Rationale for a Neisseria gonorrhoeae Susceptible-only Interpretive Breakpoint for Azithromycin.

BACKGROUND: Azithromycin (AZI) is recommended with ceftriaxone (CRO) for treatment of uncomplicated gonococcal urethritis and cervicitis in the United States, and an AZI-susceptibility breakpoint is needed. Neither the Food and Drug Administration (FDA) nor the Clinical and Laboratory Standards Institute (CLSI) has set interpretive breakpoints for AZI susceptibility. As a result, AZI antimicrobial susceptibility testing (AST) cannot be interpreted using recognized standards. This has contributed to increasingly unavailable clinical laboratory AST, although gonorrhea is on the rise with >550 000 US gonorrhea cases reported to the Centers for Disease Control and Prevention in 2017, the highest number of cases since 1991. METHODS: This article summarizes the rationale data reviewed by the CLSI in June 2018. RESULTS: The CLSI decided to set a susceptible-only interpretive breakpoint at the minimum inhibitory concentration of ≤1 µg/mL. This is also the epidemiological cutoff value (ECV) (ie, the end of the wild-type susceptibility distribution). This breakpoint presumes that AZI (1-g single dose) is used in an approved regimen that includes an additional antimicrobial agent (ie, CRO 250 mg, intramuscular single dose). CONCLUSIONS: Having a breakpoint can improve patient care and surveillance and allow future development and FDA regulatory approval of modernized AST to guide treatment. The breakpoint coincides with a European Committee on AST decision to remove previously established, differing AZI breakpoints and use the ECV as guidance for testing. The CLSI breakpoint is now the recognized standard that defines AZI susceptibility for gonococcal infections.

Multi-institute analysis of carbapenem resistance reveals remarkable diversity, unexplained mechanisms, and limited clonal outbreaks.

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta-lactamases encoded by blaKPC2, blaKPC3, and blaKPC4, which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation.

Improving communication with patients in post-traumatic amnesia: development and impact of a clinical protocol.

OBJECTIVE: To assess the impact of staff training focused on improved treatment and communication with patients in post-traumatic amnesia (PTA) or other disorders of explicit (declarative) memory. A major aim was to minimize questions demanding recall from explicit memory, e.g., orientation quizzing, and personal/medical history questions, which may produce unreliable information and exacerbate patient frustration and anxiety. METHODS: Mixed-methods design. Inpatients with impairments of explicit memory were observed before (n = 4) and after (n = 4) training, with staff interactions recorded verbatim. Records were coded for types of questions and patient responses. Clinicians who worked before and after training were surveyed regarding perceived changes in practice, team functioning, and patient behavior. RESULTS: Explicit memory questions decreased significantly, as did irrelevant or "don't know" responses from patients, with large nonparametric effect sizes noted. The frequency of questions not relying on explicit memory remained stable. Most clinicians reported positive effects on their own and others' practice with memory impaired patients, and one-quarter noted less patient frustration or agitation. CONCLUSIONS: Although questioning patients is a natural part of medical care, targeted staff training can result in positive changes in communication practice and should be considered for facilities treating patients in PTA.

The Importance of Voluntary Behavior in Rehabilitation Treatment and Outcomes.

Most rehabilitation treatments are volitional in nature, meaning that they require the patient's active engagement and effort. Volitional treatments are particularly challenging to define in a standardized fashion, because the clinician is not in complete control of the patient's role in enacting these treatments. Current recommendations for describing treatments in research reports fail to distinguish between 2 fundamentally different aspects of treatment design: the selection of treatment ingredients to produce the desired functional change and the selection of ingredients that will ensure the patient's volitional performance. The Rehabilitation Treatment Specification System (RTSS) is a conceptual scheme for standardizing the way that rehabilitation treatments are defined by all disciplines across all areas of rehabilitation. The RTSS highlights the importance of volitional behavior in many treatment areas and provides specific guidance for how volitional treatments should be specified. In doing so, it suggests important crosscutting research questions about the nature of volitional behavior, factors that make it more or less likely to occur, and ingredients that are most effective in ensuring that patients perform desired treatment activities.

A Theory-Driven System for the Specification of Rehabilitation Treatments.

