Do Inpatient Antimicrobial Stewardship Programs Help Us in the Battle Against Antimicrobial Resistance?

BACKGROUND: Antibiotic stewardship programs (ASPs) have demonstrated success at reducing costs, yet there is limited quality evidence of their effectiveness in reducing infections of high-profile drug-resistant organisms. METHODS: This retrospective, cohort study included all Kaiser Permanente Southern California (KPSC) members aged ≥18 years hospitalized in 9 KPSC hospitals from 1 January 2008 to 31 December 2016. We measured the impact of staggered ASP implementation on consumption of 18 ASP-targeted antibiotics using generalized linear mixed-effects models. We used multivariable generalized linear mixed-effects models to estimate the adjusted effect of an ASP on rates of infection with drug-resistant organisms. Analyses were adjusted for confounding by time, cluster effects, and patient- and hospital-level characteristics. RESULTS: We included 765 111 hospitalizations (288 257 pre-ASP, 476 854 post-ASP). By defined daily dose, we found a 6.1% (-7.5% to -4.7%) overall decrease antibiotic use post-ASP; by days of therapy, we detected a 4.3% (-5.4% to -3.1%) decrease in overall use of antibiotics. The number of prescriptions increased post-ASP (1.04 [1.03-1.05]). In adjusted analyses, we detected an overall increase in vancomycin-resistant enterococci infections post-ASP (1.37 [1.10-1.69]). We did not detect a change in the rates of extended-spectrum beta-lactamase, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa infections post-ASP. CONCLUSIONS: ASPs with successful reductions in consumption of targeted antibiotics may not see changes in infection rates with antibiotic-resistant organisms in the 2 to 6 years post-implementation. There are likely differing timescales for reversion to susceptibility across organisms and antibiotics, and unintended consequences from compensatory prescribing may occur.

Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization.

BACKGROUND: Obesity, race/ethnicity, and other correlated characteristics have emerged as high-profile risk factors for adverse coronavirus disease 2019 (COVID-19)-associated outcomes, yet studies have not adequately disentangled their effects. OBJECTIVE: To determine the adjusted effect of body mass index (BMI), associated comorbidities, time, neighborhood-level sociodemographic factors, and other factors on risk for death due to COVID-19. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Southern California, a large integrated health care organization. PATIENTS: Kaiser Permanente Southern California members diagnosed with COVID-19 from 13 February to 2 May 2020. MEASUREMENTS: Multivariable Poisson regression estimated the adjusted effect of BMI and other factors on risk for death at 21 days; models were also stratified by age and sex. RESULTS: Among 6916 patients with COVID-19, there was a J-shaped association between BMI and risk for death, even after adjustment for obesity-related comorbidities. Compared with patients with a BMI of 18.5 to 24 kg/m2, those with BMIs of 40 to 44 kg/m2 and greater than 45 kg/m2 had relative risks of 2.68 (95% CI, 1.43 to 5.04) and 4.18 (CI, 2.12 to 8.26), respectively. This risk was most striking among those aged 60 years or younger and men. Increased risk for death associated with Black or Latino race/ethnicity or other sociodemographic characteristics was not detected. LIMITATION: Deaths occurring outside a health care setting and not captured in membership files may have been missed. CONCLUSION: Obesity plays a profound role in risk for death from COVID-19, particularly in male patients and younger populations. Our capitated system with more equalized health care access may explain the absence of effect of racial/ethnic and socioeconomic disparities on death. Our data highlight the leading role of severe obesity over correlated risk factors, providing a target for early intervention. PRIMARY FUNDING SOURCE: Roche-Genentech.

Opportunities to Improve Antibiotic Appropriateness in U.S. ICUs: A Multicenter Evaluation.

