Consecutive antibiotic shortages highlight discrepancies between microbiology and prescribing practices for intra-abdominal infections.

Piperacillin-tazobactam (TZP) is frequently used for intra-abdominal infection (IAI). Our institution experienced consecutive shortages of TZP and cefepime, providing an opportunity to review prescribing patterns and microbiology for IAI. Hospitalized adult patients treated for IAI, based on provider selection of IAI as the indication within the antibiotic order, between March 2014 and February 2018 were identified from the University of Virginia Clinical Data Repository and Infection Prevention and Control Database. Antimicrobial utilization, microbiologic data, and clinical outcomes were compared across four year-long periods: pre-shortage, TZP shortage, cefepime shortage, and post-shortage. There were 7,668 episodes of antimicrobial prescribing for an indication of IAI during the study period. Cefepime use for IAI increased 190% during the TZP shortage; meanwhile ceftriaxone use increased by only 57%. There was no increase in in-house mortality, colonization with resistant organisms, or Clostridiodes difficile infection among patients treated with IAI during the shortage periods. Among a subset of cases randomly selected for review, Pseudomonas sp. was a rare cause of IAI, but anti-pseudomonal antibiotics were commonly prescribed empirically. We observed a large increase in cefepime utilization for IAI during a TZP shortage that was not warranted based on the observed frequency of identification of Pseudomonas sp. as the causative organism in IAI, suggesting a need to revisit national guideline recommendations.

Reducing Repeat Blood Cultures in Febrile Neutropenia: A Single-Center Experience.

Background: Limited data exist to guide blood culture ordering in persistent febrile neutropenia (FN), resulting in substantial variation in practice. Unnecessary repeat blood cultures have been associated with patient harm including increased antimicrobial exposure, hospital length of stay, catheter removal, and overall cost. Methods: We conducted a single-center study of adult hematology-oncology patients with ≥3 days of FN. The yield of blood cultures was first evaluated in a 2-year historical cohort. Additionally, a pilot pre-/postintervention study was performed in non-stem cell transplant (SCT) patients following a change in our population clinical practice guideline from a recommendation of daily blood cultures to a clinically guided approach. The primary outcome was cultures collected per days of FN after day 3 of persistent FN. Results: One hundred forty-six episodes of ≥3 days of FN in 108 patients were identified during the historical period. Day 1 blood cultures were positive in 23 of 146 (16%) episodes. Blood cultures were drawn on 374 of 513 (73%) subsequent episode-days (day 2-12) and were negative in 366 of 374 (98%). After the intervention, a 53% decrease was observed in the rate of total blood cultures collected (1.4 preintervention vs 0.7 postintervention; P = .03). Blood cultures obtained after 48 hours rarely yielded clinically significant organisms. Conclusions: Repeat blood cultures are low-yield in persistent FN without new clinical change. A pilot intervention in non-SCT patients successfully reduced the frequency of blood culture collection.

The effects of avoiding extended antimicrobial drain prophylaxis on Clostridioides difficile and postprocedural infection rates: a 5-year retrospective.

OBJECTIVE: Postprocedural infection is a consequential complication of neurosurgical intervention. Periprocedural antimicrobial prophylaxis is routinely administered to prevent infection, and in some cases, continued for extended periods while surgical drains remain in place. However, there is little evidence that extended antimicrobial administration is necessary to reduce postprocedural infection, and extended antimicrobials can be associated with harm, such as Clostridioides difficile infection. The authors sought to evaluate whether shortening the duration of postprocedural antimicrobial prophylaxis would decrease the incidence of C. difficile infection without increasing the incidence of postprocedural infection. METHODS: In this retrospective study, two general neurosurgical cohorts were examined. In one cohort, postoperative antimicrobial prophylaxis was limited to 24 hours; in the other, some patients received extended postoperative antimicrobial prophylaxis while surgical drains or external ventricular drains (EVDs) remained in place. Rates of infection with C. difficile as well as postprocedural infection after surgery and EVD placement were compared. RESULTS: Seven thousand two hundred four patients undergoing 8586 surgical procedures and 413 EVD placements were reviewed. The incidence of C. difficile infection decreased significantly from 0.5% per procedural encounter to 0.07% with the discontinuation of extended postprocedural antibiotics within 90 days of a procedure. Rates of postprocedural infection and EVD infection did not significantly change. Results were similar in subgroups of patients with closed suction drains as well as cranial and spine subgroups. CONCLUSIONS: Discontinuation of extended antimicrobial prophylaxis was associated with a significant decrease in the incidence of C. difficile infection without a concomitant change in postprocedural infections or EVD-associated infection. This study provides evidence in support of specialtfy-wide discontinuation of extended postoperative antimicrobial prophylaxis, even in the presence of closed suction drains.