The field of rehabilitation remains captive to the black-box problem: our inability to characterize treatments in a systematic fashion across diagnoses, settings, and disciplines, so as to identify and disseminate the active ingredients of those treatments. In this article, we describe the Rehabilitation Treatment Specification System (RTSS), by which any treatment employed in rehabilitation may be characterized, and ultimately classified according to shared properties, via the 3 elements of treatment theory: targets, ingredients, and (hypothesized) mechanisms of action. We discuss important concepts in the RTSS such as the distinction between treatments and treatment components, which consist of 1 target and its associated ingredients; and the distinction between targets, which are the direct effects of treatment, and aims, which are downstream or distal effects. The RTSS includes 3 groups of mutually exclusive treatment components: Organ Functions, Skills and Habits, and Representations. The last of these comprises not only thoughts and feelings, but also internal representations underlying volitional action; the RTSS addresses the concept of volition (effort) as a critical element for many rehabilitation treatments. We have developed an algorithm for treatment specification which is illustrated and described in brief. The RTSS stands to benefit the field in numerous ways by supplying a coherent, theory-based framework encompassing all rehabilitation treatments. Using a common framework, researchers will be able to test systematically the effects of specific ingredients on specific targets; and their work will be more readily replicated and translated into clinical practice.

Advancing Rehabilitation Practice Through Improved Specification of Interventions.

Rehabilitation clinicians strive to provide cost-effective, patient-centered care that optimizes outcomes. A barrier to this ideal is the lack of a universal system for describing, or specifying, rehabilitation interventions. Current methods of description vary across disciplines and settings, creating barriers to collaboration, and tend to focus mostly on functional deficits and anticipated outcomes, obscuring connections between clinician behaviors and changes in functioning. The Rehabilitation Treatment Specification System (RTSS) is the result of more than a decade of effort by a multidisciplinary group of rehabilitation clinicians and researchers to develop a theory-based framework to specify rehabilitation interventions. The RTSS describes interventions for treatment components, which consist of a target (functional change brought about as a direct result of treatment), ingredients (actions taken by clinicians to change the target), and a hypothesized mechanism of action, as stated in a treatment theory. The RTSS makes explicit the connections between functional change and clinician behavior, and recognizes the role of patient effort in treatment implementation. In so doing, the RTSS supports clinicians' efforts to work with their patients to set achievable goals, select appropriate treatments, adjust treatment plans as needed, encourage patient participation in the treatment process, communicate with team members, and translate research findings to clinical care. The RTSS may help both expert and novice clinicians articulate their clinical reasoning processes in ways that benefit treatment planning and clinical education, and may improve the design of clinical documentation systems, leading to more effective justification and reimbursement for services. Interested clinicians are invited to apply the RTSS in their local settings.

Occupational Therapy Can Benefit From an Interprofessional Rehabilitation Treatment Specification System.

To advance evidence-based practice across rehabilitation professions, clinicians, and researchers could benefit from a structured way to clearly describe the treatment interventions used by their discipline. Development of the Rehabilitation Treatment Specification System is an interprofessional effort to use a theory-driven and systematic approach to define, specify, and quantify the complex nature of rehabilitation treatments. In this article, we introduce this novel approach and provide a case example that illustrates application to clinical practice. We invite occupational therapy practitioners to consider how clear specification of the content and process of their interventions could benefit practice, research, and education.

Twenty-first Century Cures Act and Antimicrobial Susceptibility Testing: Clinical Implications in the Era of Multidrug Resistance.

Clinical laboratories act at the frontline of identification of infections caused by multidrug-resistant organisms, and yet the tools they apply are often woefully out of date. Incomplete adoption of current testing standards, updated breakpoints, and tests for new drugs across laboratories has been exacerbated by lack of coordination between standards development organizations (SDOs), pharmaceutical companies, susceptibility test manufacturers, and the US Food and Drug Administration. The 21st Century Cures Act includes provisions to enable alignment between these groups by (1) allowing recognition of breakpoints set by qualified SDOs; (2) publicly posting recognized breakpoints; and (3) reviewing breakpoints for necessary updates, every 6 months. Combined, these provisions will ensure more rapid recognition of current breakpoints, improving detection and management of resistant infections. Although several limitations remain, this will ultimately allow susceptibility test manufacturers to more readily update to current breakpoints.

Impact of 21st Century Cures Act on Breakpoints and Commercial Antimicrobial Susceptibility Test Systems: Progress and Pitfalls.