OBJECTIVES: To use a standardized tool for a multicenter assessment of antibiotic appropriateness in ICUs and identify local antibiotic stewardship improvement opportunities. DESIGN: Pilot point prevalence conducted on October 5, 2016; point prevalence survey conducted on March 1, 2017. SETTING: ICUs in 12 U.S. acute care hospitals with median bed size 563. PATIENTS: Receiving antibiotics on participating units on March 1, 2017. INTERVENTIONS: The Centers for Disease Control and Prevention tool for the Assessment of Appropriateness of Inpatient Antibiotics was made actionable by an expert antibiotic stewardship panel and implemented across hospitals. Data were collected by antibiotic stewardship program personnel at each hospital, deidentified and submitted in aggregate for benchmarking. hospital personnel identified most salient reasons for inappropriate use by category and agent. MEASUREMENTS AND MAIN RESULTS: Forty-seven ICUs participated. Most hospitals (83%) identified as teaching with median licensed ICU beds of 70. On March 1, 2017, 362 (54%) of 667 ICU patients were on antibiotics (range, 8-81 patients); of these, 112 (31%) were identified as inappropriate and administered greater than 72 hours among all 12 hospitals (range, 9-82%). Prophylactic antibiotic regimens and PICU patients demonstrated a statistically significant risk ratio of 1.76 and 1.90 for inappropriate treatment, respectively. Reasons for inappropriate use included unnecessarily broad spectrum (29%), no infection or nonbacterial syndrome (22%), and duration longer than necessary (21%). Of patients on inappropriate antibiotic therapy in surgical ICUs, a statistically significant risk ratio of 2.59 was calculated for noninfectious or nonbacterial reasons for inappropriate therapy. CONCLUSIONS: In this multicenter point prevalence study, 31% of ICU antibiotic regimens were inappropriate; prophylactic regimens were often inappropriate across different ICU types, particularly in surgical ICUs. Engaging intensivists in antibiotic stewardship program efforts is crucial to sustain the efficacy of antibiotics and quality of infectious diseases care in critical care settings. This study underscores the value of standardized assessment tools and benchmarking to be shared with local leaders for targeted antibiotic stewardship program interventions.

Rapid detection of invasive Mycobacterium chimaera disease via a novel plasma-based next-generation sequencing test.

BACKGROUND: There is an ongoing outbreak of Mycobacterium chimaera infections among patients exposed to contaminated heater-cooler devices used during cardiac surgery. Recognition of M. chimaera infection is hampered by its long latency and non-specific symptoms. Standard diagnostic methods using acid-fast bacilli (AFB) culture often require invasive sampling, have low sensitivity, and can take weeks to result. We describe the performance of a plasma-based next-generation sequencing test (plasma NGS) for the diagnosis of M. chimaera infection. METHODS: We conducted a retrospective study of 10 patients with a history of cardiac surgery who developed invasive M. chimaera infection and underwent testing by plasma NGS between February 2017 and April 2018. RESULTS: Plasma NGS detected M. chimaera in 9 of 10 patients (90%) with invasive disease in a median of 4 days from specimen collection, including all 8 patients with disseminated infection. In 7 of these 9 cases (78%), plasma NGS was the first test to provide microbiologic confirmation of M. chimaera infection. In contrast, AFB cultures required a median of 20 days to turn positive, and the median time for confirmation of M. chimaera was 41 days. Of 24 AFB blood cultures obtained in this cohort, only 4 (17%) were positive. Invasive procedures were performed in 90% of cases, and in 5 patients (50%), mycobacterial growth was achieved only by culture of these deep sites. CONCLUSIONS: Plasma NGS can accurately detect M. chimaera noninvasively and significantly faster than AFB culture, making it a promising new diagnostic tool.

Benchmarking Inpatient Antimicrobial Use: A Comparison of Risk-Adjusted Observed-to-Expected Ratios.

