Recurrent Candidemia: Trends and Risk Factors Among Persons Residing in 4 US States, 2011-2018.

Background: Candidemia is a common healthcare-associated infection with high mortality. Estimates of recurrence range from 1% to 17%. Few studies have focused on those with recurrent candidemia, who often experience more severe illness and greater treatment failure. We describe recurrent candidemia trends and risk factors. Methods: We analyzed population-based candidemia surveillance data collected during 2011-2018. Persons with >1 episode (defined as the 30-day period after a positive Candida species) were classified as having recurrent candidemia. We compared factors during the initial episode between those who developed recurrent candidemia and those who did not. Results: Of the 5428 persons identified with candidemia, 326 (6%) had recurrent infection. Recurrent episodes occurred 1.0 month to 7.6 years after any previous episode. In multivariable logistic regression controlling for surveillance site and year, recurrent candidemia was associated with being 19-44 years old (vs ≥65 years; adjusted odds ratio [aOR], 3.05 [95% confidence interval {CI}, 2.10-4.44]), being discharged to a private residence (vs medical facility; aOR, 1.53 [95% CI, 1.12-2.08]), hospitalization in the 90 days prior to initial episode (aOR, 1.66 [95% CI, 1.27-2.18]), receipt of total parenteral nutrition (aOR, 2.08 [95% CI, 1.58-2.73]), and hepatitis C infection (aOR, 1.65 [95% CI, 1.12-2.43]). Conclusions: Candidemia recurrence >30 days after initial infection occurred in >1 in 20 persons with candidemia. Associations with younger age and hepatitis C suggest injection drug use may play a modifiable role. Prevention efforts targeting central line care and total parenteral nutrition use may help reduce the risk of recurrent candidemia.

Treatment Practices for Adults With Candidemia at 9 Active Surveillance Sites-United States, 2017-2018.

BACKGROUND: Candidemia is a common opportunistic infection causing substantial morbidity and mortality. Because of an increasing proportion of non-albicans Candida species and rising antifungal drug resistance, the Infectious Diseases Society of America (IDSA) changed treatment guidelines in 2016 to recommend echinocandins over fluconazole as first-line treatment for adults with candidemia. We describe candidemia treatment practices and adherence to the updated guidelines. METHODS: During 2017-2018, the Emerging Infections Program conducted active population-based candidemia surveillance at 9 US sites using a standardized case definition. We assessed factors associated with initial antifungal treatment for the first candidemia case among adults using multivariable logistic regression models. To identify instances of potentially inappropriate treatment, we compared the first antifungal drug received with species and antifungal susceptibility testing (AFST) results from initial blood cultures. RESULTS: Among 1835 patients who received antifungal treatment, 1258 (68.6%) received an echinocandin and 543 (29.6%) received fluconazole as initial treatment. Cirrhosis (adjusted odds ratio = 2.06; 95% confidence interval, 1.29-3.29) was the only underlying medical condition significantly associated with initial receipt of an echinocandin (versus fluconazole). More than one-half (n = 304, 56.0%) of patients initially treated with fluconazole grew a non-albicans species. Among 265 patients initially treated with fluconazole and with fluconazole AFST results, 28 (10.6%) had a fluconazole-resistant isolate. CONCLUSIONS: A substantial proportion of patients with candidemia were initially treated with fluconazole, resulting in potentially inappropriate treatment for those involving non-albicans or fluconazole-resistant species. Reasons for nonadherence to IDSA guidelines should be evaluated, and clinician education is needed.

Antimicrobial Use in a Cohort of US Nursing Homes, 2017.