Antimicrobial resistance is the most pressing medical challenge of the past decade. At the front line are clinical laboratories, which are responsible for accurately reporting antimicrobial susceptibility test (AST) results to clinicians and public health authorities. The ability of the laboratory to detect resistance has been hampered by several factors. In 2016, the 21st Century Cures Act was signed into law, marking an important step toward resolving many regulatory dilemmas that hampered development and updates to commercial AST systems (cASTs). We describe the pathway and history of U.S. regulation of cASTs and outline both the rewards and unmet needs possible from the 21st Century Cures Act.

Evaluation of Modified 2-Tiered Serodiagnostic Testing Algorithms for Early Lyme Disease.

Background: The conventional 2-tiered serologic testing protocol for Lyme disease (LD), an enzyme immunoassay (EIA) followed by immunoglobulin M and immunoglobulin G Western blots, performs well in late-stage LD but is insensitive in patients with erythema migrans (EM), the most common manifestation of the illness. Western blots are also complex, difficult to interpret, and relatively expensive. In an effort to improve test performance and simplify testing in early LD, we evaluated several modified 2-tiered testing (MTTT) protocols, which use 2 assays designed as first-tier tests sequentially, without the need of Western blots. Methods: The MTTT protocols included (1) a whole-cell sonicate (WCS) EIA followed by a C6 EIA; (2) a WCS EIA followed by a VlsE chemiluminescence immunoassay (CLIA); and (3) a variable major protein-like sequence, expressed (VlsE) CLIA followed by a C6 EIA. Sensitivity was determined using serum from 55 patients with erythema migrans; specificity was determined using serum from 50 patients with other illnesses and 1227 healthy subjects. Results: Sensitivity of the various MTTT protocols in patients with acute erythema migrans ranged from 36% (95% confidence interval [CI], 25%-50%) to 54% (95% CI, 42%-67%), compared with 25% (95% CI, 16%-38%) using the conventional protocol (P = .003-0.3). Among control subjects, the 3 MTTT protocols were similarly specific (99.3%-99.5%) compared with conventional 2-tiered testing (99.5% specificity; P = .6-1.0). Conclusions: Although there were minor differences in sensitivity and specificity among MTTT protocols, each provides comparable or greater sensitivity in acute EM, and similar specificity compared with conventional 2-tiered testing, obviating the need for Western blots.

Modified Carbapenem Inactivation Method for Phenotypic Detection of Carbapenemase Production among Enterobacteriaceae.

The ability of clinical microbiology laboratories to reliably detect carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) is an important element of the effort to prevent and contain the spread of these pathogens and an integral part of antimicrobial stewardship. All existing methods have limitations. A new, straightforward, inexpensive, and specific phenotypic method for the detection of carbapenemase production, the carbapenem inactivation method (CIM), was recently described. Here we describe a two-stage evaluation of a modified carbapenem inactivation method (mCIM), in which tryptic soy broth was substituted for water during the inactivation step and the length of this incubation was extended. A validation study was performed in a single clinical laboratory to determine the accuracy of the mCIM, followed by a nine-laboratory study to verify the reproducibility of these results and define the zone size cutoff that best discriminated between CP-CRE and members of the family Enterobacteriaceae that do not produce carbapenemases. Bacterial isolates previously characterized through whole-genome sequencing or targeted PCR as to the presence or absence of carbapenemase genes were tested for carbapenemase production using the mCIM; isolates with Ambler class A, B, and D carbapenemases, non-CP-CRE isolates, and carbapenem-susceptible isolates were included. The sensitivity of the mCIM observed in the validation study was 99% (95% confidence interval [95% CI], 93% to 100%), and the specificity was 100% (95% CI, 82% to 100%). In the second stage of the study, the range of sensitivities observed across nine laboratories was 93% to 100%, with a mean of 97%; the range of specificities was 97% to 100%, with a mean of 99%. The mCIM was easy to perform and interpret for Enterobacteriaceae, with results in less than 24 h and excellent reproducibility across laboratories.

Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of Vibrio cholerae.

We evaluated the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MS) for the identification of Vibrio cholerae. MS identified all 42 isolates of V. cholerae O1 and O139 and 7 of 9 non-O1/O139 isolates. MS correctly discriminated between all Aeromonas and V. cholerae isolates. Overall, MS performed as well as or better than biochemical methods.

Cefepime vs other antibacterial agents for the treatment of Enterobacter species bacteremia.

