What's Hot This Year in Infectious Diseases Clinical Science.

The field of infectious diseases saw numerous exciting advances in 2023. Trials of new antibiotics and treatment regimens sought to address rising rates of antimicrobial resistance. Other studies focused on the most appropriate use of currently available treatments, balancing the dual goals of providing effective treatment and impactful antimicrobial stewardship. Improvements in disease prevention were made through trials of both new vaccines and new chemoprophylaxis approaches. Concerning trends this year included increasing rates of invasive group A streptococcal infections, medical tourism-associated cases of fungal meningitis, and the return of locally acquired malaria to the United States. This review covers some of these notable trials and clinical developments in infectious diseases in the past year.

Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]). Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Universal admission laboratory screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) asymptomatic infection across a large health system.

BACKGROUND: Admission laboratory screening for asymptomatic coronavirus disease 2019 (COVID-19) has been utilized to mitigate healthcare-associated severe acute respiratory coronavirus virus 2 (SARS-CoV-2) transmission. An understanding of the impact of such testing across a variety of patient populations is needed. METHODS: SARS-CoV-2 nucleic acid amplification admission testing results for all asymptomatic patients across 4 distinct inpatient facilities between April 20, 2020, and June 14, 2021, were analyzed. Positivity rates and the number needed to test (NNT) to identify 1 asymptomatic infected patient were calculated. Admission results were compared to COVID-19 community incidence rates for the system's surrounding metropolitan service area. Using a national survey of hospital epidemiologists, a clinically meaningful NNT of 1:100 was identified. RESULTS: In total, 51,187 tests were collected (positivity rate, 1.8%). During periods of high transmission, the NNT met the clinically relevant threshold in all populations. The NNT approached or met the threshold for most locations during periods of lower transmission. For all transmission levels, the NNT for fully vaccinated patients did not meet the threshold. CONCLUSIONS: Implementing an asymptomatic patient admission testing program can provide clinically relevant data based on the NNT, even during periods of lower transmission and among different patient populations. Limiting admission testing to non-fully vaccinated patients during periods of lower transmission may be a strategy to address resource concerns around this practice. Although the impact of such testing on healthcare-associated COVID-19 among patients and healthcare workers could not be clearly determined, these data provide important information as facilities weigh the costs and benefits of such testing.

A Narrative Review of Early Oral Stepdown Therapy for the Treatment of Uncomplicated Staphylococcus aureus Bacteremia: Yay or Nay?

Historically, intravenous (IV) antibiotics have been the cornerstone of treatment for uncomplicated Staphylococcus aureus bacteremia (SAB). However, IV antibiotics are expensive, increase the rates of hospital readmission, and can be associated with catheter-related complications. As a result, the potential role of oral antibiotics in the treatment of uncomplicated SAB has become a subject of interest. This narrative review article aims to summarize key arguments for and against the use of oral antibiotics to complete treatment of uncomplicated SAB and evaluates the available evidence for specific oral regimens. We conclude that evidence suggests that oral step-down therapy can be an alternative for select patients who meet the criteria for uncomplicated SAB and will comply with medical treatment and outpatient follow-up. Of the currently studied regimens discussed in this article, linezolid has the most support, followed by fluoroquinolone plus rifampin.

Long-term Outcomes of Patients With Fungal Infections Associated With Contaminated Methylprednisolone Injections.

BACKGROUND: The largest health care-associated infection outbreak in the United States occurred during 2012-2013. Following injection of contaminated methylprednisolone, 753 patients developed infection with a dematiaceous mold, Exserohilum rostratum. The long-term outcomes of these infections have not been described. METHODS: This retrospective cohort study of 440 of a total of 753 patients with proven or probable Exserohilum infection evaluated clinical and radiographic findings, antifungal therapy and associated adverse effects, and outcomes at 6 weeks, 3, 6, 9, and 12 months after diagnosis. Patients were grouped into 4 disease categories: meningitis with/without stroke, spinal or paraspinal infections, meningitis/stroke plus spinal/paraspinal infections, and osteoarticular infections. RESULTS: Among the 440 patients, 223 (51%) had spinal/paraspinal infection, 82 (19%) meningitis/stroke, 123 (28%) both, and 12 (3%) osteoarticular infection. Of 82 patients with meningitis/stroke, 18 (22%) died; among those surviving, 87% were cured at 12 months. Only 7 (3%) of 223 patients with spinal/paraspinal infection died, but at 12 months, 68% had persistent or worsening pain and only 47% were cured. For the 123 patients with both meningitis/stroke and spinal/paraspinal infection, 10 (8%) died, pain persisted in 72%, and 52% were cured at 12 months. Only 37% of those with osteoarticular infection were cured at 12 months. Adverse events from antifungal therapy were noted at 6 weeks in 71% of patients on voriconazole and 81% on amphotericin B. CONCLUSIONS: Fungal infections related to contaminated methylprednisolone injections culminated in death in 8% of patients. Persistent pain and disability were seen at 12 months in most patients with spinal/paraspinal infections.