Importance: Controlling antimicrobial resistance in health care is a public health priority, although data describing antimicrobial use in US nursing homes are limited. Objective: To measure the prevalence of antimicrobial use and describe antimicrobial classes and common indications among nursing home residents. Design, Setting, and Participants: Cross-sectional, 1-day point-prevalence surveys of antimicrobial use performed between April 2017 and October 2017, last survey date October 31, 2017, and including 15 276 residents present on the survey date in 161 randomly selected nursing homes from selected counties of 10 Emerging Infections Program (EIP) states. EIP staff reviewed nursing home records to collect data on characteristics of residents and antimicrobials administered at the time of the survey. Nursing home characteristics were obtained from nursing home staff and the Nursing Home Compare website. Exposures: Residence in one of the participating nursing homes at the time of the survey. Main Outcomes and Measures: Prevalence of antimicrobial use per 100 residents, defined as the number of residents receiving antimicrobial drugs at the time of the survey divided by the total number of surveyed residents. Multivariable logistic regression modeling of antimicrobial use and percentages of drugs within various classifications. Results: Among 15 276 nursing home residents included in the study (mean [SD] age, 77.6 [13.7] years; 9475 [62%] women), complete prevalence data were available for 96.8%. The overall antimicrobial use prevalence was 8.2 per 100 residents (95% CI, 7.8-8.8). Antimicrobial use was more prevalent in residents admitted to the nursing home within 30 days before the survey date (18.8 per 100 residents; 95% CI, 17.4-20.3), with central venous catheters (62.8 per 100 residents; 95% CI, 56.9-68.3) or with indwelling urinary catheters (19.1 per 100 residents; 95% CI, 16.4-22.0). Antimicrobials were most often used to treat active infections (77% [95% CI, 74.8%-79.2%]) and primarily for urinary tract infections (28.1% [95% CI, 15.5%-30.7%]). While 18.2% (95% CI, 16.1%-20.1%) were for medical prophylaxis, most often use was for the urinary tract (40.8% [95% CI, 34.8%-47.1%]). Fluoroquinolones were the most common antimicrobial class (12.9% [95% CI, 11.3%-14.8%]), and 33.1% (95% CI, 30.7%-35.6%) of antimicrobials used were broad-spectrum antibiotics. Conclusions and Relevance: In this cross-sectional survey of a cohort of US nursing homes in 2017, prevalence of antimicrobial use was 8.2 per 100 residents. This study provides information on the patterns of antimicrobial use among these nursing home residents.

Assessment of the Appropriateness of Antimicrobial Use in US Hospitals.

Importance: Hospital antimicrobial consumption data are widely available; however, large-scale assessments of the quality of antimicrobial use in US hospitals are limited. Objective: To evaluate the appropriateness of antimicrobial use for hospitalized patients treated for community-acquired pneumonia (CAP) or urinary tract infection (UTI) present at admission or for patients who had received fluoroquinolone or intravenous vancomycin treatment. Design, Setting, and Participants: This cross-sectional study included data from a prevalence survey of hospitalized patients in 10 Emerging Infections Program sites. Random samples of inpatients on hospital survey dates from May 1 to September 30, 2015, were identified. Medical record data were collected for eligible patients with 1 or more of 4 treatment events (CAP, UTI, fluoroquinolone treatment, or vancomycin treatment), which were selected on the basis of common infection types reported and antimicrobials given to patients in the prevalence survey. Data were analyzed from August 1, 2017, to May 31, 2020. Exposure: Antimicrobial treatment for CAP or UTI or with fluoroquinolones or vancomycin. Main Outcomes and Measures: The percentage of antimicrobial use that was supported by medical record data (including infection signs and symptoms, microbiology test results, and antimicrobial treatment duration) or for which some aspect of use was unsupported. Unsupported antimicrobial use was defined as (1) use of antimicrobials to which the pathogen was not susceptible, use in the absence of documented infection signs or symptoms, or use without supporting microbiologic data; (2) use of antimicrobials that deviated from recommended guidelines; or (3) use that exceeded the recommended duration. Results: Of 12 299 patients, 1566 patients (12.7%) in 192 hospitals were included; the median age was 67 years (interquartile range, 53-79 years), and 864 (55.2%) were female. A total of 219 patients (14.0%) were included in the CAP analysis, 452 (28.9%) in the UTI analysis, 550 (35.1%) in the fluoroquinolone analysis, and 403 (25.7%) in the vancomycin analysis; 58 patients (3.7%) were included in both fluoroquinolone and vancomycin analyses. Overall, treatment was unsupported for 876 of 1566 patients (55.9%; 95% CI, 53.5%-58.4%): 110 of 403 (27.3%) who received vancomycin, 256 of 550 (46.6%) who received fluoroquinolones, 347 of 452 (76.8%) with a diagnosis of UTI, and 174 of 219 (79.5%) with a diagnosis of CAP. Among patients with unsupported treatment, common reasons included excessive duration (103 of 174 patients with CAP [59.2%]) and lack of documented infection signs or symptoms (174 of 347 patients with UTI [50.1%]). Conclusions and Relevance: The findings suggest that standardized assessments of hospital antimicrobial prescribing quality can be used to estimate the appropriateness of antimicrobial use in large groups of hospitals. These assessments, performed over time, may inform evaluations of the effects of antimicrobial stewardship initiatives nationally.

