Geneve M. Allison

Prediction Model for 30-Day Hospital Readmissions Among Patients Discharged Receiving Outpatient Parenteral Antibiotic Therapy

BACKGROUND Factors associated with readmission for patients prescribed outpatient parenteral antibiotic therapy (OPAT) at hospital discharge have not been definitively identified. The study aim was to develop a model of 30-day readmissions for OPAT patients. METHODS A database comprising 782 OPAT patients treated between 2009 and 2011 at a single academic center was created. Variables collected included patient demographics, comorbidities, infections, and antibiotic classes. Final model discrimination was assessed using the c-statistic, and calibration was examined graphically. RESULTS Mean patient age was 58 years (range, 18-95 years), 43% were women, and the most common diagnoses were bacteremia (24%), osteomyelitis (20%), and pyelonephritis (13%). The unplanned 30-day readmission rate was 26%. The leading indications for readmission were non-infection related (30%), worsening infection (29%), and new infection (19%). The final regression model consisted of age (odds ratio [OR], 1.09 per decade; 95% confidence interval [CI], 0.99-1.21), aminoglycoside use (OR, 2.33; 95% CI, 1.17-4.57), resistant organisms (OR, 1.57; 95% CI, 1.03-2.36), and number of prior hospital discharges without intravenous antibiotics in the past 12 months (OR, 1.20 per prior admission; 95% CI, 1.09-1.32). The c-statistic was 0.61 and the highest-risk quintile of patients had almost a 3-fold higher rate of readmission compared to the lowest. CONCLUSIONS Patients prescribed OPAT are at risk for readmission. A subgroup of patients at especially high risk can be identified using easily obtainable clinical characteristics at the time of hospital discharge. More intensive interventions to prevent OPAT readmissions should be targeted and tested with those at highest risk.

Proteolytic Processing of the Cryptosporidium Glycoprotein gp40/15 by Human Furin and by a Parasite-Derived Furin-Like Protease Activity

ABSTRACT The apicomplexan parasite Cryptosporidium causes diarrheal disease worldwide. Proteolytic processing of proteins plays a significant role in host cell invasion by apicomplexan parasites. In previous studies, we described gp40/15, a Cryptosporidium sp. glycoprotein that is proteolytically cleaved to yield two surface glycopeptides (gp40 and gp15), which are implicated in mediating infection of host cells. In the present study, we showed that biosynthetically labeled gp40/15 is processed in Cryptosporidium parvum-infected HCT-8 cells. We identified a putative furin cleavage site RSRR↓ in the deduced amino acid sequence of gp40/15 from C. parvum and from all Cryptosporidium hominis subtypes except subtype 1e. Both human furin and a protease activity present in a C. parvum lysate cleaved recombinant C. parvum gp40/15 protein into 2 peptides, identified as gp40 and gp15 by size and by immunoreactivity with specific antibodies. C. hominis gp40/15 subtype 1e, in which the RSRR sequence is replaced by ISKR, has an alternative furin cleavage site (KSISKR↓) and was also cleaved by both furin and the C. parvum lysate. Site-directed mutagenesis of the C. parvum RSRR sequence to ASRR resulted in inhibition of cleavage by furin and the C. parvum lysate. Cleavage of recombinant gp40/15 and a synthetic furin substrate by the C. parvum lysate was inhibited by serine protease inhibitors, by the specific furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (Dec-RVKR-cmk), and by calcium chelators, suggesting that the parasite expresses a Ca2+ dependent, furin-like protease activity. The furin inhibitor Dec-RVKR-cmk decreased C. parvum infection of HCT-8 cells, suggesting that a furin-like protease activity may be involved in mediating host-parasite interactions.

