1, 2010 to June 30, 2015 were identified. Multivariate logistic regression was used to examine association between clinical variables within 72–96 hours of BSI and unfavorable outcomes (28-day mortality or hospital length of stay >14 days).

Results

Among 766 patients with GN-BSI, 225 (29%) had unfavorable outcomes. After adjustments for Charlson Comorbidity Index and appropriateness of empirical antimicrobial therapy in multivariate model, predictors of unfavorable outcomes included systolic blood pressure <100 mmHg or vasopressor use (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.1–2.5), heart rate >100/minute (aOR 1.7, 95% CI 1.1–2.5), respiratory rate ≥22/minute or mechanical ventilation (aOR 2.1, 95% CI 1.4–3.3), altered mental status (aOR 4.5, 95% CI 2.8–7.1), and peripheral WBC count >12 × 103/mm3 (aOR 2.7, 95% CI 1.8–4.1) at 72–96 hours from index BSI. Area under receiver operating characteristic curve of ECFC model in predicting unfavorable outcomes was 0.77 (0.84 and 0.71 in predicting 28-day mortality and prolonged hospitalization separately, respectively). Predicted 28-day mortality increased from 1% in patients with no ECFC to 3%, 7%, 16%, 32%, and 54% in presence of each additional criterion (P < 0.001). Predicted hospital length of stay was 7.5 days in patients without any ECFC and increased by 4.0 days (95% CI 3.1–4.9, P < 0.001) in presence of each additional criterion.

Conclusion

Risk of 28-day mortality or prolonged hospitalization can be estimated within 72–96 hours of GN-BSI using ECFC. These criteria may have utility in future clinical research in assessing response to antimicrobial therapy based on a standard evidence-based definition of early clinical failure.

Disclosures

P. B. Bookstaver, CutisPharma: Scientific Advisor, <$1,000. Melinta Therapeutics: Speaker’s Bureau, <$1,000.
1055. Epidemiology and Mechanisms of Carbapenem Resistance in Recurrent Extended-Spectrum β-Lactamase- Producing Enterobacteriaceae Bacteremia
Authors: Aitken Samuel L , Bhatti Micah , Sahasrabhojane Pranoti , Galloway-Pena Jessica , Li Xiqi , Tverdek Frank P , Reeves Cagney , McDaneld Patrick , Greenberg David , Shelburne Samuel
Published: November 2018

Background

Carbapenems are the treatment of choice for bacteremia caused by extended spectrum β-lactamase producing Enterobacteriaceae (ESBL-E). The emergence carbapenem resistance (CR) in ESBL-E isolates has been described; however, the rate of such resistance in clinical settings is unknown. We describe the frequency and mechanisms of CR in recurrent ESBL-E bacteremia at an NCI-designated cancer center.

Methods

We performed a prospective whole genome sequencing (WGS) study and retrospective cohort review of adult (age ≥18 years) patients with ESBL-E bacteremia between January 2015 and July 2016. Recurrent bacteremia was defined as identification of the same organism in blood culture at any time following initial successful treatment. CR was defined as resistance to meropenem. Carbapenemase production was assessed in the microbiology laboratory using Carba-NP. Available paired isolates underwent WGS via Illumina HiSeq for assessment of clonality and identification of CR mechanisms.

Results

One hundred and sixteen patients with ESBL-E bacteremia were identified. E. coli was the most common organism (86%), followed by K. pneumoniae (12%), and K. oxytoca (2%). Recurrent bacteremia was identified in 17 (15%) patients (E. coli [n = 15], K. pneumoniae [n = 2]). Of these, 6 (35%) were CR and 5/6 (83%) were Carba-NP negative. All six recurrent CR isolates occurred in patients with leukemia. Five isolate pairs were available for WGS. In four of five pairs (three E. coli, one K. pneumoniae), CR emerged from the same strain causing the original infection; one recurrence was caused by a distinct E. coli with a OXA-48-like gene. Compared with parental strains, CR E. coli contained deletions in porin-encoding genes and had increased mapping depth for genes encoding CTX-M ESBLs. The K. pneumoniae was Carba-NP negative with no identifiable CR mechanism.

Conclusion

Emergence of CR following treatment for ESBL-E bacteremia was seen only in leukemia patients and was primarily due to porin loss and amplification of ESBL genes, rather than acquisition of exogenous carbapenemases. These are the first clinical data describing the molecular mechanism of ESBL-E transformation to CR. These data serve as the basis for future studies of antimicrobial stewardship interventions to limit the emergence of CR in ESBL-E.

Disclosures

S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee. Medicines Company: Scientific Advisor, Consulting fee. Merck & Co.: Scientific Advisor, Consulting fee.
1059. Staphylococcus aureus Bacteremia Treatment: Results From Pilot Surveillance in Four US States
Authors: Kabbani Sarah , Jackson Kelly , Epstein Lauren , Gellert Anita , Bernu Carmen , Overton Rahsaan , Nadle Joelle , Dumyati Ghinwa , Lynfield Ruth , Ray Susan M , Epson Erin , See Isaac
Published: November 2018

Background

Staphylococcus aureus treatment guidelines are being revised to include proposed quality measures for evaluation of patients with S. aureus bacteremia (SAB) (e.g., infectious disease [ID] consultation, echocardiogram, and documenting clearance of bacteremia). We describe current management practices of SAB to identify opportunities for quality improvement.

