ASP Scan (Weekly) for May 03, 2019

Carbapenem reduction strategy
;
Quinolone ear drop risks
;
MDR Shigella in Vermont
;
US Candida auris uptick
;
Pause for antibiotic candidate
;
Fewer antibiotics for neonatal sepsis
;
Surgical prophylaxis risks
;
Rapid test for optimal antibiotics
;
CARB-X funding rounds
;
CRE infection outcomes
;
Reduced antibiotic for bacteriuria

Less empiric carbapenem use linked to VRE reduction in leukemia patients

A carbapenem-sparing empiric antibiotic regimen at a referral center for acute leukemia patients in Utah was associated with significant reduction in vancomycin-resistant enterococci (VRE) colonization, researchers reported today in Infection Control and Hospital Epidemiology.

In the single-center study, the researchers studied 342 consecutive leukemia patients treated from September 2011 through August 2017 at LDS hospital in Salt Lake City. The aim of the study was to determine whether a change in empiric therapy for leukemia patients with febrile neutropenia had any impact on the incidence of hospital-acquired VRE colonization. In September 2015, in response to a previous study that found use of a carbapenem for empiric therapy of febrile neutropenia was an independent risk factor for VRE colonization in leukemia patients, the hospital changed the empiric antibiotic from a carbapenem to a cycling regimen of cefepime and piperacillin/tazobactam.

Of the 342 patients, 214 were admitted during the carbapenem period and 128 during the cycling period. Weekly surveillance for VRE stool colonization showed that the change in empiric antibiotics was associated with a significant decrease in VRE colonization (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27 to 0.66). In addition, an analysis of representative stool samples found there was a switch in the dominant VRE multilocus sequence types (from ST664 and ST967 prior to the change to ST186 and ST896 after) and some changes in the gastrointestinal microbiome. Patients during the carbapenem period also had longer hospital stays and durations of severe neutropenia and 10% higher hospital costs.

"In conclusion, less carbapenem use was associated with a reduction in VRE colonization, a decreased duration of neutropenia, and a decrease in hospital length of hospital stay, reduced costs, as well as possibly beneficial effects on potentially important gastrointestinal microbiota such as Blautia spp," the authors of the study write.
May 3 Infect Control Hosp Epidemiol abstract

 

Study links quinolone ear drops to increased risk of eardrum perforation

Originally published by CIDRAP News May 2

The results of a comparative safety study show that the use of quinolone ear drops to treat acute otitis externa (AOE) in children and adults is associated with a previously unreported increased risk of tympanic membrane perforation (TMP), researchers from the University of Florida report today in Clinical Infectious Diseases.

Using Medicaid clinical encounter and pharmacy billing records from 1999 through 2010, the researchers analyzed treatment outcomes in 94,333 patients treated for AOE, an uncomplicated ear infection that is not known to cause eardrum perforation. Quinolone ear drops and other ototopical antibiotics are frequently used to treat AOE, but because quinolones have been linked to soft-tissue damage, such as tendon rupture, the researchers wanted to see whether quinolone ear drops increase the risk of TMP.

Of the patients included in the study, 43,653 were treated with quinolone ear drops with or without corticosteroids and 50,680 were treated with neomycin-plus-hydrocortisone ear drops. Overall, 38 cases of TMP were diagnosed in patients exposed to quinolone ear drops during follow-up, compared with 25 in neomycin-exposed patients. When adjusted for demographics and other covariates, the risk of TMP associated with quinolone ear drops was more than twice that of neomycin ear drops (adjusted HR, 2.26; 95% CI, 1.34 to 3.83).

When comparing individual quinolone preparations against neomycin, the adjusted HRs were 2.53 for ofloxacin (95% CI, 1.27 to 5.05), 2.24 for ciprofloxacin plus hydrocortisone (95% CI, 1.03 to 4.85), and 2.30 for ciprofloxacin plus dexamethasone (95% CI, 1.09 to 4.87). Sensitivity analyses were consistent with the primary analysis.

The authors of the study conclude that, given the findings, the risks and benefits of otic quinolones should be considered prior to treatment of AOE. "Therapy duration, volume dispensed, and refills should be limited to what is necessary to ensure clinical cure," they write. "Patients should be counseled on risk of TMP and monitored for TMPs in follow-up visits."
May 2 Clin Infect Dis abstract

 

Officials detail MDR Shigella outbreak in Vermont retirement community

Originally published by CIDRAP News May 2

A report today from the Centers for Disease Control and Prevention (CDC) and the Vermont Department of Health (VDH) describes a foodborne outbreak of diarrhea caused by multidrug-resistant (MDR) Shigella sonnei in a Vermont retirement community.