Risk Factors and Outcomes Associated With Acquisition of Daptomycin and Linezolid-Nonsusceptible Vancomycin-Resistant Enterococcus.

BACKGROUND: Vancomycin-resistant enterococcus (VRE) causes substantial health care-associated infection with increasing reports of resistance to daptomycin or linezolid. We conducted a case-control study reporting 81 cases of daptomycin and linezolid-nonsusceptible VRE (DLVRE), a resistance pattern not previously reported. METHODS: We reviewed VRE isolates from June 2010 through June 2015 for nonsusceptibility to both daptomycin (minimum inhibitory concentration [MIC] > 4) and linezolid (MIC ≥ 4). We matched cases by year to control patients with VRE susceptible to both daptomycin and linezolid and performed retrospective chart review to gather risk factor and outcome data. RESULTS: We identified 81 DLVRE cases. Resistance to both daptomycin and linezolid was more common than resistance to either agent individually. Compared with susceptible VRE, DLVRE was more likely to present as bacteremia without focus (P < 0.01), with DLVRE patients more likely to be immune suppressed (P = .04), to be neutropenic (P = .03), or to have had an invasive procedure in the prior 30 days (P = .04). Any antibiotic exposure over the prior 30 days conferred a 4-fold increased risk for DLVRE (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.43-12.63; P = .01); multivariate analysis implicated daptomycin days of therapy (DOT) over the past year as a specific risk factor (OR, 1.10; 95% CI, 1.01-1.19; P = .03). DLVRE cases had longer hospitalizations (P = .04) but no increased risk for in-hospital death. CONCLUSIONS: DLVRE is an emerging multidrug-resistant pathogen associated with immune suppression, neutropenia, and recent invasive procedure. Prior antibiotic exposure, specifically daptomycin exposure, confers risk for acquisition of DLVRE.

Detection of (1,3)-ß-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis.

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-ß-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis.

Effect of Statin Coadministration on the Risk of Daptomycin-Associated Myopathy.

Background: Daptomycin-associated myopathy has been identified in 2%-14% of patients, and rhabdomyolysis is a known adverse effect. Although risk factors for daptomycin-associated myopathy are poorly defined, creatine phosphokinase (CPK) monitoring and temporary discontinuation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," has been recommended. Methods: We conducted a single-center, retrospective, matched case-control risk factor analysis in adult and pediatric patients from 2004 to 2015. Patients in whom myopathy (defined as CPK values above the upper limit of normal) developed during daptomycin treatment were matched 1:1 to no-myopathy controls with at least the same duration of therapy. Risk factors independently associated with myopathy were determined using multivariable conditional logistic regression. Secondary analysis was performed in patients with rhabdomyolysis, defined as CPK values ≥10 times the upper limit of normal. Results: Of 3042 patients reviewed, 128 (4.2%) were identified as having daptomycin-associated myopathy, 25 (0.8%) of whom had rhabdomyolysis; 121 (95%) of the 128 were adults, and the mean duration of therapy before CPK elevation was 16.7 days (range, 1-58 days). In multivariate analysis, deep abscess treatment (odds ratio, 2.80; P = .03), antihistamine coadministration (3.50; P = .03), and statin coadministration (2.60; P = .03) were independent risk factors for myopathy. Obesity (odds ratio, 3.28; P = .03) and statin coadministration (4.67; P = .03) were found to be independent risk factors for rhabdomyolysis, and older age was associated with reduced risk (0.97; P = .05). Conclusions: Statin coadministration with daptomycin was independently associated with myopathy and rhabdomyolysis. This is the first study to provide strong evidence supporting this association. During coadministration, we recommend twice-weekly CPK monitoring and consideration of withholding statins.

Medically Attended Catheter Complications Are Common in Patients With Outpatient Central Venous Catheters.

