Shionogi Announces Publication of a New Systematic Review in Chest Highlighting the Importance of Early, Appropriate Therapy to Improve Meaningful Outcomes Like Mortality in Patients with Severe Bacterial Infections

OSAKA, Japan, AMSTERDAM, NL and FLORHAM PARK, N.J., October 5, 2020 – Shionogi Inc., the U.S. subsidiary of Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President & CEO: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) today announce the publication of a new systematic review in Chest Journal, funded by Shionogi B.V, the European subsidiary of Shionogi, examining the effect of delayed appropriate antibiotic therapy on the outcomes of patients with severe bacterial infections.¹ The review was carried out to characterize the impact of time to effective therapy for antimicrobials and guide treatment decisions to optimize prompt appropriate antibiotic therapy for patients most at risk. The study found that mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay.¹

Severe bacterial infections requiring in-hospital treatment are associated with considerable mortality, morbidity and healthcare costs. Physicians must often initiate antibiotic therapy before the pathogen causing the infection and its drug-resistance profile are confirmed, due to the lack of rapid diagnostic techniques. However, with the growing issue of antimicrobial resistance (AMR), it is necessary to limit unnecessary antibiotic use. This makes it challenging to initiate early appropriate therapy, and as a result many patients with severe bacterial infections experience delays.¹ This systematic review provides support for the recommended approach of early broad-spectrum empiric therapy, followed by de-escalation to targeted treatment, rather than use of antibiotic escalation strategies. Results also highlight the need for increased availability of rapid techniques to determine antibiotic susceptibility to identify patients with or without drug-resistant infections. This would facilitate rapid de-escalation of broad-spectrum therapy and rapid escalation in cases where empiric therapy is not optimal for the causative pathogen.

The results from this systematic review of 37 studies showed that there was a high prevalence of delayed appropriate antibiotic therapy in hospitalized patients with severe bacterial infections, with over a quarter (27%) experiencing a delay.¹ Mortality was significantly lower in patients who did not experience delayed appropriate antibiotic therapy compared with those who did (OR 0.57 [95% CI, 0.45–0.72]).¹ Mortality was also significantly lower in the no-delay group for patients with infections caused by Gram-negative pathogens (there was no significant difference seen in patients with infections caused by Gram-positive pathogens).¹

“The results of this study highlight the need to provide appropriate therapy early in the course of infection, especially Gram-negative infections, to improve meaningful outcomes such as mortality and provides support for the recommended approach of early broad-spectrum empiric therapy, followed by de-escalation to targeted treatment,” said Evan J. Zasowski, Primary Investigator of the study.

“This is a valuable study which demonstrates the importance of early initiation of appropriate antibiotic therapy whilst ensuring proper stewardship of these drugs, in order to try and combat the threat of antimicrobial resistance,” said John Keller, senior executive officer, global business division, Shionogi & Co., Ltd. “It also underscores the need for increased availability of rapid diagnostic tests to determine antibiotic susceptibility to identify patients with or without drug-resistant infections and ensure they are given the appropriate treatment in the shortest time possible to ensure the best possible patient outcomes. We support this stewardship approach for our product cefiderocol, which has recently received approval from the U.S. FDA for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible Gram-negative microorganisms.”

Antimicrobial resistance (AMR) is a major health burden which urgently needs to be addressed. In Europe about 25,000 patients die from an infection with multidrug-resistant bacteria every year.² Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.³ If no action is taken, antibiotic resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD.⁴

Shionogi has a strong heritage in the field of anti-infectives and has been developing antimicrobial therapies for more than 60 years. Shionogi is proud to be one of the few large pharmaceutical companies that continues to focus on research and development in anti-infectives. The company invests the highest proportion of its pharmaceutical revenues in relevant anti-infectives R&D compared to other large pharmaceutical companies.⁵

 For more information please refer to: https://www.shionogi.com/global/en/sustainability/amr.html

FETROJA® (cefiderocol) is a cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, FETROJA binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.⁶ These mechanisms allow FETROJA to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.⁷ FETROJA has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.^8,9 Data from multinational surveillance studies for FETROJA demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, Enterobacterales, and S. maltophilia.¹⁰The clinical significance of the in vitro data is unknown. FETROJA has poor in vitro activity against Gram-positive or anaerobic bacteria.

Cefiderocol, under the brand name FETCROJA®, is approved by the European Commission for the treatment of infections due to aerobic Gram-negative bacteria in adults 18 years or older with limited treatment options.

FETROJA (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

FETROJA is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. 

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA.

An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. 

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. 

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. 

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Cephalosporins, including FETROJA, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

The most common adverse reactions occurring in (≥2%) of patients receiving FETROJA compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving FETROJA compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%).

Shionogi & Co., Ltd. is a Japanese major research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” The company currently markets products in several therapeutic areas including anti-infectives, pain, cardiovascular diseases, and gastroenterology. Our pipeline is focused on infectious disease, pain, CNS, and oncology. For more information on Shionogi & Co., Ltd., visit https://www.shionogi.com/global/en/. Shionogi Inc. is the U.S. subsidiary of Shionogi & Co., Ltd. based in N.J. For more information on Shionogi Inc., please visit www.shionogi.com. 

This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also, for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

Shionogi Inc. U.S. Media Contact
Takashi Koide
Associate Director, Corporate Development & Communications  
+1 973-524-5418
takashi.koide@shionogi.com