Tolerability of Cefazolin in Nafcillin-Intolerant Patients for the Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

BACKGROUND: Non-immunoglobulin E (IgE)-mediated hypersensitivity reactions (HSRs) to nafcillin are commonly reported, but scarce data are available to guide appropriate antibiotic change following these reactions. Although cefazolin is an attractive therapeutic alternative in methicillin-susceptible Staphylococcus aureus (MSSA) infections when patients experience an HSR to nafcillin, more data are needed to evaluate the tolerability of cefazolin after switching from nafcillin. The purpose of this study was to describe the tolerability of cefazolin in patients who develop a suspected non-IgE-mediated HSR to nafcillin. METHODS: This was a retrospective, descriptive case series of patients who received nafcillin for an MSSA infection, experienced a suspected non-IgE-mediated HSR, and were switched to cefazolin between October 2015 and November 2019 at a single academic medical center. The primary objective was to identify the percentage of patients who completed cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin. RESULTS: There were 80 patients with 87 prespecified non-IgE-mediated HSRs during the study period. Seventy-one (89%) patients completed cefazolin, with 53 (75%) of these patients completing at least 2 weeks of therapy. One patient was ultimately switched from cefazolin to daptomycin due to concern for treatment failure. Eight patients (10%) did not tolerate cefazolin after switching from nafcillin. Of these, 3 patients experienced an unrelated HSR, whereas 5 patients experienced the same non-IgE-mediated HSR that was attributed to nafcillin and discontinued cefazolin within 7 days. The most common HSR cited was immune-mediated nephritis; however, the majority were clinically presumed but did not meet objective diagnostic criteria. CONCLUSIONS: Treatment with cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin appears to be safe, even for patients requiring a prolonged duration of cefazolin.

Implementation of a Rapid Phenotypic Susceptibility Platform for Gram-Negative Bloodstream Infections With Paired Antimicrobial Stewardship Intervention: Is the Juice Worth the Squeeze?

BACKGROUND: Implementation of the Accelerate PhenoTM Gram-negative platform (RDT) paired with antimicrobial stewardship program (ASP) intervention projects to improve time to institutional-preferred antimicrobial therapy (IPT) for Gram-negative bacilli (GNB) bloodstream infections (BSIs). However, few data describe the impact of discrepant RDT results from standard of care (SOC) methods on antimicrobial prescribing. METHODS: A single-center, pre-/post-intervention study of consecutive, nonduplicate blood cultures for adult inpatients with GNB BSI following combined RDT + ASP intervention was performed. The primary outcome was time to IPT. An a priori definition of IPT was utilized to limit bias and to allow for an assessment of the impact of discrepant RDT results with the SOC reference standard. RESULTS: Five hundred fourteen patients (PRE 264; POST 250) were included. Median time to antimicrobial susceptibility testing (AST) results decreased 29.4 hours (P < .001) post-intervention, and median time to IPT was reduced by 21.2 hours (P < .001). Utilization (days of therapy [DOTs]/1000 days present) of broad-spectrum agents decreased (PRE 655.2 vs POST 585.8; P = .043) and narrow-spectrum beta-lactams increased (69.1 vs 141.7; P < .001). Discrepant results occurred in 69/250 (28%) post-intervention episodes, resulting in incorrect ASP recommendations in 10/69 (14%). No differences in clinical outcomes were observed. CONCLUSIONS: While implementation of a phenotypic RDT + ASP can improve time to IPT, close coordination with Clinical Microbiology and continued ASP follow up are needed to optimize therapy. Although uncommon, the potential for erroneous ASP recommendations to de-escalate to inactive therapy following RDT results warrants further investigation.

The Role of fosA in Challenges with Fosfomycin Susceptibility Testing of Multispecies Klebsiella pneumoniae Carbapenemase-Producing Clinical Isolates.