Background: Increasing antibiotic resistance has made benchmarking appropriate inpatient antibiotic use a worldwide priority supported by expert societies and regulatory bodies; however, standard risk adjustment for fair interfacility comparison has been elusive. We describe a risk-adjusted antibiotic exposure ratio that may help facilitate assessment of antimicrobial use. Methods: This was a retrospective cohort study of 2.7 million admissions evaluating a wide array of potential explanatory variables for correlation with expected antibiotic consumption in a 2-step approach using recursive partitioning and Poisson regression. Observed-to-expected ratios of risk-adjusted antibiotic use were calculated. Three models of varying complexity were compared: (1) a complex ratio consisting of all available antibiotic use risk factors in a hierarchical model; (2) a simplified antimicrobial stewardship program (ASP) ratio using common facility and encounter factors in a single-level model; and (3) a facility ratio using only broad hospital characteristics. Results: Diagnosis-related groups, infection present on admission, patient class, and unit type were the major predictors of expected antibiotic use. Aside from a history of gram-positive resistance in the prior 12 months for anti-methicillin-resistant Staphylococcus aureus drugs, additional clinical and comorbid history information did not improve the model. The simplified ASP ratio demonstrated higher Pearson correlation (R2 = 0.97-0.99) to the complex ratio than the facility ratio (R2 = 0.57-0.85) and provided clinical explanations when discordant. Conclusions: The simplified ASP ratio is derived from a parsimonious model that incorporates disease burden through patient-level risk adjustment and better informs stewardship assessment. This may allow for improved comparison of antibiotic use between healthcare facilities.

Testing for Coccidioidomycosis among Community-Acquired Pneumonia Patients, Southern California, USA1.

We conducted a cohort study to identify characteristics associated with testing for, and testing positive for, coccidioidomycosis among patients with community-acquired pneumonia in southern California, USA. Limited and delayed testing probably leads to underdiagnosis among non-Hispanic black, Filipino, or Hispanic patients and among high-risk groups, including persons in whom antimicrobial drug therapy has failed.

Safety of Seasonal Influenza Vaccination in Hospitalized Surgical Patients: A Cohort Study.

BACKGROUND: Despite recommendations to vaccinate surgical inpatients against influenza, vaccination rates remain low in this population, due in part to concerns about potential negative effects on postsurgical care. OBJECTIVE: To evaluate whether influenza vaccination in the perioperative period increases health care utilization and evaluations for postsurgical infection after discharge. DESIGN: Retrospective cohort study. SETTING: Members of Kaiser Permanente Southern California. PARTICIPANTS: Patients aged 6 months or older who had inpatient surgery with admission and discharge between 1 September and 31 March from 2010 to 2013. MEASUREMENTS: All influenza vaccinations administered between 1 August and 30 April in the 2010-2011, 2011-2012, and 2012-2013 influenza seasons. Outcomes included rates of outpatient visits, readmission, emergency department (ED) visits, fever (temperature ≥38.0 °C), and clinical laboratory evaluations for infection (urine culture, complete blood count, blood culture, and wound culture) in the 7 days after discharge. RESULTS: Of the 42 777 surgeries included in adjusted analyses, vaccine was administered during hospitalization in 6420. No differences were detected between the vaccinated and unvaccinated groups in risk for inpatient visits (rate ratio [RR], 1.12 [95% CI, 0.96 to 1.32]), ED visits (RR, 1.07 [CI, 0.96 to 1.20]), postdischarge fever (RR, 1.00 [CI, 0.76 to 1.31]), or clinical evaluations for infection (RR, 1.06 [CI, 0.99 to 1.13]). A marginal increase in risk for outpatient visits (RR, 1.05 [CI, 1.00 to 1.10]; P = 0.032) was found. LIMITATION: The study did not distinguish between planned and unplanned readmissions or outpatient visits. CONCLUSION: No strong evidence of increased risk for adverse outcomes was found in comparisons of patients who received influenza vaccine during a surgical hospitalization and those who did not. The data support the recommendation to vaccinate surgical inpatients against influenza. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Predictors of the isolated hepatitis B core antibody pattern in HIV-infected and -uninfected men in the multicenter AIDS cohort study.