Writing in the latest Morbidity and Mortality Weekly Report (MMWR), CDC and VDH epidemiologists say the outbreak occurred in from Oct 1, 2018, through Nov 8, 2018, and sickened 75 residents, visitors, and staff members (24 with confirmed infections and 51 with probable infections). The median patient age was 80, and 75% of patients were female. Six of the patients were hospitalized and two died, although shigellosis was not considered to be the primary cause of death.

High-quality single nucleotide polymorphism analysis predicted that initial isolates from the outbreak were MDR and closely related to a concurrent multistate cluster. Antibiotic susceptibility testing found resistance to trimethoprim-sulfamethoxazole, ampicillin, and ceftriaxone and decreased susceptibility to azithromycin.

Interviews and a review of facility records indicate the earliest cases involved a staff member who prepared food while ill from Oct 11 through Oct 14 and six visitors who dined at the facility on Oct 14. A questionnaire was subsequently given to residents and staff members asking about meal exposure and other known shigellosis risk factors.

A case-control study that included 36 patients and 172 residents and staff members who didn't get sick during the outbreak period found that illness was associated with eating several meals at the facility from Oct 11 through 14. The strongest associations were found among those who dined at the facility on Oct 14 (odds ratio [OR], 5.6; 95% CI, 2.4 to 14.10), specifically during brunch (OR, 5.5; 95% CI, 2.3 to 13.3) and breakfast (OR, 5.3; 95% CI, 1.2 to 22.9).

The authors say the outbreak demonstrates that MDR shigellosis, which is rare in retirement communities, can affect a wide range of populations. In addition, they write, the fact that the outbreak likely started with a staff member who was working while ill highlights the need for nonpunitive sick leave policies.
May 3 MMWR Notes from the field

 

US Candida auris case count tops 600

Originally published by CIDRAP News May 1

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 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

Originally published by CIDRAP News May 1

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

Originally published by CIDRAP News May 1

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 (HR, 3.5; 95% 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

Originally published by CIDRAP News May 1

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

 

Rapid susceptibility test promising for optimal antibiotics in bacteremia

Originally published by CIDRAP News Apr 30

South Korean scientists have demonstrated strong potential of a rapid antimicrobial susceptibility test called QMAC-dRAST for selecting optimal targeted antibiotics for patients who have bacteremia, according to a study today in the Journal of Antimicrobial Chemotherapy.

The test is made by QuantaMatrix Inc, a South Korean company, and the study was conducted by researchers from the National University College of Medicine in Seoul and QuantaMatrix. They compared QMAC-dRAST, which can produce results within 6 hours, with MALDI-TOF MS, a type of mass spectrometry that can yield results in less than an hour and has been successfully used for selecting empirical antibiotics for bloodstream infections.

The investigators assessed 359 patients who had positive blood cultures, and infectious disease (ID) physicians decided on antibiotic regimens with consensus at each time point of receiving results of Gram staining, MALDI-TOF MS, and antimicrobial susceptibility testing (AST) using QMAC-dRAST.

The ID physicians with MALDI-TOF MS results chose optimal targeted antibiotics in 255 cases (71.0%), with appropriate antibiotic selection in 303 (84.4%). The proportion of optimal targeted antibiotic selection and appropriate antibiotic selection was significantly lower for resistant strains than for susceptible strains (62.5% vs 79.2% and 68.2% vs 100%, respectively).

QMAC-dRAST results led to optimal antibiotic treatment in 95 (91.3%) of the 104 cases receiving non-optimal targeted antibiotics. Optimal targeted treatments based on QMAC-dRAST results were possible in 322 (98.2%) of the 328 cases with monobacterial infection and in 345 (96.1%) of the 359 cases with monobacterial and polymicrobial infection.

The authors conclude, "MALDI-TOF MS has a high chance of failure in guiding ID physicians to optimal antibiotics, especially against resistant organisms. With increasingly common resistant organisms, rapid AST is needed to identify optimal targeted antibiotics early in bacteraemia."
Apr 30 J Antimicrob Chemother abstract

 

CARB-X announces new funding rounds

Originally published by CIDRAP News Apr 30

CARB-X today announced four new rounds of funding for companies seeking to develop novel antibiotics and other products to address drug-resistant infections.

Each of the four funding rounds has a specific scope and different application period: Round 1 will be restricted to non-traditional approaches, round 2 to vaccines and biotherapeutics, round 3 to diagnostics, and round 4 to direct-acting small molecule antibiotics. CARB-X is planning a webinar on May 16 to discuss the funding rounds and the application process.

Since its inception in June 2016, CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) has awarded more than $110 million in funding to 42 projects that seek to address high-priority drug-resistant bacteria. In addition to financial support, CARB-X also provides scientific and business advice to help move the projects through the early development phases.