BACKGROUND: Carbapenems are recommended for treatment of Enterobacter infections with AmpC phenotypes. Although isolates are typically susceptible to cefepime in vitro, there are few data supporting its clinical efficacy. METHODS: We reviewed all cases of Enterobacter species bacteremia at 2 academic hospitals from 2005 to 2011. Outcomes of interest were (1) persistent bacteremia ≥1 calendar day and (2) in-hospital mortality. We fit logistic regression models, adjusting for clinical risk factors and Pitt bacteremia score and performed propensity score analyses to compare the efficacy of cefepime and carbapenems. RESULTS: Three hundred sixty-eight patients experienced Enterobacter species bacteremia and received at least 1 antimicrobial agent, of whom 52 (14%) died during hospitalization. Median age was 59 years; 19% were neutropenic, and 22% were in an intensive care unit on the day of bacteremia. Twenty-nine (11%) patients had persistent bacteremia for ≥1 day after antibacterial initiation. None of the 36 patients who received single-agent cefepime (0%) had persistent bacteremia, as opposed to 4 of 16 (25%) of those who received single-agent carbapenem (P < .01). In multivariable models, there was no association between carbapenem use and persistent bacteremia (adjusted odds ratio [aOR], 1.52; 95% CI, .58-3.98; P = .39), and a nonsignificant lower odds ratio with cefepime use (aOR, 0.52; 95% CI, .19-1.40; P = .19). In-hospital mortality was similar for use of cefepime and carbapenems in adjusted regression models and propensity-score matched analyses. CONCLUSIONS: Cefepime has a similar efficacy as carbapenems for the treatment of Enterobacter species bacteremia. Its use should be further explored as a carbapenem-sparing agent in this clinical scenario.

Opening the black box: lessons learned from an interdisciplinary inquiry into the learning-based contents of brain injury rehabilitation.

This article describes challenges encountered and lessons learned in an effort to explore the black box of rehabilitation. A multidisciplinary team created detailed, mutually exclusive operational definitions for the contents of learning-based treatments administered in a brain injury unit. The function and activity levels of the International Classification of Functioning, Disability and Health were used to organize content definitions, which included examples of therapy activities and therapist behaviors, such as cues. Pairs of trained coders independently identified defined learning episodes within each minute of 128 videotaped physical, occupational, or speech therapy sessions. Interrater agreement was generally acceptable and did not vary by discipline of session, discipline of coder, or whether coders were clinically trained. Disagreements typically involved the threshold for determining that a learning episode had occurred, or deciding between function and activity codes where the surface content of the sessions were similar. The focus on individual therapy sessions allowed for rich qualitative detail, but a less granular analysis will be necessary for comprehensive efforts to characterize the contents of therapy.

Development of a theory-driven rehabilitation treatment taxonomy: conceptual issues.

Many rehabilitation treatment interventions, unlike pharmacologic treatments, are not operationally defined, and the labels given to such treatments do not specify the active ingredients that produce the intended treatment effects. This, in turn, limits the ability to study and disseminate treatments, to communicate about them clearly, or to train new clinicians to administer them appropriately. We sought to begin the development of a system of classification of rehabilitation treatments and services that is based on their active ingredients. To do this, we reviewed a range of published descriptions of rehabilitation treatments and treatments that were familiar to the authors from their clinical and research experience. These treatment examples were used to develop preliminary rules for defining discrete treatments, identifying the area of function they directly treat, and identifying their active ingredients. These preliminary rules were then tested against additional treatment examples, and problems in their application were used to revise the rules in an iterative fashion. The following concepts, which emerged from this process, are defined and discussed in relation with the development of a rehabilitation treatment taxonomy: rehabilitation treatment taxonomy; treatment and enablement theory; recipient (of treatment); essential, active, and inactive ingredients; mechanism of action; targets and aims of treatment; session; progression; dosing parameters; and social and physical environment. It is hoped that articulation of the conceptual issues encountered during this project will be useful to others attempting to promote theory-based discussion of rehabilitation effects and that multidisciplinary discussion and research will further refine these rules and definitions to advance rehabilitation treatment classification.

Toward a theory-driven classification of rehabilitation treatments.

