Stewardship / Resistance Scan for May 01, 2019

US Candida auris uptick
Pause for antibiotic candidate
Fewer antibiotics for neonatal sepsis
Surgical prophylaxis risks

US Candida auris case count tops 600

Confirmed and probable Candida auris cases in the United States through Mar 31 rose to 643, an increase of 56 from the end of February, the Centers for Disease Control and Prevention (CDC) said in an update yesterday.

Illnesses caused by the multidrug-resistant fungus have been reported in 12 states, though 95% are in New York (323), Illinois (160), and New Jersey (128). The other states reporting cases are California (2), Connecticut (1), Florida (13), Indiana (1), Maryland (3), Massachusetts (7), Oklahoma (2), Texas (2), and Virginia (1).

Of the 643 cases, 613 are confirmed and 30 are listed as probable. Screening for C auris has found an additional 1,123 patients who are colonized. The number of colonized patients has grown by 67 since the CDC's last update. The screening is part of the CDC's efforts to control the spread of the fungus, which is known to persist on surfaces in healthcare facilities and spread among patients.

Since its first identification in 2009 in Japan, C auris has triggered outbreaks in healthcare facilities in more than 20 countries and has shown resistance to three major antifungal drug classes. C auris can cause serious invasive infections in patients who have compromised immune systems, and the CDC has estimated that 30% to 60% of patients with infections have died.
Apr 30 CDC C auris case count


FDA turns down new antibiotic candidate over manufacturing concerns

Citing concerns about manufacturing standards, the US Food and Drug Administration (FDA) has rejected Nabriva Therapeutics' New Drug Application (NDA) for Contepo (fosfomycin for injection) for complicated urinary tract infections (cUTIs), including pyelonephritis.

Dublin-based Nabriva announced yesterday that the FDA has asked the company to address issues related to facility inspections and manufacturing deficiencies at one of its contract manufacturers before approving the NDA, but did not request any new clinical data or raise safety concerns about the drug. Nabriva said it plans to request a "Type A" meeting to discuss the FDA's findings.

"We need to meet with the FDA to get a better understanding of the issues identified during the facility inspection, what concerns remain based on the responses submitted during the expedited 4-month review process, and whether or not the manufacturer's corrective actions sufficiently addressed them," Nabriva CEO Ted Schroeder said today during a company conference call.

Contepo is an investigational, intravenous formulation of fosfomycin that has been used outside the United States for cUTIs and other infections for 45 years. Currently, only oral fosmfomycin is FDA-approved for treating cUTIs. Nabriva believes Contepo could be a first-in-class treatment because it has activity against gram-positive and gram-negative pathogens, including multidrug-resistant (MDR) strains, and it uses a new dosing approach that optimizes the compound's pharmacokinetics and pharmacodynamics.

The FDA previously granted Contepo Qualified Infectious Disease Product and Fast Track designations for cUTIs, complicated intra-abdominal infections, hospital-acquired and ventilator-associated bacterial pneumonia, and acute bacterial skin and skin-structure infections.
Apr 30 Nabriva press release


Study suggests shorter empiric antibiotic course for neonatal sepsis

A study today in the Pediatric Infectious Disease Journal suggests that empiric antibiotics with gram-negative coverage for infants who have suspected early-onset sepsis (EOS) can be safely stopped after 24 hours.

The retrospective analysis of blood samples collected from the neonatal intensive care unit at McMaster Children's Hospital in Ontario over a 10-year period included 7,480 blood cultures (from 9,245 neonates) that were sent to the microbiology laboratory for evaluation of sepsis.

The investigators used BacT/Alert 3D, an automated microbial detection system that can identify positive blood samples faster than traditional blood culture methods. The aim was to analyze the time taken to detect positive blood cultures and determine whether empiric antibiotics could be discontinued by 24 or 36 hours to rule out sepsis. Generally, clinicians wait 48 hours before deciding to discontinue antibiotics, but concerns about inappropriate antibiotic use have prompted re-evaluation of this practice.

Of the 7,480 blood cultures performed, 885 grew microorganisms, and 845 culture reports from 627 neonates were analyzed. Definite or opportunistic pathogens caused 815 infections (96%), and the rest were contaminants. EOS accounted for 54 of the positive cultures, and late-onset sepsis (LOS) for 791. Gram-negative organisms grew faster than gram-positive organisms, with 99% of gram-negatives having detectable growth by 24 hours, compared with 67.2% of gram-positives. Cultures from EOS were positive significantly earlier than LOS. After adjusting for covariates, gram-negative status was an independent predictor of early detection of a positive blood culture (hazard ratio, 3.5; 95% confidence interval [CI], 2.7 to 4.5).

"This suggests that empiric antibiotics with Gram-negative coverage can be safely stopped if the 24-hour BacT/Alert is reported negative, provided there are no clinical or laboratory parameters suggesting sepsis," the authors of the study write. "Empirical Gram-positive coverage can be stopped between 48 and 72 hours, particularly if there is no setting for an opportunistic infection, such as prematurity, immunodeficiency or indwelling catheters."
May 1 Pediatr Infect Dis J study


Longer surgical prophylaxis linked to higher risk of adverse events

A national cohort study of patients in the Veterans Administration (VA) healthcare system has found that increasing the duration of surgical antibiotic prophylaxis was not associated with additional reductions in surgical-site infection (SSI), but it was associated with increases in adverse events in a dose-dependent fashion. The findings appeared in JAMA Surgery.

In the study, a team led by researchers with the VA Boston Healthcare System analyzed data on 79,058 patients who underwent cardiac, total joint replacement, colorectal, and vascular procedures in the VA healthcare system from October 2008 through September 2013. The outcomes of interest were 30-day SSI, 7-day incidence of acute kidney injury (AKI), and 90-day incidence of Clostridioides difficile infection. The exposure variables of interest were duration and type of surgical prophylaxis.

After adjusting for SSI risk factors, the researchers found that antibiotic courses lasting more than 24 hours did not lead to reductions in SSI among any of the types of surgery evaluated. But adjusted odds of AKI increased with each additional day of prophylaxis, rising by 3.2% in cardiac procedures after 24 to less than 48 hours (adjusted odds ratio [aOR], 1.03; 95% CI, 0.95 to 1.12), by 22.3% after 48 to less than 72 hours (aOR, 1.22; 95% CI, 1.08 to 1.39), and by 82.0% after 72 hours or more (aOR, 1.82; 95% CI, 1.54 to 2.16). A similar increase in AKI risk was observed for non-cardiac procedures.

Odds of C difficile infection for all procedures increased nonsignificantly by 7.8% after 24 to less than 48 hours of antimicrobial prophylaxis (aOR, 1.08; 95% CI, 0.89 to 1.31) and significantly increased by 142.6% after 48 to less than 72 hours (aOR, 2.43; 95% CI, 1.80 to 3.27) and by 265.1% after 72 hours or more (aOR, 3.65; 95% CI, 2.40 to 5.55).

The analysis also found that use of vancomycin was a significant risk factor for AKI in cardiac procedures (aOR, 1.17; 95% CI, 1.10 to 1.25) and noncardiac procedures (aOR, 1.21; 95% CI, 1.13 to 1.30). 

The authors conclude, "These data should be used to inform policy surrounding surgical prophylaxis and may have broader implications for antimicrobial stewardship programs aiming to reduce harms associated with unnecessary antimicrobial exposures. Every day—and every dose—matters."
Apr 24 JAMA Surg study

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