With multidrug-resistant (MDR) Enterobacterales on the rise, a nontoxic antimicrobial agent with a unique mechanism of action such as fosfomycin seems attractive. However, establishing accurate fosfomycin susceptibility testing for non-Escherichia coli isolates in a clinical microbiology laboratory remains problematic. We evaluated fosfomycin susceptibility by multiple methods with 96 KPC-producing clinical isolates of multiple strains and species collected at a single center between 2008 and 2016. In addition, we assessed the presence of fosfomycin resistance genes from whole-genome sequencing (WGS) data using NCBI's AMRFinder and custom HMM search. Susceptibility testing was performed using a glucose-6-phosphate-supplemented fosfomycin Etest and Kirby-Bauer disk diffusion (DD) assays, and the results were compared to those obtained by agar dilution. Clinical Laboratory and Standards Institute (CLSI) breakpoints for E. coli were applied for interpretation. Overall, 63% (60/96) of isolates were susceptible by Etest, 70% (67/96) by DD, and 88% (84/96) by agar dilution. fosA was detected in 80% (70/88) of previously sequenced isolates, with species-specific associations and alleles, and fosA-positive isolates were associated with higher MIC distributions. Disk potentiation testing was performed using sodium phosphonoformate to inhibit fosA and showed significant increases in the zone diameter of DD testing for isolates that were fosA positive compared to those that were fosA negative. The addition of sodium phosphonoformate (PPF) corrected 10/14 (71%) major errors in categorical agreement with agar dilution. Our results indicate that fosA influences the inaccuracy of susceptibility testing by methods readily available in a clinical laboratory compared to agar dilution. Further research is needed to determine the impact of fosA on clinical outcomes.

The effect of rapid diagnostic testing with Infectious Diseases fellow consultative intervention on the management of enterococcal bloodstream infection.

BACKGROUND: Rapid diagnostics for enterococcal bloodstream infections (E-BSIs) can decrease the time to speciation and determination of vancomycin resistance but may not lead to improved antibiotic stewardship. METHODS: Over 3 years, the time to administration of institutionally preferred antibiotics (IPT) for patients with E-BSI was evaluated and compared between 3 intervention groups: before (baseline) and after implementation of a rapid diagnostic (BC-GP), and the use of BC-GP with an Infectious Diseases (ID) fellow-driven consultative intervention (BC-GP + ID). RESULTS: A total of 110 patients (63 baseline, 13 BC-GP, 34 BC-GP + ID) with E-BSI were evaluated. Evaluation of Enterococcus faecium BSI showed that the time IPT was significantly reduced with BC-GP + ID by 10.6 h from baseline (P = 0.02) and 5.4 h from BC-GP (P = 0.04). CONCLUSIONS: An ID fellow-driven stewardship intervention was associated with a significant improvement in time to IPT for patients with E. faecium but not E. faecalis BSI.

Reduced Clostridium difficile Tests and Laboratory-Identified Events With a Computerized Clinical Decision Support Tool and Financial Incentive.

We hypothesized that a computerized clinical decision support tool for Clostridium difficile testing would reduce unnecessary inpatient tests, resulting in fewer laboratory-identified events. Census-adjusted interrupted time-series analyses demonstrated significant reductions of 41% fewer tests and 31% fewer hospital-onset C. difficile infection laboratory-identified events following this intervention.Infect Control Hosp Epidemiol 2018;39:737-740.

A Healthcare Improvement Intervention Combining Nucleic Acid Microarray Testing With Direct Physician Response for Management of Staphylococcus aureus Bacteremia.

Background: Nucleic acid microarray (NAM) testing for detection of Staphylococcus aureus bacteremia (SAB) and S. aureus resistance gene determinants can reduce time to targeted antibiotic administration. Evidence-based management of SAB includes bedside infectious diseases (ID) consultation. As a healthcare improvement initiative at our institution, with the goal of improving management and outcomes for subjects with SAB, we implemented NAM with a process for responding to positive NAM results by directly triggered, mandatory ID consultation. Methods: Preintervention, SAB was identified by traditional culture and results passively directed to antibiotic stewardship program (ASP) pharmacists. Postintervention, SAB in adult inpatients was identified by Verigene Gram-Positive Blood Culture test, results paged directly to ID fellow physicians, and consultation initiated immediately. In the new process, ASP assisted with management after the initial consultation. A single-center, retrospective, pre-/postintervention analysis was performed. Results: One hundred six preintervention and 120 postintervention subjects were assessed. Time to ID consultation after notification of a positive blood culture decreased 26.0 hours (95% confidence interval [CI], 45.1 to 7.1 hours, P < .001) postintervention compared with preintervention. Time to initiation of targeted antibiotic decreased by a mean of 21.2 hours (95% CI, 31.4 to 11.0 hours, P < .001) and time to targeted antibiotics for methicillin-sensitive S. aureus decreased by a mean of 40.7 hours (95% CI, 58.0 to 23.5 hours, P < .001). The intervention was associated with lower in-hospital (13.2% to 5.8%, P = .047) and 30-day (17.9% to 8.3%, P = .025) mortality. Conclusions: Compared with an ASP-directed response to traditionally detected SAB, an efficient physician response to NAM was associated with improved care and outcomes for SAB.

