Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant Klebsiella pneumoniae Extraintestinal Colonization and Infection.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality, only a subset of patients acquiring CRKP extraintestinal colonization will develop clinical infection. Here, we sought to ascertain the relative importance of patient characteristics and CRKP genetic background in determining patient risk of infection. Machine learning models classifying colonization versus infection were built using whole-genome sequences and clinical metadata from a comprehensive set of 331 CRKP extraintestinal isolates collected across 21 long-term acute-care hospitals over the course of a year. Model performance was evaluated based on area under the receiver operating characteristic curve (AUROC) on held-out test data. We found that patient and genomic features were predictive of clinical CRKP infection to similar extents (AUROC interquartile ranges [IQRs]: patient = 0.59 to 0.68, genomic = 0.55 to 0.61, combined = 0.62 to 0.68). Patient predictors of infection included the presence of indwelling devices, kidney disease, and length of stay. Genomic predictors of infection included presence of the ICEKp10 mobile genetic element carrying the yersiniabactin iron acquisition system and disruption of an O-antigen biosynthetic gene in a sublineage of the epidemic ST258 clone. Altered O-antigen biosynthesis increased association with the respiratory tract, and subsequent ICEKp10 acquisition was associated with increased virulence. These results highlight the potential of integrated models including both patient and microbial features to provide a more holistic understanding of patient clinical trajectories and ongoing within-lineage pathogen adaptation.IMPORTANCE Multidrug-resistant organisms, such as carbapenem-resistant Klebsiella pneumoniae (CRKP), colonize alarmingly large fractions of patients in regions of endemicity, but only a subset of patients develop life-threatening infections. While patient characteristics influence risk for infection, the relative contribution of microbial genetic background to patient risk remains unclear. We used machine learning to determine whether patient and/or microbial characteristics can discriminate between CRKP extraintestinal colonization and infection across multiple health care facilities and found that both patient and microbial factors were predictive. Examination of informative microbial genetic features revealed variation within the ST258 epidemic lineage that was associated with respiratory tract colonization and increased rates of infection. These findings indicate that circulating genetic variation within a highly prevalent epidemic lineage of CRKP influences patient clinical trajectories. In addition, this work supports the need for future studies examining the microbial genetic determinants of clinical outcomes in human populations, as well as epidemiologic and experimental follow-ups of identified features to discern generalizability and biological mechanisms.

Poor clinical outcomes associated with community-onset urinary tract infections due to extended-spectrum cephalosporin-resistant Enterobacteriaceae.

OBJECTIVE: Resistance to extended-spectrum cephalosporins (ESC) among Enterobacteriaceae (EB) is increasingly prevalent. We sought to determine the clinical outcomes associated with community-onset ESC-resistant (ESC-R) EB urinary tract infections (UTIs) in a US health system. DESIGN: Retrospective cohort study.PatientsAll patients presenting to the emergency departments (EDs) or outpatient practices with EB UTIs between 2010 and 2013 were included. Exposed patients had ESC-R EB UTIs. Unexposed patients had ESC-susceptible EB UTIs and were matched to exposed subjects 1:1 on study year. Multivariable logistic regression analyses were performed to evaluate the association between ESC-R EB UTI and the outcomes of clinical failure and inappropriate initial antibiotic therapy (IIAT). RESULTS: A total of 302 patients with community-onset EB UTI were included, with 151 exposed and unexposed. On multivariable analyses, UTI due to an ESC-R EB was significantly associated with clinical failure (odds ratio [OR], 7.07; 95% confidence interval [CI], 3.16-15.82; P<.01). Other independent risk factors for clinical failure included infection with Citrobacter spp and need for hemodialysis. UTI due to an ESC-R EB was also significantly associated with IIAT (OR, 4.40; 95% CI, 2.64-7.33; P<.01). CONCLUSIONS: Community-onset UTI due to an ESC-R EB organism is significantly associated with clinical failure, which may be due in part to IIAT. Further studies are needed to determine which patients in the community are at high risk for drug-resistant infection to help inform prompt diagnosis and appropriate antibiotic prescribing for ESC-R EB.

High fluoroquinolone MIC is associated with fluoroquinolone treatment failure in urinary tract infections caused by fluoroquinolone susceptible Escherichia coli.