Antibody Responses to the Immunodominant Cryptosporidium gp15 Antigen and gp15 Polymorphisms in a Case–Control Study of Cryptosporidiosis in Children in Bangladesh

Although Cryptospridium hominis is the dominant Cryptosporidium species infecting humans, immune responses to cognate antigens in C. hominis-infected persons have not been reported. We investigated antibody responses to the immunodominant gp15 antigen from C. hominis and C. parvum, in C. hominis-infected Bangladeshi children less than five years of age with diarrhea (cases) and uninfected children with diarrhea (controls). We also investigated polymorphisms in the C. hominis gp15 sequence from cases. Serum IgG responses to gp15 from both species were significantly greater in cases than controls. In spite of polymorphisms in the gp15 sequence, there was a significant correlation between antibody levels to gp15 from both species, indicating cross-reactivity to conserved epitopes. Cases with acute diarrhea had a significantly greater serum IgA response to gp15 compared with those with persistent diarrhea, suggesting that this response may be associated with protection from prolonged disease. These findings support further investigation of gp15 as a vaccine candidate.

Serum IgG Response to Cryptosporidium Immunodominant Antigen gp15 and Polymorphic Antigen gp40 in Children with Cryptosporidiosis in South India

ABSTRACT The surface-associated glycopeptides gp40, one of the most polymorphic Cryptosporidium antigens, and gp15, one of the most immunodominant Cryptosporidium antigens, are putative vaccine candidates because they mediate infection in vitro and induce immune responses in vivo. We evaluated antibody responses to these antigens before and after the first episode of symptomatic cryptosporidiosis in 51 children from a birth cohort study in an area in South India where Cryptosporidium is endemic and a major cause of parasitic diarrhea. IgG levels to gp15 and to homotypic and heterotypic gp40 antigens were measured in pre- and postdiarrheal sera by enzyme-linked immunosorbent assay (ELISA). There was a significant IgG response to gp15 (P < 0.001) following the first episode of cryptosporidial diarrhea. Using a general additive model, we determined the estimated time of the peak IgG response to gp15 to be 9.3 weeks (confidence interval, 5.2 to 13.4) following the diarrheal episode. In a subset of 30 children infected with Cryptosporidium hominis subtype Ia, there was a significant difference in IgG responses to homotypic C. hominis Ia and to heterotypic Cryptosporidium parvum II gp40 antigens (P = 0.035). However, there was also a significant correlation (P = 0.001) in the responses to both antigens in individual children, suggesting that while responses are in part subtype specific, there is significant cross-reactivity to both antigens. This is the first report of the characterization of immune responses to cryptosporidiosis in Indian children and the first study to investigate human immune responses to the polymorphic gp40 antigen. However, further studies are needed to determine whether immune responses to these antigens are protective against subsequent infections.

Systemic Antibody Responses to the Immunodominant p23 Antigen and p23 Polymorphisms in Children with Cryptosporidiosis in Bangladesh

Cryptosporidium is a major cause of diarrhea in children in developing countries. However, there is no vaccine available and little is known about immune responses to protective antigens. We investigated antibody responses to p23, a putative vaccine candidate, in children in Bangladesh with cryptosporidiosis and diarrhea (cases) and uninfected children with diarrhea (controls), and p23 gene polymorphisms in infecting species. Serum IgM, IgG, and IgA responses to p23 were significantly greater in cases than controls after three weeks of follow-up. Cases with acute diarrhea had significantly greater serum IgA and IgM responses than those with persistent diarrhea, which suggested an association with protection from prolonged disease. The p23 sequences were relatively conserved among infecting species and subtype families. Although most children were infected with Cryptosporidium hominis, there was a cross-reactive antibody response to C. parvum antigen. These results support further development of p23 as a vaccine candidate.

Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches

OBJECTIVES β-Lactam antibiotics are commonly used in outpatient parenteral antimicrobial therapy (OPAT), but data regarding outcomes of long-term therapy are limited. The purpose of this study was to compare treatment success, readmission and antibiotic switch rates in patients treated with β-lactam antibiotics as OPAT. METHODS We carried out a retrospective review of all patients, discharged from Tufts Medical Center with cefazolin, ceftriaxone, ertapenem or oxacillin, between January 2009 and June 2013. A competing risks analysis was used to compare the cumulative incidence of first occurrence of treatment success, antibiotic switch and 30 day readmission for each drug. RESULTS Four hundred patients were identified (cefazolin n = 38, ceftriaxone n = 104, ertapenem n = 128 and oxacillin n = 130). Baseline demographics were similar. Treatment success rates were higher for ceftriaxone and ertapenem (cefazolin 61%, ceftriaxone 81%, ertapenem 73% and oxacillin 58%; P < 0.001). Thirty-day all-cause readmissions were similar (cefazolin 21%, ceftriaxone 14%, ertapenem 20% and oxacillin 15%; P = 0.46). In 400 OPAT courses, 37 out of 50 antibiotic switches were accomplished without readmission. Adverse drug events (ADEs) were the most common reason for outpatient antibiotic switches (31/37, 84%). The ADE rate was higher for the oxacillin group (cefazolin 2.0 versus ceftriaxone 1.5 versus ertapenem 2.9 versus oxacillin 8.4 per 1000 OPAT days; P < 0.001). CONCLUSIONS OPAT with β-lactam antibiotics is effective, but antibiotic switches for adverse events were more frequent with oxacillin use. Clinicians should be cognizant of the risk of readmissions and ADEs in OPAT patients, as the value of OPAT lies in reducing patient morbidity and readmissions by managing ADEs and preventing clinical failures.

A national survey of infectious disease practitioners on their use of outpatient parenteral antimicrobial therapy (OPAT).

Abstract Background: The use of outpatient parenteral antimicrobial therapy (OPAT) is standard medical practice; however, significant heterogeneity in practice exists. We hypothesized that formal OPAT programs are associated with increased physician participation in patient safety activities. Methods: United States Infectious Disease (ID) physicians were contacted and asked to participate in an electronic survey from April through June 2012. Data were analyzed using SPSS version 20. Results: In all, 3718 physicians were contacted and 316 (8.5%) responded. Respondents practice in 47 states; the majority (79%) practice adult ID, 11% pediatric ID, 10% a combination of the two. Sixty percent reported that ID consultation was not mandatory before OPAT, and 75% of these respondents thought it should be compulsory. The most common indications were osteomyelitis, prosthetic joint infections, and endocarditis, and the most common antibiotics were vancomycin, ceftriaxone, and ertapenem. Most respondents (59%) discharge patients with OPAT weekly, and have a median number of 11 OPAT patients (95% confidence interval (CI) 8.5–13.4). Half of respondents have a formal OPAT program. Fifty-two percent report no systematic method of communication between inpatient and outpatient physicians when patients are discharged with OPAT, 49% have no systematic method of lab tracking, and 34% have no method of ensuring patient adherence to clinic visits. All of these patient safety measures were more likely to be present in practice sites with formal OPAT programs (p < 0.001). Conclusions: Opportunities exist for improving OPAT monitoring and patient safety. Formal OPAT programs provide the framework for safe and effective care and are to be encouraged.

Where is the leak in the pipeline? Investigating gender differences in academic promotion at an academic medical centre

BackgroundWomen are still under-represented in the senior ranks of academic medicine. As local surveys represent a critical initial step in addressing the challenges of gender disparities in academic promotion within institutions, we surveyed faculty at an academic medical centre to identify factors to improve the academic advancement of women.MethodsWe conducted an electronic survey of all full-time faculty members in a Department of Medicine assessing academic rank and factors important in consideration for promotion.Results106 faculty members (46 %) responded to the survey; 40 % of the respondents were women. There was a statistically significant gender gap in faculty rank (p = 0.002), with only 2 of 17 full professor positions occupied by women. Among faculty who had not yet requested promotion, women were more likely to report that they did not think an academic promotion would benefit them (69 vs. 32 % in men, p = 0.01), and to report a lack of encouragement for requesting promotion (50 vs. 29 %, p = 0.08).ConclusionsTargeting the perceived value of academic promotion among women faculty, increasing junior faculty mentorship and modifying annual review processes could address gender disparities in academic medicine ranks.