Antimicrobial Use in US Hospitals: Comparison of Results From Emerging Infections Program Prevalence Surveys, 2015 and 2011.

BACKGROUND: In the 2011 US hospital prevalence survey of healthcare-associated infections and antimicrobial use 50% of patients received antimicrobial medications on the survey date or day before. More hospitals have since established antimicrobial stewardship programs. We repeated the survey in 2015 to determine antimicrobial use prevalence and describe changes since 2011. METHODS: The Centers for Disease Control and Prevention's Emerging Infections Program sites in 10 states each recruited ≤25 general and women's and children's hospitals. Hospitals selected a survey date from May-September 2015. Medical records for a random patient sample on the survey date were reviewed to collect data on antimicrobial medications administered on the survey date or day before. Percentages of patients on antimicrobial medications were compared; multivariable log-binomial regression modeling was used to evaluate factors associated with antimicrobial use. RESULTS: Of 12 299 patients in 199 hospitals, 6084 (49.5%; 95% CI, 48.6-50.4%) received antimicrobials. Among 148 hospitals in both surveys, overall antimicrobial use prevalence was similar in 2011 and 2015, although the percentage of neonatal critical care patients on antimicrobials was lower in 2015 (22.8% vs 32.0% [2011]; P = .006). Fluoroquinolone use was lower in 2015 (10.1% of patients vs 11.9% [2011]; P < .001). Third- or fourth-generation cephalosporin use was higher (12.2% vs 10.7% [2011]; P = .002), as was carbapenem use (3.7% vs 2.7% [2011]; P < .001). CONCLUSIONS: Overall hospital antimicrobial use prevalence was not different in 2011 and 2015; however, differences observed in selected patient or antimicrobial groups may provide evidence of stewardship impact.

Documentation of acute change in mental status in nursing homes highlights opportunity to augment infection surveillance criteria.

Acute change in mental status (ACMS), defined by the Confusion Assessment Method, is used to identify infections in nursing home residents. A medical record review revealed that none of 15,276 residents had an ACMS documented. Using the revised McGeer criteria with a possible ACMS definition, we identified 296 residents and 21 additional infections. The use of a possible ACMS definition should be considered for retrospective nursing home infection surveillance.

Burden of Candidemia in the United States, 2017.

BACKGROUND: Candidemia is a common healthcare-associated bloodstream infection with high morbidity and mortality. There are no current estimates of candidemia burden in the United States (US). METHODS: In 2017, the Centers for Disease Control and Prevention conducted active population-based surveillance for candidemia through the Emerging Infections Program in 45 counties in 9 states encompassing approximately 17 million persons (5% of the national population). Laboratories serving the catchment area population reported all blood cultures with Candida, and a standard case definition was applied to identify cases that occurred in surveillance area residents. Burden of cases and mortality were estimated by extrapolating surveillance area cases to national numbers using 2017 national census data. RESULTS: We identified 1226 candidemia cases across 9 surveillance sites in 2017. Based on this, we estimated that 22 660 (95% confidence interval [CI], 20 210-25 110) cases of candidemia occurred in the US in 2017. Overall estimated incidence was 7.0 cases per 100 000 persons, with highest rates in adults aged ≥ 65 years (20.1/100 000), males (7.9/100 000), and those of black race (12.3/100 000). An estimated 3380 (95% CI, 1318-5442) deaths occurred within 7 days of a positive Candida blood culture, and 5628 (95% CI, 2465-8791) deaths occurred during the hospitalization with candidemia. CONCLUSIONS: Our analysis highlights the substantial burden of candidemia in the US. Because candidemia is only one form of invasive candidiasis, the true burden of invasive infections due to Candida is higher. Ongoing surveillance can support future burden estimates and help assess the impact of prevention interventions.