BACKGROUND: Suboptimal clinical response to fluoroquinolone (FQ) therapy has been clearly documented in patients with Salmonella typhi infection with reduced FQ susceptibility. However, the clinical impact of reduced FQ susceptibility on other infections including E. coli urinary tract infections (UTIs) has never been evaluated. METHODS: We conducted a retrospective cohort study of female patients with fluoroquinolone susceptible E. coli (FQSEC) UTIs who received FQ therapy at outpatient services within University of Pennsylvania Health System, Philadelphia. Exposed patients were those with high MIC-FQSEC UTIs (the levofloxacin MIC > 0.12 but ≤ 2 mg/L) while unexposed patients were those with low MIC-FQSEC UTIs (the levofloxacin MIC ≤ 0.12 mg/L). The primary treatment outcome was treatment failure within 10 weeks after initiation of FQ therapy. RESULTS: From May 2008 to April 2011, we enrolled 29 exposed patients and 246 unexposed patients. Two patients in each group experienced treatment failure; exposed vs. unexposed (6.9 vs. 0.8%; p = 0.06). Risk difference and risk ratio (RR) for treatment failure were 0.06 [95% CI -0.03-0.15; exact-p = 0.06] and 8.48 [95% CI 1.24-57.97; exact-p = 0.06], respectively. After adjusting for underlying cerebrovascular disease, the RR was 7.12 (95% CI 1.20-42.10; MH-p = 0.04). CONCLUSION: Our study demonstrated the negative impact of reduced FQ susceptibility on the treatment response to FQ therapy in FQSEC UTIs. This negative impact may be more intensified in other serious infections. Future studies in other clinical situations should be conducted to fill the gap of knowledge.

Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum ß-lactamase bacteremia.

BACKGROUND: The effectiveness of piperacillin-tazobactam (PTZ) for the treatment of extended-spectrum ß-lactamase (ESBL) bacteremia is controversial. We compared 14-day mortality of PTZ vs carbapenems as empiric therapy in a cohort of patients with ESBL bacteremia who all received definitive therapy with a carbapenem. METHODS: Patients hospitalized between January 2007 and April 2014 with monomicrobial ESBL bacteremia were included. A decrease of >3 doubling dilutions in the minimum inhibitory concentration for third-generation cephalosporins tested in combination with 4 µg/mL of clavulanic acid was used to confirm ESBL status. The primary exposure was empiric therapy, defined as antibiotic therapy administered to a patient before ESBL status was known. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. The primary outcome was time to death from the first day of bacteremia. Propensity scores using inverse probability of exposure weighting (IPW) were used to estimate the probability that a patient would receive PTZ vs carbapenems empirically. We calculated overall hazard ratios for mortality censored at 14 days using Cox proportional hazards models on an IPW-adjusted cohort. RESULTS: A total of 331 unique patients with ESBL bacteremia were identified. One hundred three (48%) patients received PTZ empirically and 110 (52%) received carbapenems empirically. The adjusted risk of death was 1.92 times higher for patients receiving empiric PTZ compared with empiric carbapenem therapy (95% confidence interval, 1.07-3.45). CONCLUSIONS: PTZ appears inferior to carbapenems for the treatment of ESBL bacteremia. For patients at high risk of invasive ESBL infections, early carbapenem therapy should be considered. Our findings should not be extended to ß-lactam/ß-lactamase inhibitor combinations in development, as limited clinical data are available for these agents.

Clinical and molecular epidemiology of Escherichia coli sequence type 131 among hospitalized patients colonized intestinally with fluoroquinolone-resistant E. coli.

This study examined molecular and epidemiologic factors associated with Escherichia coli sequence type 131 (ST131) among hospitalized patients colonized intestinally with fluoroquinolone (FQ)-resistant E. coli between 2002 and 2004. Among 86 patients, 21 (24%) were colonized with ST131. The proportion of ST131 isolates among colonizing isolates increased significantly over time, from 8% in 2002 to 50% in 2004 (P = 0.003). Furthermore, all 19 clonally related isolates were ST131. Future studies should identify potential transmissibility differences between ST131 and non-ST131 strains.

Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline.

Eighteen patients received tigecycline as treatment for infection due to multidrug-resistant gram-negative bacilli, including Acinetobacter baumannii and Klebsiella pneumoniae carbapenemase- and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Pretherapy minimum inhibitory concentration values for tigecycline predicted clinical success. Observed evolution of resistance during therapy raises concern about routine use of tigecycline in treatment of such infections when other therapies are available.

Impact of automatic orders to discontinue vancomycin therapy on vancomycin use in an antimicrobial stewardship program.

We examined the possible unintended consequences of a 72-hour automatic order to discontinue vancomycin therapy in an antimicrobial stewardship program (ASP). Of 120 patients, 11 had vancomycin therapy discontinued at 72 hours without a call to the ASP, and 7 experienced a treatment interruption of 6-36 hours. All discontinuation of therapy was considered appropriate, and the 7 treatment interruptions did not have clear clinical consequences. Only one-third of patients had ASP stickers that warned of impending discontinuation of vancomycin therapy placed appropriately in the medical record.

Comparison of unit-specific and hospital-wide antibiograms: potential implications for selection of empirical antimicrobial therapy.