BACKGROUND: The significance of hepatitis B core antibody (anti-HBc) without hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is unclear. METHODS: This cohort study included men enrolled in the Multicenter AIDS Cohort to determine clinical and laboratory predictors of isolated anti-HBc. RESULTS: A total of 2286 subjects (51% human immunodeficiency virus [HIV]-infected) were followed over 3.9 years. Overall, 16.9% (387) had at least 1 visit with isolated anti-HBc. The isolated anti-HBc pattern was stable 84% of the time, and transitioned to or from a pattern of past infection (anti-HBc and anti-HBs). Isolated anti-HBc was associated with HIV infection (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.73-2.79) and hepatitis C virus (HCV; OR, 4.21; 95% CI; 2.99-5.91). The HCV association was stronger for chronic HCV infection (OR, 6.76; 95% CI, 5.08-8.99) than for cleared HCV (OR, 3.03; 95% CI, 1.83-5.03). HIV infection, chronic HCV, and cleared HCV infection all remained associated with isolated anti-HBc in multivariable models (OR, 1.74; 95% CI, 1.33-2.29; OR, 6.24; 95% CI, 4.62-8.42; and OR, 2.77; 95% CI, 1.65-4.66, respectively). Among HIV-infected subjects, highly active antiretroviral therapy was negatively associated (OR, 0.79; 95% CI, .66-.95) with isolated anti-HBc. CONCLUSIONS: Isolated anti-HBc is associated with HIV and HCV coinfection, especially active HCV replication, and most commonly occurs as a transition to or from the pattern of natural immunity (anti-HBc and anti-HBs). The isolated anti-HBc pattern likely represents resolved HBV infection with low or undetected anti-HBs.

Latent Tuberculosis Infection Treatment Practices in Two Large Integrated Health Systems in California, 2009-2018.

Background: Treatment of latent tuberculosis infection (LTBI) is highly effective at preventing active tuberculosis (TB) disease. Understanding LTBI treatment practices in US health system settings is critical to identify opportunities to improve treatment prescription, initiation, and completion, and thus to prevent TB disease. Methods: We assessed LTBI treatment practices among a cohort of adults after their first positive LTBI test (tuberculin skin test [TST] or interferon gamma release assay [IGRA]) between 2009 and 2018 at 2 large integrated health systems in California. We described the prescription, initiation, and completion of LTBI treatment (isoniazid [INH], rifampin, and rifamycin-INH short-course combinations) by demographic and clinical characteristics. We used multivariable robust Poisson regression to examine factors that were independently associated with treatment prescription and completion. Results: Among 79 302 individuals with a positive LTBI test, 33.0% were prescribed LTBI treatment, 28.3% initiated treatment, and 18.5% completed treatment. Most individuals were prescribed INH (82.0%), but treatment completion was higher among those prescribed rifamycin-INH short-course combinations (69.6% for INH + rifapentine and 70.3% for INH + rifampin) compared with those prescribed INH (56.3%) or rifampin (56.6%). In adjusted analyses, treatment prescription and completion were associated with older age, female sex, more comorbidities, immunosuppression, not being born in a high-TB incidence country, and testing positive with IGRA vs TST. Conclusions: LTBI treatment is underutilized, requiring tailored interventions to support treatment prescription and completion for patients with LTBI.

Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles.