Methods

We conducted a pilot assessment of SAB cases reported to CDC’s Emerging Infections Program active, laboratory- and population-based surveillance from 24 hospitals in four states during 1–2 months in 2017 or 2018. An SAB case was the isolation of S. aureus from a blood culture among adults (≥18 years) in the catchment area. We collected clinical and demographic information and performed a descriptive analysis of management of SAB cases.

Results

Among 109 SAB cases identified, 50 (46%) were methicillin-resistant S. aureus (MRSA). While hospitalized, 87 (80%) patients were evaluated by ID consultation, 90 (83%) underwent an echocardiogram (26 were transesophageal), and 92 (84%) had documented clearance of bacteremia. During the hospitalization, 15 (14%) died and 12 (11%) left against medical advice (AMA). Of those who survived and did not leave AMA, median duration of hospitalization after initial culture was 10.5 days (interquartile range 7–18). In total, 10 survivors (9% of cases) completed at least 2 weeks of antibiotics while hospitalized, and 65 (60% of cases) were discharged on antibiotic therapy. Among the 25 MRSA patients discharged on antibiotics, common treatments were vancomycin (64%), daptomycin (8%), ceftaroline (8%), and linezolid (4%). Among the 40 methicillin-susceptible SAB patients discharged on antibiotics, cefazolin (56%), ceftriaxone (13%), cefepime (5%), linezolid (5%), nafcillin (3%), and vancomycin (3%) were most common. The remainder of outpatient treatments included oral β-lactams, clindamycin, doxycycline, levofloxacin, and erythromycin.

Conclusion

Overall, the majority of patients with SAB underwent evaluation according to the proposed quality measures and received therapy with targeted anti-staphylococcal agents, although opportunities to optimize treatment remain. Hospitalized patients who leave AMA represent a particular challenge for effective SAB therapy.

Disclosures

All authors: No reported disclosures.
1064. Clinical Outcomes of Daptomycin in Combination With Ceftaroline or Anti-Staphylococcal Penicillins for Patients With Persistent MRSA Bacteremia
Authors: Bouchard Jeannette , Oleksiuk Louise-Marie , Shields Ryan K
Published: November 2018

Background

Daptomycin-β-lactam (DAP-BL) combinations demonstrate in vitro synergy against MRSA; however, the clinical efficacy of combo is limited. Our objective was to compare the outcomes of patients with persistent MRSA bacteremia treated with DAP-BL combinations.

Methods

Retrospective, cohort study of hospitalized patients receiving DAP with ceftaroline (CPT) or oxacillin (OXA) between March 2012 and February 2018. Patients with persistent MRSA bacteremia despite ≥4 days of vancomycin therapy were included. Clinical success was defined as resolution of signs and symptoms of infection, microbiological eradication and in hospital survival.

Results

Thirty-two patients included. Forty-four percent were male, median age was 61 (range: 26–78), and the median Charlson score was 2 (range: 0–11). Sixteen percent were IVDU. Sources of bacteremia included endocarditis (31%), bone/joint (31%), skin soft tissue (28%), and catheter (25%); 53% had more than one source. At the onset of combo therapy, median Pitt Bacteremia score was 1 (0–7). ID was consulted in all patients. Twenty-three and nine patients received DAP in combo with CPT or OXA, respectively. Baseline demographics, underlying disease, and clinical characteristics were comparable between groups. Patients receiving DAP-CPT had higher median Pitt Bacteremia scores (2 vs. 1; P = 0.04) and shorter median durations of prior vancomycin (8 vs. 10 days; P = 0.02) than did patients receiving DAP-OXA. Source control was pursued equally between groups. Median time to clearance of bacteremia following combo therapy was 3 (0–24) vs. 2 (−1–16) days in the DAP-CPT and DAP-OXA groups, respectively (P = 0.45). Corresponding rates of clinical success (43% vs. 56%) and microbiologic eradication (78% for both) did not vary between groups (figure). In hospital mortality occurred in 39% of patients receiving DAP-CPT and 0% of patients receiving DAP-OXA (P = 0.03). Adverse events occurred in 35% and 44% of patients, respectively.

Conclusion

We have demonstrated high rates of microbiologic eradication and reasonable clinical success rates with DAP-BL combination therapy. Patients receiving DAP-CPT had higher severity of illness at baseline, which paralleled with higher mortality. These data provide compelling evidence for future studies designed to determine the optimal BL in combination with DAP for persistent MRSA bacteremia.

Disclosures

R. K. Shields, Allergan: Grant Investigator, Research grant. Pfizer: Consultant and Scientific Advisor, Speaker honorarium. Shionogi: Scientific Advisor, Consulting fee. Roche: Grant Investigator, Research grant. Venatorx: Grant Investigator, Research grant. Medicines Company: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Accelerate Diagnostics: Scientific Advisor, Consulting fee.