The Changing Epidemiology of Candidemia in the United States: Injection Drug Use as an Increasingly Common Risk Factor-Active Surveillance in Selected Sites, United States, 2014-2017.

BACKGROUND: Injection drug use (IDU) is a known, but infrequent risk factor on candidemia; however, the opioid epidemic and increases in IDU may be changing the epidemiology of candidemia. METHODS: Active population-based surveillance for candidemia was conducted in selected US counties. Cases of candidemia were categorized as IDU cases if IDU was indicated in the medical records in the 12 months prior to the date of initial culture. RESULTS: During 2017, 1191 candidemia cases were identified in patients aged >12 years (incidence: 6.9 per 100 000 population); 128 (10.7%) had IDU history, and this proportion was especially high (34.6%) in patients with candidemia aged 19-44. Patients with candidemia and IDU history were younger than those without (median age, 35 vs 63 years; P < .001). Candidemia cases involving recent IDU were less likely to have typical risk factors including malignancy (7.0% vs 29.4%; relative risk [RR], 0.2 [95% confidence interval {CI}, .1-.5]), abdominal surgery (3.9% vs 17.5%; RR, 0.2 [95% CI, .09-.5]), and total parenteral nutrition (3.9% vs 22.5%; RR, 0.2 [95% CI, .07-.4]). Candidemia cases with IDU occurred more commonly in smokers (68.8% vs 18.5%; RR, 3.7 [95% CI, 3.1-4.4]), those with hepatitis C (54.7% vs 6.4%; RR, 8.5 [95% CI, 6.5-11.3]), and in people who were homeless (13.3% vs 0.8%; RR, 15.7 [95% CI, 7.1-34.5]). CONCLUSIONS: Clinicians should consider injection drug use as a risk factor in patients with candidemia who lack typical candidemia risk factors, especially in those with who are 19-44 years of age and have community-associated candidemia.

Epidemiology of Antibiotic Use for Urinary Tract Infection in Nursing Home Residents.

OBJECTIVES: Describe antibiotic use for urinary tract infection (UTI) among a large cohort of US nursing home residents. DESIGN: Analysis of data from a multistate, 1-day point prevalence survey of antimicrobial use performed between April and October 2017. SETTING AND PARTICIPANTS: Residents of 161 nursing homes in 10 US states of the Emerging Infections Program (EIP). METHODS: EIP staff reviewed nursing home medical records to collect data on systemic antimicrobial drugs received by residents, including therapeutic site, rationale for use, and planned duration. For drugs with the therapeutic site documented as urinary tract, pooled mean and nursing home-specific prevalence rates were calculated per 100 nursing home residents, and proportion of drugs by selected characteristics were reported. Data were analyzed in SAS, version 9.4. RESULTS: Among 15,276 residents, 407 received 424 antibiotics for UTI. The pooled mean prevalence rate of antibiotic use for UTI was 2.66 per 100 residents; nursing home-specific rates ranged from 0 to 13.6. One-quarter of antibiotics were prescribed for UTI prophylaxis, with a median planned duration of 111 days compared with 7 days when prescribed for UTI treatment (P < .001). Fluoroquinolones were the most common (18%) drug class used. CONCLUSIONS AND IMPLICATIONS: One in 38 residents was receiving an antibiotic for UTI on a given day, and nursing home-specific prevalence rates varied by more than 10-fold. UTI prophylaxis was common with a long planned duration, despite limited evidence to support this practice among older persons in nursing homes. The planned duration was ≥7 days for half of antibiotics prescribed for treatment of a UTI. Fluoroquinolones were the most commonly used antibiotics, despite their association with significant adverse events, particularly in a frail and older adult population. These findings help to identify priority practices for nursing home antibiotic stewardship.