BACKGROUND: Necrotizing fasciitis is a life-threatening infection requiring urgent surgical and medical therapy. Staphylococcus aureus has been a very uncommon cause of necrotizing fasciitis, but we have recently noted an alarming number of these infections caused by community-associated methicillin-resistant S. aureus (MRSA). METHODS: We reviewed the records of 843 patients whose wound cultures grew MRSA at our center from January 15, 2003, to April 15, 2004. Among this cohort, 14 were identified as patients presenting from the community with clinical and intraoperative findings of necrotizing fasciitis, necrotizing myositis, or both. RESULTS: The median age of the patients was 46 years (range, 28 to 68), and 71 percent were men. Coexisting conditions or risk factors included current or past injection-drug use (43 percent); previous MRSA infection, diabetes, and chronic hepatitis C (21 percent each); and cancer and human immunodeficiency virus infection or the acquired immunodeficiency syndrome (7 percent each). Four patients (29 percent) had no serious coexisting conditions or risk factors. All patients received combined medical and surgical therapy, and none died, but they had serious complications, including the need for reconstructive surgery and prolonged stay in the intensive care unit. Wound cultures were monomicrobial for MRSA in 86 percent, and 40 percent of patients (4 of 10) for whom blood cultures were obtained had positive results. All MRSA isolates were susceptible in vitro to clindamycin, trimethoprim-sulfamethoxazole, and rifampin. All recovered isolates belonged to the same genotype (multilocus sequence type ST8, pulsed-field type USA300, and staphylococcal cassette chromosome mec type IV [SCCmecIV]) and carried the Panton-Valentine leukocidin (pvl), lukD, and lukE genes, but no other toxin genes were detected. CONCLUSIONS: Necrotizing fasciitis caused by community-associated MRSA is an emerging clinical entity. In areas in which community-associated MRSA infection is endemic, empirical treatment of suspected necrotizing fasciitis should include antibiotics predictably active against this pathogen.

Platelet count is associated with plasma HIV type 1 RNA and disease progression.

Thrombocytopenia is a common finding among HIV-1-infected individuals. In addition to their function in hemostasis, platelets have been found to play a role in host immune defenses and to directly interact with HIV-1. To explore the role of platelets in HIV-1 infection, we examined the relationship between platelet number and the natural history of HIV-1 disease in the well-characterized Hemophilia Growth and Development Study cohort. In a multivariate analysis platelets were found to be inversely related to plasma HIV-1 RNA with increasing platelets associated with lower plasma HIV-1 RNA levels (p < 0.001). Despite this, increasing platelet count was independently associated with enhanced risk of progression to AIDS and death (p < 0.001 for both). While there may be multiple explanations for these novel observations, they do generate hypotheses related to the potential influence platelets may have on the natural history of HIV-1 disease.

A Comprehensive Assessment Across the Healthcare Continuum: Risk of Hospital-Associated Clostridium difficile Infection Due to Outpatient and Inpatient Antibiotic Exposure.

BACKGROUND: Limitations in sample size, overly inclusive antibiotic classes, lack of adjustment of key risk variables, and inadequate assessment of cases contribute to widely ranging estimates of risk factors for Clostridium difficile infection (CDI). OBJECTIVE: To incorporate all key CDI risk factors in addition to 27 antibiotic classes into a single comprehensive model. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Southern California. PATIENTS: Members of Kaiser Permanente Southern California at least 18 years old admitted to any of its 14 hospitals from January 1, 2011, through December 31, 2012. METHODS: Hospital-acquired CDI cases were identified by polymerase chain reaction assay. Exposure to major outpatient antibiotics (10 classes) and those administered during inpatient stays (27 classes) was assessed. Age, sex, self-identified race/ethnicity, Charlson Comorbidity Score, previous hospitalization, transfer from a skilled nursing facility, number of different antibiotic classes, statin use, and proton pump inhibitor use were also assessed. Poisson regression estimated adjusted risk of CDI. RESULTS: A total of 401,234 patients with 2,638 cases of incident CDI (0.7%) were detected. The final model demonstrated highest CDI risk associated with increasing age, exposure to multiple antibiotic classes, and skilled nursing facility transfer. Factors conferring the most reduced CDI risk were inpatient exposure to tetracyclines and first-generation cephalosporins, and outpatient macrolides. CONCLUSIONS Although type and aggregate antibiotic exposure are important, the factors that increase the likelihood of environmental spore acquisition should not be underestimated. Operationally, our findings have implications for antibiotic stewardship efforts and can inform empirical and culture-driven treatment approaches.