OBJECTIVE: To identify differences between unit-specific and hospital-wide antibiograms and to determine the potential impact of these differences on selection of empirical antimicrobial therapy. SETTING: A 625-bed tertiary care medical center. METHODS: Antimicrobial susceptibility results were collected for all inpatient clinical bacterial isolates recovered over a 3-year period; isolates were categorized by the hospital location of the patient at the time of sampling and by the anatomic site from which the isolate was recovered. Antibiograms from each unit were compiled for the most commonly isolated organisms and were compared to the hospital-wide antibiogram. RESULTS: A total of 9,970 bacterial isolates were evaluated in this study, including 2,646 enterococcal isolates, 2,806 S. aureus isolates, 2,795 E. coli isolates, and 1,723 Pseudomonas aeruginosa isolates. The percentages of bacterial isolates resistant to antimicrobials were significantly higher in the medical ICU and surgical ICU than the hospital-wide antibiogram would have predicted, whereas the percentages of isolates susceptible to antimicrobials were significantly higher in the non-ICU units, compared with the hospital overall. However, on general medicine units, the prevalence of susceptibility to levofloxacin was significantly lower than that for the hospital overall. CONCLUSIONS: Unit-specific antibiograms are important for making informed decisions about empirical antimicrobial therapy, because the hospital-wide antibiogram may mask important differences in susceptibility rates across different units. These differences may have important implications for selecting the optimal empirical antimicrobial therapy.

Identification of optimal combinations for empirical dual antimicrobial therapy of Pseudomonas aeruginosa infection: potential role of a Combination Antibiogram.

To better determine the optimal combinations for empirical dual antimicrobial therapy of Pseudomonas aeruginosa infection, we evaluated the utility of a novel combination antibiogram. Although the combination antibiogram allowed modest fine-tuning of choices for dual antibiotic therapy, selections based on the 2 antibiograms did not differ substantively. Drug combinations with the broadest coverage were consistently composed of an aminoglycoside and a beta-lactam.

Longitudinal trends in antimicrobial susceptibilities across long-term-care facilities: emergence of fluoroquinolone resistance.

BACKGROUND: Antibiotic resistance in the longterm-care facility (LTCF) setting is of increasing concern due to both the increased morbidity and mortality related to infections in this debilitated population and the potential for transfer of resistant organisms to other healthcare settings. Longitudinal trends in antibiotic resistance in LTCFs have not been well described. DESIGN: Correlational longitudinal survey study. SETTING: Four LTCFs in Pennsylvania. SUBJECTS: All clinical cultures of residents of the participating LTCFs (700 total beds) from 1998 through 2003. We assessed the annual prevalence of resistance to various antimicrobials of interest for the following organisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, and enterococcus species. RESULTS: A total of 4,954 clinical isolates were obtained during the study. A high prevalence of antimicrobial resistance was noted for many organism-drug combinations. This was especially true for fluoroquinolone susceptibility among the Enterobacteriaceae (susceptibility range, 51.3% to 92.2%). In addition, the prevalence of resistance to various agents differed significantly across study sites. Finally, significant increasing trends in resistance were noted over time and were most pronounced for fluoroquinolone susceptibility among the Enterobacteriaceae. CONCLUSIONS: The prevalence of antimicrobial resistance has increased significantly in LTCFs, although trends have varied substantially across different institutions. These trends have been particularly pronounced for fluoroquinolone resistance among the Enterobacteriaceae. These findings demonstrate that antimicrobial resistance is widespread and increasing in LTCFs, highlighting the need for future studies to more clearly elucidate the risk factors for, and potential interventions against, emerging resistance in these settings.

Patients' request for and emergency physicians' prescription of antimicrobial prophylaxis for anthrax during the 2001 bioterrorism-related outbreak.

BACKGROUND: Inappropriate use of antibiotics by individuals worried about biological agent exposures during bioterrorism events is an important public health concern. However, little is documented about the extent to which individuals with self-identified risk of anthrax exposure approached physicians for antimicrobial prophylaxis during the 2001 bioterrorism attacks in the United States. METHODS: We conducted a telephone survey of randomly selected members of the Pennsylvania Chapter of the American College of Emergency Physicians to assess patients' request for and emergency physicians' prescription of antimicrobial agents during the 2001 anthrax attacks. RESULTS: Ninety-seven physicians completed the survey. Sixty-four (66%) respondents had received requests from patients for anthrax prophylaxis; 16 (25%) of these physicians prescribed antibiotics to a total of 23 patients. Ten physicians prescribed ciprofloxacin while 8 physicians prescribed doxycycline. CONCLUSION: During the 2001 bioterrorist attacks, the majority of the emergency physicians we surveyed encountered patients who requested anthrax prophylaxis. Public fears may lead to a high demand for antibiotic prophylaxis during bioterrorism events. Elucidation of the relationship between public health response to outbreaks and outcomes would yield insights to ease burden on frontline clinicians and guide strategies to control inappropriate antibiotic allocation during bioterrorist events.