In vivo emergence of ceftaroline resistance during therapy for MRSA vertebral osteomyelitis

Sir, Ceftaroline, the active metabolite of ceftaroline fosamil, was approved by the US FDA in 2010 and by the European Commission in 2012 for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This medication has also been reported to be used for the sporadic treatment of other severe MRSA infections, including osteomyelitis and epidural abscesses. A middle-aged man with diabetes mellitus was admitted for incision and drainage of a septic left wrist. Source control was achieved. Tissue cultures grew MRSA (strain 89, Table 1), with ceftaroline MIC of 0.75 mg/L by broth microdilution (incremental dilution steps). Vancomycin was initiated, but was switched to ceftaroline fosamil due to rising serum creatinine and impending cardiac catheterization for a myocardial infarction. He improved and was discharged on renally adjusted ceftaroline fosamil 600 mg every 12 h. During his hospitalization, the patient complained of chronic sciatica back pain. Physical examination was notable for no spinal tenderness. However, back pain progressed post-discharge, and MRI showed vertebral osteomyelitis and collections in bilateral psoas muscles. He was readmitted for CT-guided aspiration of the right psoas fluid collection, which grew MRSA (strain 91) with ceftaroline MIC 4–6 mg/L (Table 1) and antibiotics were changed to vancomycin. Peripheral blood cultures revealed two MRSA isolate morphologies (strains 86 and 88). He underwent laminectomy and facetectomy for epidural abscess drainage with lumbar debridement, fusion and fixation. Cultures from the epidural abscess again grew MRSA. Trans-thoracic echocardiogram was negative for vegetations. The patient was discharged and completed 12 weeks of intravenous antibiotics followed by 12 months of oral doxycycline after inflammatory markers normalized. More than 1 year after surgery the patient was ambulating independently with a cane and living at home, and inflammatory markers had remained normal for .4 months after completing antibiotics. The patient gave verbal and written informed consent for the publication of this case report. The baseline MRSA (strain 89) and subsequent ceftarolineresistant isolates (strains 86, 88 and 91) were subjected to WGS. Genome sequence data were utilized to extract epidemiological information related to isolate ST, spa and SCCmec determination, as previously described. The DNA genes and/or regions obtained from the baseline MRSA (strain 89) were considered as the reference for comparison purposes with the three selected follow-up isolates included in the study. The following proteins were investigated: PBP1, PBP2, PBP2a, PBP3 and PBP4. Other DNA sequence regions analysed were mecI, mecR and the mecA ribosomal binding site and the vraSR regulation network (cell wall stress response operon). All downstream DNA analysis was performed using the Lasergene package (DNAStar). All four isolates belonged to ST5, had a spa type t002 and carried an SCCmec type II, associated with MRSA USA100 clone. Follow-up isolates showed Glu447Lys and Ala601Ser alterations in the penicillin-binding domain (PBD) of PBP2a. The additional alteration observed at the PBD (Ala601Ser) has not

Infectious Diseases Specialty Intervention is Associated with Better Outcomes among Privately Insured Individuals Receiving Outpatient Parenteral Antimicrobial Therapy

BACKGROUND Outpatient parenteral antimicrobial therapy (OPAT) can be managed by specialists in infectious diseases (ID) or by other physicians. Better management of OPAT can reduce the likelihood of readmission or emergency department (ED) use. The relative success of ID specialists and other physicians in managing OPAT has received little study. METHODS We analyzed a national database of insurance claims for privately insured individuals under age 65, locating inpatient acute-care stays in 2013 and 2014 that were followed by OPAT. Through propensity scoring, patients who received outpatient ID intervention (ID-led OPAT) were matched 1-to-1 with those who did not (Other OPAT). We estimated regression models of hospital and ED admissions and of total healthcare payments over the first 30 days after discharge. RESULTS The final analytic sample of 8200 observations was well balanced on clinical and demographic characteristics. Soft-tissue infection and osteomyelitis were the most common infections in the index event, each affecting more than 40% of individuals. Relative to those with Other OPAT, people with ID-led OPAT had lower odds of an ED admission (odds ratio [OR] 0.449, 95% confidence interval [CI] 0.311-0.645) or hospitalization (OR 0.661, 95% CI 0.557-0.791) over 30 days, and they accumulated