What is the available evidence of treating patients with Avycaz (ceftazidime/avibactam) and aztreonam for Stenotrophomonas maltophilia infections?

Comment by InpharmD Researcher

The available evidence appears limited to case reports for treating patients with Avycaz (ceftazidime/avibactam) and aztreonam for Stenotrophomonas maltophilia infections suggests that this antibiotic combination may be a potential option, especially in cases of pan-drug resistant infections with limited treatment alternatives. However, additional evidence is largely limited to in vitro susceptibility data, and more randomized studies with larger patient populations are needed to definitively establish the role of this combination therapy. Caution is warranted, as routine susceptibility testing for the Avycaz-aztreonam combination is not widely available.

Background

Due to the growing resistance concerns, a 2021 review recommends combination ceftazidime-avibactam plus aztreonam be used as salvage therapy in extensively drug-resistant isolates. Notably, there is little clinical data on the use of ceftazidime (with or without avibactam and/or aztreonam) for Stenotrophomonas infections, as the evidence is largely based on in vitro susceptibilities. The review recommends ceftazidime-avibactam 2.5 g Q8H with concurrent aztreonam 2 g Q8H (8 g if septic shock) for salvage therapy. Caution should be exercised, as susceptibility testing for the combination therapy is not routinely available. Recent reviews do not recommend routine ceftazidime monotherapy even if in vitro sensitivity is predicted. [1], [2]

Despite the intrinsic resistance, ceftazidime is a weak inducer of L2. However, recent in vitro studies have shown that S. maltophilia exposure to ceftazidime has resulted in decreasing susceptibility (47%–75% during 1997–99 to 30.5%–36.8% during 2009–12). More recent literature suggests the susceptibility of Stenotrophomonas to ceftazidime may be around 17.1% (using an MIC 50% of 64 mg/L); susceptibility to ceftazidime-avibactam is reported to be around 19.5%. A 2020 French study reported resistance rates around 61% to ceftazidime and 33% to ceftazidime-avibactam when isolated from respiratory secretions in hospitalized patients. A 2023 paper from Iran found ceftazidime susceptibility to be 31.8%. [3], [4], [5]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the available evidence across any trials including but not limited to randomized, observational, and case reports in treating patients with Avycaz and aztreonam for Stenotrophomonas maltophilia infections?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-3 for your response.

Dual Therapy with Aztreonam & Ceftazidime/Avibactam Against Multi-Drug Resistant Stenotrophomonas maltophilia on Tricuspid Valve Endocarditis
Design	Case report
Case presentation	A 38-year-old male with a history of intravenous drug use, chronic hepatitis C, and recent MSSA endocarditis was admitted with sepsis. Workup revealed tricuspid valve endocarditis with pulmonary septic emboli due to Stenotrophomonas maltophilia. Initial antibiotics included levofloxacin, metronidazole, and piperacillin-tazobactam, followed by levofloxacin and minocycline. The patient required valve replacement on day 6. Repeat cultures showed the S. maltophilia was pan-resistant, including to ceftazidime, levofloxacin, minocycline, trimethoprim-sulfamethoxazole, and chloramphenicol. The organism also showed intermediate resistance to minocycline, and high minimum inhibitory concentrations to eravacycline and tigecycline. The microbiology department was consulted, and in vitro testing was recommended using aztreonam combined with ceftazidime/avibactam as a potential treatment option for this multi-drug resistant infection. Upon reveal that aztreonam with ceftazidime was susceptible, the patient completed 6 weeks of treatment with aztreonam, ceftazidime, and minocycline. Microbiological clearance was conformed along with clinical recovery from infection.
Study Author Conclusions	Although the surgical excision was key, treatment with ATM and CZA provided effective antimicrobial treatment in the setting of persistent positive blood culture. ATM with CZA should be considered for cases of pan-drug resistant S. maltophilia with limited treatment options.