Incidence of polymerase chain reaction-diagnosed Clostridium difficile in a large high-risk cohort, 2011-2012.

OBJECTIVE: To describe incidence rates (IRs) of polymerase chain reaction (PCR)-diagnosed Clostridium difficile infection (CDI) in a large high-risk cohort. PATIENTS AND METHODS: Members of Kaiser Permanente Southern California 1 year or older who were admitted to any of 14 Kaiser Permanente hospitals from January 1, 2011, through December 31, 2012, were included in the study. The CDI cases were identified by PCR in the inpatient and outpatient settings. The CDI IRs per 10,000 inpatient-days are estimated by year, surveillance category, age, sex, race/ethnicity, and Charlson comorbidity index. Recurrence rates are presented by age, sex, and race/ethnicity. Death and colectomy in the 30 days after CDI diagnosis, white blood cell count, and serum creatinine level are assessed. RESULTS: Among 268,655 patients, 4286 (1.6%) had CDI. Among these patients, 671 (15.7%) had recurrent infections. The IR was highest among community-onset, health care facility-associated infections (11.1 per 10,000 inpatient-days). The CDI IRs differed by age, sex, and race/ethnicity. Overall, 528 patients (12.3%) died within 30 days of a positive CDI test result. The CDI IRs increased 34% with implementation of PCR testing. CONCLUSION: Increasingly, PCR is being used because of its higher diagnostic sensitivity. Reassessing the epidemic using PCR updates our understanding of CDI risk. Our capacity to identify patients presenting in the outpatient setting after discharge provides a more accurate picture of health care-associated CDI rates, particularly because the community appears to assume an increasing role in CDI onset and possibly transmission. The CDI burden differs by race, comorbidity, sex, and previous health care use. The detected increase in CDI incidence after transitioning to PCR diagnosis was modest compared with previous studies.

Asymptomatic sexually transmitted infections in HIV-infected men who have sex with men: prevalence, incidence, predictors, and screening strategies.

Sexually transmitted infections (STIs) have increased among men who have sex with men (MSM) and are associated with unsafe sex practices, intrinsic morbidity, and enhanced genital shedding and transmission of HIV. Screening for asymptomatic STIs is recommended as part of the HIV prevention efforts, however, optimal screening strategies among HIV-infected MSM have not been well defined. In this study, conducted from April 2004 to September 2006, 212 HIV-infected MSM from two urban HIV clinics were screened for asymptomatic STIs. Testing for Neisseria gonorrhea and Chlamydia trachomatis from pharynx, rectum, and urine, as well as serologic testing for syphilis were performed initially, and then after 6 and 12 months. A self-administered questionnaire was used to assess possible predictors of incident asymptomatic STIs. A cost analysis was performed to assess different screening strategies for detecting incident STIs. The baseline prevalence of STIs was 14% (n = 29; 95% confidence interval [CI] 9%-19%) and the incidence of new infections was 20.8 cases per 100 person years (95% CI 14.8-28.4 cases per 100 person years). Younger age, higher CD4 cell count, and marijuana use were associated with increased risk of acquiring an asymptomatic STI. The laboratory cost to detect one positive STI did not significantly differ between once- and twice-yearly screening. However, almost half of all incident STIs were detected at the 6-month screening visit, potentially resulting in an increased duration of infectivity if these cases remained undiagnosed. In conclusion, prevalent and incident asymptomatic STIs are common among HIV-infected MSM. Our data support current Center for Disease Control and Prevention STI guidelines that recommend routine screening at increased frequency for HIV-infected MSM.

Novel inhalational murine model of invasive pulmonary aspergillosis.

We developed a novel model of invasive aspergillosis (IA) that recapitulates human disease. Mice were immunosuppressed with cyclophosphamide and cortisone acetate and then infected in an aerosol chamber. This procedure reproducibly delivered 1 x 10(3) to 3 x 10(3) conidia to the lungs. Lethal pulmonary IA developed over 2 weeks and was prevented by amphotericin B.