OBJECTIVE Outpatient central venous catheters (CVCs) are being used more frequently; however, data describing mechanical complications and central-line-associated bloodstream infections (CLABSI) in the outpatient setting are limited. We performed a retrospective observational cohort study to understand the burden of these complications to elucidate their impact on the healthcare system. METHODS Data were retrospectively collected on patients discharged from Vanderbilt University Medical Center with a CVC in place and admitted into the care of Vanderbilt Home Care Services. Risk factors for medically attended catheter-associated complications (CACs) and outpatient CLABSIs were analyzed. RESULTS A CAC developed in 143 patients (21.9%), for a total of 165 discrete CAC events. Among these, 76 (46%) required at least 1 visit to the emergency department or an inpatient admission, while the remaining 89 (54%) required an outpatient clinic visit. The risk for developing a CAC was significantly increased in female patients, patients with a CVC with >1 lumen, and patients receiving total parenteral nutrition. The absolute number of CLABSIs identified in the study population was small at 16, or 2.4% of the total cohort. CONCLUSIONS Medically attended catheter complications were common among outpatients discharged with a CVC, and reduction of these events should be the focus of outpatient quality improvement programs. Infect Control Hosp Epidemiol 2018;39:439-444.

Reducing Inappropriate Testing for the Evaluation of Diarrhea Among Hospitalized Patients.

BACKGROUND: Diarrhea is one of the most common illnesses in the United States. Evaluation frequently does not follow established guidelines. The objective of this study was to evaluate the effectiveness of a computerized physician order entry-based test guidance algorithm with regard to the clinical, financial, and operational impacts. METHODS: Our population was patients with diarrheal illness at a tertiary academic medical center. The intervention was a computerized physician order entry-based test guidance algorithm that restricted the use of stool cultures and ova and parasites testing of diarrhea in the adult inpatient location vs nonintervention sites, which were the emergency department, pediatric inpatient and adult and pediatric outpatient locations. We measured stool culture, ova and parasites, and Clostridium difficile testing rates from July 1, 2012 to January 31, 2016. Additionally, we calculated advisor usage, consults generated, accuracy of information, and cost savings. RESULTS: There was a significant decrease in stool culture and ova and parasites testing rates at the adult inpatient (P = .001 for both), pediatric (P < .001 for both), and adult emergency department (P < .001; P = .009) locations. The decrease at the intervention site was immediate, whereas the other locations showed a delayed but sustained decrease that suggests a collateral impact. A significant increase in the rate of stool culture and ova and parasites testing was observed in the outpatient setting (P = .02 and P = .001). We estimate that $21,931 was saved annually. CONCLUSIONS: A point-of-order test restriction algorithm for hospitalized adults with diarrhea reduced stool testing. Similar programs should be considered at other institutions and for the evaluation of other conditions.

Improvement in Diagnosis of Histoplasma Meningitis by Combined Testing for Histoplasma Antigen and Immunoglobulin G and Immunoglobulin M Anti-Histoplasma Antibody in Cerebrospinal Fluid.

Background: Central nervous system (CNS) histoplasmosis is a life-threatening condition and represents a diagnostic and therapeutic challenge. Isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF) or brain tissue is diagnostic; however, culture is insensitive and slow growth may result in significant treatment delay. We performed a retrospective multicenter study to evaluate the sensitivity and specificity of a new anti-Histoplasma antibody enzyme immunoassay (EIA) for the detection of IgG and IgM antibody in the CSF for diagnosis of CNS histoplasmosis, the primary objective of the study. The secondary objective was to determine the effect of improvements in the Histoplasma galactomannan antigen detection EIA on the diagnosis of Histoplasma meningitis. Methods: Residual CSF specimens from patients with Histoplasma meningitis and controls were tested for Histoplasma antigen and anti-Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody using assays developed at MiraVista Diagnostics. Results: A total of 50 cases and 157 controls were evaluated. Fifty percent of patients with CNS histoplasmosis were immunocompromised, 14% had other medical conditions, and 36% were healthy. Histoplasma antigen was detected in CSF in 78% of cases and the specificity was 97%. Anti-Histoplasma IgG or IgM antibody was detected in 82% of cases and the specificity was 93%. The sensitivity of detection of antibody by currently available serologic testing including immunodiffusion and complement fixation was 51% and the specificity was 96%. Testing for both CSF antigen and antibody by EIA was the most sensitive approach, detecting 98% of cases. Conclusions: Testing CSF for anti-Histoplasma IgG and IgM antibody complements antigen detection and improves the sensitivity for diagnosis of Histoplasma meningitis.

Does Intrawound Vancomycin Application During Spine Surgery Create Vancomycin-Resistant Organism?