Analysis of substrate binding in individual active sites of bifunctional human ATIC.

Aminoimidazolecarboxamide ribonucleotide formyl transferase (AICARFT): Inosine monophosphate cyclohydrolase (IMPCH, collectively called ATIC) is a bifunctional enzyme that catalyses the penultimate and final steps in the purine de novo biosynthesis pathway. The bifunctional protein is dimeric and each monomer contains two different active sites both of which are capable of binding nucleotide substrates, this means to a potential total of four distinct binding events might be observed. Within this work we used a combination of site-directed and truncation mutants of ATIC to independently investigate the binding at these two sites using calorimetry. A single S10W mutation is sufficient to block the IMPCH active site allowing investigation of the effects of mutation on ligand binding in the AICARFT active site. The majority of nucleotide ligands bind selectively at one of the two active sites with the exception of xanthosine monophosphate, XMP, which, in addition to binding in both AICARFT and IMPCH active sites, shows evidence for cooperative binding with communication between symmetrically-related active sites in the two IMPCH domains. The AICARFT site is capable of independently binding both nucleotide and folate substrates with high affinity however no evidence for positive cooperativity in binding could be detected using the model ligands employed in this study.

Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene blaKPC.

The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort against this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms, including conjugation and transposition; however, the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is unknown. Using a combination of short- and long-read whole-genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolates from a single hospital over 5 years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of blaKPC occurs at multiple nested genetic levels, with transmission of blaKPC strains between individuals, frequent transfer of blaKPC plasmids between strains/species, and frequent transposition of blaKPC transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this by the use of reference-based methods. We also demonstrate that, as a consequence of the genetic mobility observed in this study, plasmid structures can be extremely dynamic, and therefore these reference-based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that nonclonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance.

An Infectious Diseases Physician-Led Antimicrobial Stewardship Program at a Small Community Hospital Associated With Improved Susceptibility Patterns and Cost-Savings After the First Year.

The importance of antimicrobial stewardship is increasingly recognized, yet data from community hospitals are limited. Despite an initially low acceptance rate, an Infectious Diseases physician-led program at a 70-bed rural hospital was associated with a 42% decrease in anti-infective expenditures and susceptibility improvement in Pseudomonas aeruginosa over 3 years.

Control of simultaneous outbreaks of carbapenemase-producing enterobacteriaceae and extensively drug-resistant Acinetobacter baumannii infection in an intensive care unit using interventions promoted in the Centers for Disease Control and Prevention 2012 carbapenemase-resistant Enterobacteriaceae Toolkit.

OBJECTIVE: We describe the efficacy of enhanced infection control measures, including those recommended in the Centers for Disease Control and Prevention's 2012 carbapenem-resistant Enterobacteriaceae (CRE) toolkit, to control concurrent outbreaks of carbapenemase-producing Enterobacteriaceae (CPE) and extensively drug-resistant Acinetobacter baumannii (XDR-AB). DESIGN: Before-after intervention study. SETTING: Fifteen-bed surgical trauma intensive care unit (ICU). METHODS: We investigated the impact of enhanced infection control measures in response to clusters of CPE and XDR-AB infections in an ICU from April 2009 to March 2010. Polymerase chain reaction was used to detect the presence of blaKPC and resistance plasmids in CRE. Pulsed-field gel electrophoresis was performed to assess XDR-AB clonality. Enhanced infection-control measures were implemented in response to ongoing transmission of CPE and a new outbreak of XDR-AB. Efficacy was evaluated by comparing the incidence rate (IR) of CPE and XDR-AB before and after the implementation of these measures. RESULTS: The IR of CPE for the 12 months before the implementation of enhanced measures was 7.77 cases per 1,000 patient-days, whereas the IR of XDR-AB for the 3 months before implementation was 6.79 cases per 1,000 patient-days. All examined CPE shared endemic blaKPC resistance plasmids, and 6 of the 7 XDR-AB isolates were clonal. Following institution of enhanced infection control measures, the CPE IR decreased to 1.22 cases per 1,000 patient-days (P = .001), and no more cases of XDR-AB were identified. CONCLUSIONS: Use of infection control measures described in the Centers for Disease Control and Prevention's 2012 CRE toolkit was associated with a reduction in the IR of CPE and an interruption in XDR-AB transmission.

