Top Infectious Disease News of the Week—October 13, 2019

#5: Evaluating the Role of New Beta-Lactam Agents for Uncommon Pathogens

Stenotrophomonas maltophilia, Achromo-bacter xylosoxidans, and Burkholderia spp are relatively uncommon pathogens that are increasingly seen as causes of clinically significant infections, particularly respiratory tract infections among immunocompromised hosts and other vulnerable populations.^1-4

Patients with cystic fibrosis (CF) are at an elevated risk for chronic infections and morbidity. According to the 2017 Cystic Fibrosis Patient Registry, which provides comprehensive data on nearly 30,000 patients with CF, S maltophilia was identified in 12.9% of patients, A xylosoxidans in 5.7%, and Burkholderia cepacia complex in a further 2.5%.5 Patients with cancer, specif­ically those with a hematologic malignancy, are also at height­ened risk for infections with these organisms.^6-8 Infection with S maltophilia can have devastating complications in patients with a hematologic malignancy, for which mortality approaches 100% in patients with hemorrhagic pneumonia.⁹

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#4: Did the 2016 Fluoroquinolone Boxed Warning Change Outpatient Treatment of Uncomplicated UTIs?

The treatment of urinary tract infections in the outpatient setting represents an area with an opportunity for antimicrobial stewardship efforts. According to the 2010 Infectious Diseases Society of America (IDSA) guidelines, nitrofurantoin, trimethoprim-sulfamethoxazole, and Fosfomycin are recommended first-line antibiotic treatment options for acute uncomplicated cystitis. Although fluoroquinolones are efficacious against common urinary pathogens, they are associated with a “propensity for collateral damage” and consequently should be reserved for patients who are unable to receive treatment with the first-line agents.¹

On May 12, 2016, the US Food and Drug Administration (FDA) issued a safety announcement reinforcing the recommendation to avoid fluoroquinolones in uncomplicated urinary tract infections (uUTI), as well as in acute sinusitis and acute bronchitis. Other treatment options are often available for these uncomplicated infections to avoid the “disabling and potentially permanent serious side effects” of fluoroquinolones on the tendons, muscles, joints, nerves, and central nervous system.² On July 26, 2016, this statement was formally added to the boxed warning on fluoroquinolone drug labelling.³

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#3: "Antibiotic Never Events": The Ideal Target to Reduce Antimicrobial Exposure

Several antimicrobial stewardship strategies are aimed at improving the quality of antibiotic use, including the provision of guidelines for optimal antibiotic selection, de-escalation of therapy, reduc­tion of prolonged duration of therapy, and conversion of antibiotic treat­ment from an intravenous to an oral route.¹

However, with the pressing global threat of antimicro­bial resistance, consideration of the highest-yield activ­ities that maximally reduce the quantity of antibiotic exposure is of critical significance. For example, reducing duration of therapy or using a narrower-spectrum anti­biotic will reduce the risk of antibiotic resistance, Clostridioides difficile infection, and adverse effects, but if the patient has a noninfectious condition, the highest-yield approach to reducing collateral damage is avoiding antibiotic use in the first place. When no benefit of antibiotic use exists, any harm is unnecessary and avoidable.

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#2: FDA Approves Baloxavir Marboxil for Patients at High Risk of Flu Complications

The US Food and Drug Administration (FDA) has approved a supplemental New Drug Application for baloxavir marboxil (Xofluza) for the treatment of influenza in individuals who are at increased risk of developing flu-related complications.

Baloxavir marboxil is a first-in-class, 1 dose oral agent that was first approved by the FDA in 2018 for the treatment of acute, uncomplicated influenza in individuals 12 years and older, who have been symptomatic for less than 48 hours. The medication had a novel proposed mechanism of action that inhibits polymerase acidic endonuclease, an enzyme essential for viral replication. When it was approved in 2018, it became the first new antiviral to treat influenza in 20 years.

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#1: FDA Advisory Committee Backs Cefiderocol Efficacy for cUTI 14-2

The US Food and Drug Administration convened a meeting of the Antimicrobial Advisory Committee to discuss the new drug application of cefiderocol. The application, submitted by Shionogi Inc., proposes the agent for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis due to gram-negative bacteria in patients with limited or no other alternative treatments.

Cefiderocol is a siderophore cephalosporin. Its mechanism of entry and stability is active against all classes of β-lactamases, which enables it to overcome the primary mechanisms of gram-negative bacterial resistance to βlactam antibiotics.

Cefiderocol was evaluated in 3 studies: a randomized, active controlled noninferiority trial for cUTI which compared cefiderocol to imipenem-cilastatin; a descriptive study (CREDIBLE-CR) which compared cefiderocol to best available therapy in patients with infections due to carbapenem-resistant organisms; and top-line results from a recently completed active-controlled noninferiority trial in hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) (APEKS-NP) comparing cefiderocol to meropenem.

During the committee meeting, concern over the increased mortality observed in the CREDIBLE-CR study was expressed.

The CREDIBLE-CR study was a descriptive study with no pre-specified hypothesis testing. In this trial, patients with HABP/VABP, cUTI, and bloodstream infections/sepsis due to carbapenem-resistant organisms were randomized to receive cefiderocol or best available therapy, of which 66% were colistin-based regimens. The study all-cause mortality rate was higher in the cefiderocol group compared to the best available therapy group at Day 14 (18.8% versus 12.2%) and Day 28 (24.8% versus 18.4%) respectively. "The greatest mortality difference disfavoring Cefiderocol was noted in the HABP/VABP subgroup, followed by the BSI/sepsis subgroup," the FDA documents read.

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