Population-Based Active Surveillance for Culture-Confirmed Candidemia - Four Sites, United States, 2012-2016.

PROBLEM/CONDITION: Candidemia is a bloodstream infection (BSI) caused by yeasts in the genus Candida. Candidemia is one of the most common health care-associated BSIs in the United States, with all-cause in-hospital mortality of up to 30%. PERIOD COVERED: 2012-2016. DESCRIPTION OF SYSTEM: CDC's Emerging Infections Program (EIP), a collaboration among CDC, state health departments, and academic partners that was established in 1995, was used to conduct active, population-based laboratory surveillance for candidemia in 22 counties in four states (Georgia, Maryland, Oregon, and Tennessee) with a combined population of approximately 8 million persons. Laboratories serving the catchment areas were recruited to report candidemia cases to the local EIP program staff. A case was defined as a blood culture that was positive for a Candida species collected from a surveillance area resident during 2012-2016. Isolates were sent to CDC for species confirmation and antifungal susceptibility testing. Any subsequent blood cultures with Candida within 30 days of the initial positive culture in the same patient were considered part of the same case. Trained surveillance officers collected clinical information from the medical chart for all cases, and isolates were sent to CDC for species confirmation and antifungal susceptibility testing. RESULTS: Across all sites and surveillance years (2012-2016), 3,492 cases of candidemia were identified. The crude candidemia incidence averaged across sites and years during 2012-2016 was 8.7 per 100,000 population; important differences in incidence were found by site, age group, sex, and race. The crude annual incidence was the highest in Maryland (14.1 per 100,000 population) and lowest in Oregon (4.0 per 100,000 population). The crude annual incidence of candidemia was highest among adults aged ≥65 years (25.5 per 100,000 population) followed by infants aged <1 year (15.8). The crude annual incidence was higher among males (9.4) than among females (8.0) and was approximately 2 times greater among blacks than among nonblacks (13.7 versus 5.8). Ninety-six percent of cases occurred in patients who were hospitalized at the time of or during the week after having a positive culture. One third of cases occurred in patients who had undergone a surgical procedure in the 90 days before the candidemia diagnosis, 77% occurred in patients who had received systemic antibiotics in the 14 days before the diagnosis, and 73% occurred in patients who had had a central venous catheter (CVC) in place within 2 days before the diagnosis. Ten percent were in patients who had used injection drugs in the past 12 months. The median time from admission to candidemia diagnosis was 5 days (interquartile range [IQR]: 0-16 days). Among 2,662 cases that were treated in adults aged >18 years, 34% were treated with fluconazole alone, 30% with echinocandins alone, and 34% with both. The all-cause, in-hospital case-fatality ratio was 25% for any time after admission; the all-cause in-hospital case-fatality ratio was 8% for <48 hours after a positive culture for Candida species. Candida albicans accounted for 39% of cases, followed by Candida glabrata (28%) and Candida parapsilosis (15%). Overall, 7% of isolates were resistant to fluconazole and 1.6% were resistant to echinocandins, with no clear trends in resistance over the 5-year surveillance period. INTERPRETATION: Approximately nine out of 100,000 persons developed culture-positive candidemia annually in four U.S. sites. The youngest and oldest persons, men, and blacks had the highest incidences of candidemia. Patients with candidemia identified in the surveillance program had many of the typical risk factors for candidemia, including recent surgery, exposure to broad-spectrum antibiotics, and presence of a CVC. However, an unexpectedly high proportion of candidemia cases (10%) occurred in patients with a history of injection drug use (IDU), suggesting that IDU has become a common risk factor for candidemia. Deaths associated with candidemia remain high, with one in four cases resulting in death during hospitalization. PUBLIC HEALTH ACTION: Active surveillance for candidemia yielded important information about the disease incidence and death rate and persons at greatest risk. The surveillance was expanded to nine sites in 2017, which will improve understanding of the geographic variability in candidemia incidence and associated clinical and demographic features. This surveillance will help monitor incidence trends, track emergence of resistance and species distribution, monitor changes in underlying conditions and predisposing factors, assess trends in antifungal treatment and outcomes, and be helpful for those developing prevention efforts. IDU has emerged as an important risk factor for candidemia, and interventions to prevent invasive fungal infections in this population are needed. Surveillance data documenting that approximately two thirds of candidemia cases were caused by species other than C. albicans, which are generally associated with greater antifungal resistance than C. albicans, and the presence of substantial fluconazole resistance supports 2016 clinical guidelines recommending a switch from fluconazole to echinocandins as the initial treatment for candidemia in most patients.