BACKGROUND: Surgical site infection (SSI) following spine surgery is a morbid and expensive complication. The use of intrawound vancomycin is emerging as a solution to reduce SSI. The development of vancomycin-resistant pathogens is an understandable concern. OBJECTIVE: To determine the occurrence of vancomycin-resistant SSI in patients with and without use of intrawound vancomycin. METHODS: Patients undergoing elective spine surgery were dichotomized based on whether intrawound vancomycin was applied. Outcome was occurrence of SSI requiring return to the operating room within postoperative 90 days. The intrawound culture and vancomycin minimal inhibitory concentrations (MIC) were reviewed. Analyses were conducted to compare the pathogen profile and MIC for vancomycin in patients who received vancomycin and those who did not. RESULTS: Of the total 2802 patients, 43% (n = 1215) had intrawound vancomycin application during the index surgery. The use of vancomycin was associated with significantly lower deep SSI rates (1.6% [n = 20] vs 2.5% [n = 40], P = .02). The occurrence of Staphylococcus aureus SSI was significantly lower in the patients who had application of intrawound vancomycin (32% vs 65%, P = .003). None of the patients who had application of intrawound vancomycin powder, and subsequently developed an S aureus SSI, demonstrated pathogens with resistance to vancomycin. All patients had MIC < 2 µg/mL, the vancomycin susceptibility threshold. The occurrence of gram-negative SSI (28% vs 7%) and culture negative fluid collection (16% vs 5%) was higher in the vancomycin cohort. CONCLUSIONS: The use of intrawound vancomycin during the index spine surgery was protective against SSI following spine surgery. The application of intrawound vancomycin during index surgery does not appear to create vancomycin-resistant organisms in the event of an SSI.

The influence of contaminated urine cultures in inpatient and emergency department settings.

We retrospectively evaluated 131 patients with contaminated urine cultures during a 12-month period. Sixty-four patients (48.8%) experienced 139 potential complications related to these specimens. The most common complication was inappropriate antibiotic administration (noted in 58 patients [44.3%]). Contaminated urine cultures led to additional diagnostic evaluation and unnecessary antibiotic use.

Provider knowledge of trivalent inactivated and high-dose influenza vaccines.

OBJECTIVE: The objective of this study was to assess provider knowledge about trivalent inactivated and high dose influenza vaccines. Hence, a 20-item survey was distributed to providers within the Internal Medicine department at an urban academic medical center. RESULTS: Two hundred and eighty-one (24.5%) providers responded. The correct response rate was 63.2%. The highest performing subspecialties were infectious diseases (80.5%), endocrinology (69.2%), and pulmonary (68%). Those who received an influenza vaccine during the most recent season scored significantly higher than those who did not (63.6% vs. 43.6%, p=.001). Areas where respondents did poorly included questions pertaining to contraindications to immunizations (27.4%), common adverse events after immunization (29.2%), target antigen (73.5%), number of strains in the trivalent inactivated vaccine (62.9%), and time to immunity (61.4%). High dose vaccine knowledge was poor, with 37% of providers unaware of its existence. CONCLUSION: Significant gaps in provider knowledge exist regarding both trivalent inactivated and high dose influenza vaccines.

Histoplasma capsulatum endocarditis: multicenter case series with review of current diagnostic techniques and treatment.

Infective endocarditis is an uncommon manifestation of infection with Histoplasma capsulatum. The diagnosis is frequently missed, and outcomes historically have been poor. We present 14 cases of Histoplasma endocarditis seen in the last decade at medical centers throughout the United States. All patients were men, and 10 of the 14 had an infected prosthetic aortic valve. One patient had an infected left atrial myxoma. Symptoms were present a median of 7 weeks before the diagnosis was established. Blood cultures yielded H. capsulatum in only 6 (43%) patients. Histoplasma antigen was present in urine and/or serum in all but 3 of the patients and provided the first clue to the diagnosis of histoplasmosis for several patients. Antibody testing was positive for H. capsulatum in 6 of 8 patients in whom the test was performed. Eleven patients underwent surgery for valve replacement or myxoma removal. Large, friable vegetations were noted at surgery in most patients, confirming the preoperative transesophageal echocardiography findings. Histopathologic examination of valve tissue and the myxoma revealed granulomatous inflammation and large numbers of organisms in most specimens. Four of the excised valves and the atrial myxoma showed a mixture of both yeast and hyphal forms on histopathology. A lipid formulation of amphotericin B, administered for a median of 29 days, was the initial therapy in 11 of the 14 patients. This was followed by oral itraconazole therapy, in all but 2 patients. The length of itraconazole suppressive therapy ranged from 11 months to lifelong administration. Three patients (21%) died within 3 months of the date of diagnosis. All 3 deaths were in patients who had received either no or minimal (1 day and 1 week) amphotericin B.

Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide.

Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who have received these drugs concomitantly, clinicians should consider the potential drug interaction between these agents, and the risks and benefits of continued therapy must be considered.