"Our goal is to select the best, most innovative projects that have the potential to prevent, diagnose and treat drug-resistant infections that are killing hundreds of thousands of people each year worldwide," CARB-X executive director Kevin Outterson, JD, said in a press release. "We plan to grow the portfolio through these funding rounds and expand the number of different approaches to increase the chances of delivering urgently-needed medicines and diagnostics to patients."
Apr 30 CARB-X press release

 

CRE bloodstream infections linked to worse outcomes in poorer countries

Originally published by CIDRAP News Apr 30

The results of a multinational study yesterday in The Lancet Infectious Diseases show that carbapenem resistance is associated with longer hospital stays and increased mortality in patients with bloodstream infections in low- and middle-income countries (LMICs).

The study, conducted at 16 tertiary hospitals in Bangladesh, Colombia, Egypt, Ghana, India, Lebanon, Nepal, Nigeria, Pakistan, and Vietnam from August 2014 through June 2015, included 297 patients with carbapenem-resistant Enterebacteriaceae (CRE) and carbapenem-susceptible Enterobaceteriaceae (CSE) infections.

The researchers wanted to compare outcomes in the two groups because while CRE bloodstream infections have been associated with poorer outcomes, most studies have been conducted in high-income countries. Multistate-modeling was used to estimate excess length of hospital stay associated with carbapenem resistance, and proportional subdistribution hazards models were applied to estimate the effect of carbapenem resistance on in-hospital death and probability of discharge alive.

Crude mortality was 20% for patients with CSE bloodstream infection (35 of 174) and 35% for those with CRE bloodstream infection (43 of 123 patients). Carbapenem resistance was associated with increased length of hospital stay (3.7 days, 95% CI, 0.3 to 6.9), increased probability of in-hospital mortality (adjusted subdistribution HR, 1.75; 95% CI, 1.04 to 2.94), and decreased probability of discharge alive (HR, 0.61; 95% CI, 0.45 to 0.83).

Multilocus sequence typing of patient isolates identified various clades of Escherichia coli and Klebsiella pneumoniae (the two most common species of Enterobacteriaceae detected), with marginal overlap between strains in the CRE and CSE clades. Polymerase chain reaction screening of 208 isolates revealed that blaNDM and blaOXA-48-like were the most commonly identified carbapenemase-encoding genes.

"This study contributes to an improved understanding of the scale of the emerging threat of carbapenem-resistance in LMICs," the authors of the study write. "In the future, affordable surveillance mechanism, interventions to prevent infection, and management strategies should be developed to reduce the burden of bloodstream infections caused by CRE in LMICs."

An accompanying commentary says the findings indicate global action against CRE is needed. "At a minimum, every country should have a national action plan tasked with measuring the prevalence of CRE and other resistant phenotypes, promoting the prudent use of antibiotics in health care and in animal husbandry, immunising their population, and investing in water sanitation," write Federico Perez, MD, and Robert Bonomo, MD, of the Louis Stokes Cleveland Veteran Affairs Medical Center and Case Western Reserve University.
Apr 29 Lancet Infect Dis abstract
Apr 29 Lancet Infect Dis comment

 

Hospital intervention reduces treatment for asymptomatic bacteremia

Originally published by CIDRAP News Apr 30

Raising the threshold for identifying uropathogens from inpatient urine cultures averted treatment for asymptomatic bacteriuria and candiduria (ASB/C) in nearly a third of patients at an acute care hospital, Canadian researchers reported yesterday in JAMA Internal Medicine.

In a research letter, clinicians from Sunnybrook Health Sciences Centre in Toronto describe a controlled interrupted time series study conducted after the hospital raised the threshold for identifying and reporting growth in urine cultures from 104 colony-forming units per milliliter (CFU/mL) to 105 CFU/mL. With this change, all urine cultures with low colony counts (defined as 104 to 105 CFU/mL) were issued with a report stating that these organisms usually represent ASB/C, which does not require antibiotic therapy.

In the study, the clinicians compared the rate of monthly treatment for ASB/C in the period before and after the threshold was raised; secondary outcomes included days of antibiotic therapy and a composite clinical outcome of hospital readmission, death, or transfer to clinical care within 14 days.

Over 2 years, there were 609 patients (30%) with a low colony count and 1,432 (70%) with a high colony count, of which 608 and 690 were included in the analysis, respectively. The results showed that the intervention was associated with a reduction in antibiotic prescribing for ASB/C in the low-colony-count group compared with the high-colony-count group (incidence rate ratio, 0.14; 95% CI, 0.03 to 0.64, P = .01). There were no significant clinical changes between the two groups.

The authors say raising the threshold to 105 CFU/mL was associated with sustained reduction of antibiotic prescribing for ASB/C on the order of 70 fewer treatment courses per year, which would avert an estimated 14 adverse drug events annually.
Apr 29 JAMA Internal Med abstract

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