Neonatal and Pediatric Candidemia: Results From Population-Based Active Laboratory Surveillance in Four US Locations, 2009-2015.

INTRODUCTION: Candida is a leading cause of healthcare-associated bloodstream infections in the United States. Infants and children have unique risk factors for candidemia, and the Candida species distribution in this group is different that among adults; however, candidemia epidemiology in this population has not been described recently. METHODS: We conducted active population-based candidemia surveillance in 4 US metropolitan areas between 2009 and 2015. We calculated incidences among neonates (0-30 days old), infants (0-364 days old), and noninfant children (1-19 years old), documented their clinical features and antifungal drug resistance. RESULTS: We identified 307 pediatric candidemia cases. Incidence trends varied according to site, but overall, the incidence in neonates decreased from 31.5 cases/100000 births in 2009 to 10.7 to 11.8 cases/100000 births between 2012 and 2015, the incidence in infants decreased from 52.1 cases/100000 in 2009 to 15.7 to 17.5 between 2012 and 2015, and the incidence in noninfant children decreased steadily from 1.8 cases/100000 in 2009 to 0.8 in 2014. Common underlying conditions were prematurity in neonates (78%), surgery in nonneonate infants (38%), and malignancy in noninfant children (28%). Most neonate cases were caused by C albicans (67%), whereas non-C. albicans species accounted for 60% of cases in nonneonate infants and noninfant children. Fluconazole and echinocandin resistance rates were low overall. Thirty-day crude mortality was 13%. CONCLUSIONS: The incidence of candidemia among neonates and infants declined after 2009 but remained stable from 2012 to 2015. Antifungal drug resistance is uncommon. Reasons for the lack of recent declines in neonatal and infant candidemia deserve further exploration. In this article, we describe the epidemiology of candidemia in children in the United States and on the basis of data collected as part of US Centers for Disease Control and Prevention active population-based surveillance. Trends in incidence, clinical characteristics, species distribution, and resistance rates are presented.

Combining PARP-1 inhibition and radiation in Ewing sarcoma results in lethal DNA damage.

Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5-1 µmol/L vs. >5 µmol/L) and to radiation (IC50 2-4 Gy vs. >6 Gy). PARP-1 inhibition with short hairpin RNA (shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36-54 vs. 26-28) and sustained DNA damage at 24 hours (24-29 vs. 6-8). This DNA damage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-N-MC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1-dependent manner.

Overcoming evasive resistance from vascular endothelial growth factor a inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducible factor 1α.

Increased levels of hypoxia and hypoxia-inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged antiangiogenic therapy of tumors not only delays tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene Set Enrichment Analysis of microarrays from pretreatment biopsies found that the Gene Ontology category "Response to hypoxia" was upregulated in poor responders and that the hierarchical clustering based on 140 hypoxia-responsive genes reliably separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. In four sarcoma cell lines, HIF-1α shRNA or Dox at low concentrations blocked HIF-1α induction of VEGF-A by 84-97% and carbonic anhydrase 9 by 83-93%. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 with HIF-1α shRNA or metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, at least in part via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α target genes that may promote resistance to antiangiogenic and other therapies. HIF-1α inhibition blocks this evasive resistance and augments destruction of the tumor vasculature.