Healthcare-associated infections during the coronavirus disease 2019 (COVID-19) pandemic and the modulating effect of centralized surveillance.

We analyzed efficacy of a centralized surveillance infection prevention (CSIP) program in a healthcare system on healthcare-associated infection (HAI) rates amid the coronavirus disease 2019 (COVID-19) pandemic. HAI rates were variable in CSIP and non-CSIP facilities. Central-line-associated bloodstream infection (CLABSI), C. difficile infection (CSI), and surgical-site infection (SSI) rates were negatively correlated with COVID-19 intensity in CSIP facilities.

Development and implementation of a centralized surveillance infection prevention program in a multi-facility health system: A quality improvement project.

Objective: To develop, implement, and evaluate the effectiveness of a unique centralized surveillance infection prevention (CSIP) program. Design: Observational quality improvement project. Setting: An integrated academic healthcare system. Intervention: The CSIP program comprises senior infection preventionists who are responsible for healthcare-associated infection (HAI) surveillance and reporting, allowing local infection preventionists (LIPs) a greater portion of their time to non-surveillance patient safety activities. Four CSIP team members accrued HAI responsibilities at 8 facilities. Methods: We evaluated the effectiveness of the CSIP program using 4 measures: recovery of LIP time, efficiency of surveillance activities by LIPs and CSIP staff, surveys characterizing LIP perception of their effectiveness in HAI reduction, and nursing leaders' perception of LIP effectiveness. Results: The amount of time spent by LIP teams on HAI surveillance was highly variable, while CSIP time commitment and efficiency was steady. Post-CSIP implementation, 76.9% of LIPs agreed that they spend adequate time on inpatient units, compared to 15.4% pre-CSIP; LIPs also reported more time to allot to non-surveillance activities. Nursing leaders reported greater satisfaction with LIP involvement with HAI reduction practices. Conclusion: CSIP programs are a little-reported strategy to ease burden on LIPs with reallocation of HAI surveillance. The analyses presented here will aid health systems in anticipating the benefit of CSIP programs.

Water Cultures Are More Sensitive Than Swab Cultures for the Detection of Environmental Legionella.

Water cultures were significantly more sensitive than concurrently collected swab cultures (n=2,147 each) in detecting Legionella pneumophila within a Veterans Affairs healthcare system. Sensitivity for water versus swab cultures was 90% versus 30% overall, 83% versus 48% during a nosocomial Legionnaires' disease outbreak, and 93% versus 22% post outbreak. Infect Control Hosp Epidemiol 2018;39:108-110.

Improving the Diagnosis of Legionella Pneumonia within a Healthcare System through a Systematic Consultation and Testing Program.

RATIONALE: Legionella testing is not recommended for all patients with pneumonia, but rather for particular patient subgroups. As a result, the overall incidence of Legionella pneumonia may be underestimated. OBJECTIVES: To determine the incidence of Legionella pneumonia in a veteran population in an endemic area after introduction of a systematic infectious diseases consultation and testing program. METHODS: In response to a 2011-2012 outbreak, the VA Pittsburgh Healthcare System mandated infectious diseases consultations and testing for Legionella by urine antigen and sputum culture in all patients with pneumonia. MEASUREMENTS AND MAIN RESULTS: Between January 2013 and December 2015, 1,579 cases of pneumonia were identified. The incidence of pneumonia was 788/100,000 veterans per year, including 352/100,000 veterans per year and 436/100,000 veterans per year with community-associated pneumonia (CAP) and health care-associated pneumonia, respectively. Ninety-eight percent of patients with suspected pneumonia were tested for Legionella by at least one method. Legionella accounted for 1% of pneumonia cases (n = 16), including 1.7% (12/706) and 0.6% (4/873) of CAP and health care-associated pneumonia, respectively. The yearly incidences of Legionella pneumonia and Legionella CAP were 7.99 and 5.99/100,000 veterans, respectively. The sensitivities of urine antigen and sputum culture were 81% and 60%, respectively; the specificity of urine antigen was >99.97%. Urine antigen testing and Legionella cultures increased by 65% and 330%, respectively, after introduction of our program. CONCLUSIONS: Systematic testing of veterans in an endemic area revealed a higher incidence of Legionella pneumonia and CAP than previously reported. Widespread urine antigen testing was not limited by false positivity.