Rehabilitation is in need of an organized system or taxonomy for classifying treatments to aid in research, practice, training, and interdisciplinary communication. In this article, we describe a work-in-progress effort to create a rehabilitation treatment taxonomy (RTT) for classifying rehabilitation interventions by the underlying treatment theories that explain their effects. In the RTT, treatments are grouped together according to their targets, or measurable aspects of functioning they are intended to change; ingredients, or measurable clinician decisions and behaviors responsible for effecting changes; and the hypothesized mechanisms of action by which ingredients are transformed into changes in the target. Four treatment groupings are proposed: structural tissue properties, organ functions, skilled performances, and cognitive/affective representations, which are similar in the types of targets addressed, ingredients used, and mechanisms of action that account for change. The typical ingredients and examples of clinical treatments associated with each of these groupings are explored, and the challenges of further subdivision are discussed. Although a Linnaean hierarchical tree structure was envisioned at the outset of work on the RTT, further development may necessitate a model with less rigid boundaries between classification groups, and/or a matrix-like structure for organizing active ingredients along selected continua, to allow for both qualitative and quantitative variations of importance to treatment effects.

Performance of United States serologic assays in the diagnosis of Lyme borreliosis acquired in Europe.

BACKGROUND: Physicians in the United States sometimes need to evaluate a patient for suspected Lyme borreliosis (LB) who may have acquired the infection in Europe. Using serum samples from European LB patients, we compared the performance of European and US serodiagnostic tests, including newer-generation assays containing Vmp-like sequence, expressed or its C6 peptide. METHODS: The sensitivity of each assay was determined using 64 serum samples from LB patients with early or late disease manifestations who acquired the infection in Europe. Specificity was measured using 100 sera from healthy subjects from a nonendemic area. RESULTS: For the detection of European-acquired infection, conventional 2-tiered testing (enzyme-linked immunosorbent assay [ELISA] followed by immunoblotting) using US assays had an overall sensitivity and specificity of 52% and 100%, compared with 81% (P = .0007) and 99% (P = 1.00) using analogous European tests. The sensitivity of a US C6 ELISA used as a stand-alone test (88% overall) was statistically comparable to that of conventional 2-tiered testing using European tests (P = .47) and was 100% specific. Similarly, an alternative 2-tiered algorithm using a standard US ELISA followed by a C6 ELISA was comparably sensitive (84% overall) compared with conventional 2-tiered testing using European assays (P = .82), and specificity remained 100%. CONCLUSIONS: European assays outperformed analogous US assays in a conventional 2-tiered testing algorithm. However, a C6 ELISA used as a stand-alone test or in the second tier of a 2-tiered algorithm performed comparably to conventional 2-tiered testing using European assays, and can be used for evaluation of any patient, regardless of travel history.

Background and rationale for revised clinical and laboratory standards institute interpretive criteria (Breakpoints) for Enterobacteriaceae and Pseudomonas aeruginosa: I. Cephalosporins and Aztreonam.

Widespread resistance in Enterobacteriaceae and Pseudomonas aeruginosa to cephalosporin and monobactam antibiotics due to extended-spectrum ß-lactamases (ESBLs) has resulted in the need for reassessment of the interpretative criteria (breakpoints) established for these agents more than 2 decades ago. Following extensive evaluation, the Clinical and Laboratory Standards Institute recently adopted and published new breakpoints for these agents for use in clinical laboratories and provided updated recommendations for use of the ESBL screening test. This paper summarizes the background and supportive rationale for new interpretative criteria for cephalosporins and aztreonam for testing Enterobacteriaceae.

Better tests, better care: improved diagnostics for infectious diseases.

In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.

New Delhi metallo-ß-lactamase-producing Enterobacteriaceae, United States.

We characterized 9 New Delhi metallo-ß-lactamase-producing Enterobacteriaceae (5 Klebsiella pneumoniae, 2 Escherichia coli, 1 Enterobacter cloacae, 1 Salmonella enterica serovar Senftenberg) isolates identified in the United States and cultured from 8 patients in 5 states during April 2009-March 2011. Isolates were resistant to ß-lactams, fluoroquinolones, and aminoglycosides, demonstrated MICs ≤1 µg/mL of colistin and polymyxin, and yielded positive metallo-ß-lactamase screening results. Eight isolates had blaNDM-1, and 1 isolate had a novel allele (blaNDM-6). All 8 patients had recently been in India or Pakistan, where 6 received inpatient health care. Plasmids carrying blaNDM frequently carried AmpC or extended spectrum ß-lactamase genes. Two K. pneumoniae isolates and a K. pneumoniae isolate from Sweden shared incompatibility group A/C plasmids with indistinguishable restriction patterns and a common blaNDM fragment; all 3 were multilocus sequence type 14. Restriction profiles of the remaining New Delhi metallo-ß-lactamase plasmids, including 2 from the same patient, were diverse.