First clinical cases of OXA-48-producing carbapenem-resistant Klebsiella pneumoniae in the United States: the "menace" arrives in the new world.

OXA-48 has emerged as a major carbapenemase associated with the Enterobacteriaceae in Europe, North Africa, and Asia. We report the first two clinical cases of OXA-48-type carbapenemase-producing Enterobacteriaceae in the United States from patients recently hospitalized in Saudi Arabia and India. Each is more carbapenem resistant than nearly all previously reported OXA-48-type-producing Enterobacteriaceae.

Molecular dissection of an outbreak of carbapenem-resistant enterobacteriaceae reveals Intergenus KPC carbapenemase transmission through a promiscuous plasmid.

Carbapenem-resistant Enterobacteriaceae (CRE) have emerged as major causes of health care-associated infections worldwide. This diverse collection of organisms with various resistance mechanisms is associated with increased lengths of hospitalization, costs of care, morbidity, and mortality. The global spread of CRE has largely been attributed to dissemination of a dominant strain of Klebsiella pneumoniae producing a serine ß-lactamase, termed K. pneumoniae carbapenemase (KPC). Here we report an outbreak of KPC-producing CRE infections in which the degree of horizontal transmission between strains and species of a promiscuous plasmid is unprecedented. Sixteen isolates, comprising 11 unique strains, 6 species, and 4 genera of bacteria, were obtained from 14 patients over the first 8 months of the outbreak. Of the 11 unique strains, 9 harbored the same highly promiscuous plasmid carrying the KPC gene bla(KPC). The remaining strains harbored distinct bla(KPC) plasmids, one of which was carried in a strain of Klebsiella oxytoca coisolated from the index patient and the other generated from transposition of the bla(KPC) element Tn4401. All isolates could be genetically traced to the index patient. Molecular epidemiological investigation of the outbreak was aided by the adaptation of nested arbitrary PCR (ARB-PCR) for rapid plasmid identification. This detailed molecular genetic analysis, combined with traditional epidemiological investigation, provides insights into the highly fluid dynamics of drug resistance transmission during the outbreak. IMPORTANCE The ease of horizontal transmission of carbapenemase resistance plasmids across strains, species, and genera of bacteria observed in this study has several important public health and epidemiological implications. First, it has the potential to promote dissemination of carbapenem resistance to new populations of Enterobacteriaceae, including organisms of low virulence, leading to the establishment of reservoirs of carbapenem resistance genes in patients and/or the environment and of high virulence, raising the specter of untreatable community-associated infections. Second, recognition of plasmid-mediated outbreaks, such as those described here, is problematic because analysis of resistance plasmids from clinical isolates is laborious and technically challenging. Adaptation of nested arbitrary PCR (ARB-PCR) to investigate the plasmid outbreak facilitated our investigation, and the method may be broadly applicable to other outbreaks due to other conserved mobile genetic elements. Whether infection control measures that focus on preventing transmission of drug-resistant clones are effective in controlling dissemination of these elements is unknown.

Bacterial community-acquired pneumonia in older patients.

Pneumonia in the elderly remains a major source of morbidity and mortality in an age group that is growing in numbers. It remains unclear whether the propensity of older adults to develop community-acquired pneumonia represents an aging of host defenses, secondary effects of comorbid disease, or both. The signs and symptoms of pneumonia in the elderly are more subtle than in younger populations, which may lead to a delay in diagnosis. Although therapy for community-acquired pneumonia in the elderly is the same as for younger populations, mortality is higher, leading to an important role for prevention.

Economic evaluation in critical care medicine.

Scarce resources are a reality in all health care systems. There is a constant challenge to maximize health benefits within the resources available. This is particularly relevant when caring for critically ill patients, given the resource-intensive technologies and medicines used and the highly specialized professionals required. Moreover, given the high acuity of illness, decision makers and health care providers in critical care units must constantly assess the value derived from therapies and resources used. Economic evaluation is the comparative analysis of alternative health care interventions in their relative costs (resource use) and effectiveness (health effects). Economic evaluations have been increasingly published in critical care journals and read by clinicians. This article illustrates how the basic principles of health economics can be applied to health care decision making through the use of economic evaluation. We demonstrate how economic evaluation can link medical outcomes, quality of life, and costs in a common index, even for therapies for different medical conditions and with different health outcomes. This article highlights the need for randomized clinical trials and economic evaluations of therapies in critical care medicine for which the effect of the therapy on health outcomes and/or costs are unknown.