Identifying the risk factors for hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) infection among patients colonized with MRSA on admission.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospital-acquired infections. MRSA-colonized inpatients who may benefit from undergoing decolonization have not been identified. OBJECTIVE: To identify risk factors for MRSA infection among patients who are colonized with MRSA at hospital admission. DESIGN: A case-control study. SETTING: A 146-bed Veterans Affairs hospital. PARTICIPANTS: Case patients were those patients admitted from January 2003 to August 2011 who were found to be colonized with MRSA on admission and then developed MRSA infection. Control subjects were those patients admitted during the same period who were found to be colonized with MRSA on admission but who did not develop MRSA infection. METHODS: A retrospective review. RESULTS: A total of 75 case patients and 150 control subjects were identified. A stay in the intensive care unit (ICU) was the significant risk factor in univariate analysis (P<.001). Prior history of MRSA (P=.03), transfer from a nursing home (P=.002), experiencing respiratory failure (P<.001), and receipt of transfusion (P=.001) remained significant variables in multivariate analysis. Prior history of MRSA colonization or infection (P=.02]), difficulty swallowing (P=.04), presence of an open wound (P=.02), and placement of a central line (P=.02) were identified as risk factors for developing MRSA infection for patients in the ICU. Duration of hospitalization, readmission rate, and mortality rate were significantly higher in case patients than in control subjects (P < .001, .001, and <.001, respectively). CONCLUSIONS: MRSA-colonized patients admitted to the ICU or admitted from nursing homes have a high risk of developing MRSA infection. These patients may benefit from undergoing decolonization.

Prevalence and functional analysis of sequence variants in the ATR checkpoint mediator Claspin.

Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein essential for the ATR and CHK1-dependent checkpoint elicited by replicative stress or the presence of ssDNA. Here, we describe a study to determine whether mutational disruption of CLSPN contributes to cancer susceptibility and sporadic tumorigenesis. We resequenced CLSPN from the germline of selected cancer families with a history of breast cancer (n = 25) or a multicancer phenotype (n = 46) as well as from a panel of sporadic cancer cell lines (n = 52) derived from a variety of tumor types. Eight nonsynonymous variants, including a recurrent mutation, were identified from the germline of two cancer-prone individuals and five cancer cell lines of breast, ovarian, and hematopoietic origin. None of the variants was present within population controls. In contrast, mutations were rare within genes encoding the CLSPN-interacting protein ATR and its binding partner ATRIP. One variant of CLSPN, encoding the I783S missense mutation, was defective in its ability to mediate CHK1 phosphorylation following DNA damage and was unable to rescue sensitivity to replicative stress in CLSPN-depleted cells. Taken together, these observations raise the possibility that CLSPN may encode a component of the DNA-damage response pathway that is targeted by mutations in human cancers, suggesting the need for larger population-based studies to investigate whether CLSPN variants contribute to cancer susceptibility.

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts.

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations.

Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.

PURPOSE: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. RESULTS: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. CONCLUSION: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.

Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR.

PURPOSE: Small-molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have shown modest yet reproducible response rates in patients with squamous cell carcinoma of the head and neck (SCCHN). Somatic mutations in EGFR have recently been shown to be predictive of a clinical response in patients with non-small cell lung cancer (NSCLC) treated with these inhibitors. The objective of this study was to determine if such mutations, or recently reported mutations in ERBB2, also underlie EGFR-TKI responsiveness in SCCHN patients. EXPERIMENTAL DESIGN: We sequenced the kinase domain of EGFR and exon 20 of ERBB2 in tumor specimens from eight responsive patients. In addition, mutational analysis was done on tumor specimens from nine gefitinib nonresponders and 65 unselected cases of SCCHN. RESULTS: None of eight TKI-responsive specimens had mutations within the kinase domain of EGFR. EGFR amplification was also not associated with drug responsiveness. However, a single responsive case had a somatic missense mutation within exon 20 of ERBB2. CONCLUSION: Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.

Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities.

BACKGROUND: Many clinicians do not comply with guidelines regarding antimicrobial resistance (AR). In response, the Centers for Disease Control and Prevention developed a national Campaign to Prevent Antimicrobial Resistance in Healthcare Settings that presents 4 strategies and 12 evidence-based steps. METHODS: To assess clinicians' perceptions of AR, barriers and facilitators to preventing AR, and how best to reach clinicians, a questionnaire and 4 focus groups were conducted after presentation of the Campaign at 4 Pittsburgh Regional Healthcare Initiative hospitals. RESULTS: One hundred seventeen clinicians completed the questionnaire; 28 participated in the focus groups. Clinicians were significantly more likely to perceive that AR was a problem nationally than in their own institution (95% vs 77%; P<.001) or practice (95% vs 65%; P =.002), consistent with focus group results (93% nationally vs 46% institution or practice). The 3 Campaign steps with the most barriers to implementation were "Treat infection, not colonization" (35%), "Stop treatment when infection is cured or unlikely" (35%), and "Practice antimicrobial control" (33%). Clinicians in the focus groups cited the additional barriers of the health care culture, lack of knowledge, and the nursing shortage; facilitators included education, information technology, and consults. Computer programs, posters, and local data were suggested for reaching clinicians about AR. CONCLUSIONS: Clinicians perceive AR to be a complex national problem but less relevant to their own institution or practice. Providing clinicians with information and steps for preventing AR, as in the Campaign, may affect their perceptions of the problem and motivate them to take actions to ensure patient safety.

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.