References:

Alexander J, Carr A, Minor SB, Navas D. 1607. Dual Therapy with Aztreonam & Ceftazidime/Avibactam Against Multi-Drug Resistant Stenotrophomonas maltophilia on Tricuspid Valve Endocarditis. Open Forum Infect Dis. 2020;7(Suppl 1):S798. Published 2020 Dec 31. doi:10.1093/ofid/ofaa439.1787

Synergistic combination of aztreonam and ceftazidime/avibactam against resistant Stenotrophomonas maltophilia on pancreatitis
Design	Case report
Case presentation	A 65-year-old male with a history of type II diabetes was admitted with acute pancreatitis, voluminous ascites, and signs of sepsis after undergoing an echo-endoscopy procedure with pancreas biopsy. He was initially treated with metronidazole, ceftriaxone, and meropenem, but once admitted, his antibiotic therapy was adjusted to meropenem and linezolid. Due to a probable pancreatic fistula, a percutaneous drainage was performed on day 8, and the culture of the retroperitoneal fluid revealed a multi-drug resistant (MDR) Stenotrophomonas maltophilia. In vitro testing showed the organism was resistant to various antibiotics, but susceptible to the combination of aztreonam (ATM) and ceftazidime/avibactam (CZA). The patient was then treated with a regimen of ATM, CZA, and teicoplanin, which led to improvements in his inflammatory markers and clinical condition. However, the patient developed pancreatic necrosis requiring partial pancreatectomy, during which a Candida lusitaniae infection was also identified. After initiating fluconazole, the patient's condition continued to improve, and he was discharged after 6 weeks of antimicrobial therapy with a prescription for oral levofloxacin and fluconazole. Follow-up laboratory tests showed no recurrence of the infection.
Study Author Conclusions	The aztreonam and ceftazidime/avibactam is a potential antibiotic combination to treat life-threatening infections caused by Gram-negative MβL producers. However, randomized studies with more patients need to be performed in order to define the role of this antibiotic combination in the treatment of infections caused by S. maltophilia

References:

De Almeida Torres N, Morales Junior R, Bueno Lopes LF, Zeigler R, Everson Uip D. Synergistic combination of aztreonam and ceftazidime/avibactam against resistant Stenotrophomonas maltophilia on pancreatitis. J Infect Dev Ctries. 2023;17(6):881-885. Published 2023 Jun 30. doi:10.3855/jidc.17290

Optimization of Aztreonam in Combination With Ceftazidime/Avibactam in a Cystic Fibrosis Patient With Chronic Stenotrophomonas maltophilia Pneumonia Using Therapeutic Drug Monitoring: A Case Study
Design	Case report
Case presentation	An 11-year-old, 30-kg, white female with cystic fibrosis (CF) and a history of liver disease, failure to thrive, and chronic Mycobacterium avium complex pneumonia presented with a CF pulmonary exacerbation and had a history of infections with methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, and Stenotrophomonas maltophilia in the past 12 months. She was admitted 6 times within the same time frame due to recurrent exacerbations believed to be caused by S. maltophilia, which was the predominant organism found in her cultures. Her pulmonary function had significantly declined, with her forced expiratory volume (FEV1) decreasing from 91% to 53%. During the last admission, a bronchoalveolar lavage confirmed the presence of S. maltophilia, which was resistant to ceftazidime, aztreonam, and ceftazidime-avibactam, but susceptible to minocycline and trimethoprim-sulfamethoxazole. Previous therapies prescribed for her exacerbations due to S. maltophilia included various combinations of antibiotics, but she failed to respond. During the current admission, the infectious disease and pulmonary teams decided to initiate a combination therapy of ceftazidime/avibactam, aztreonam, and minocycline to combat the persistence of S. maltophilia, which exhibits intrinsic resistance to multiple antibiotics due to its low membrane permeability, presence of chromosomally encoded multidrug resistance efflux pumps, and antibiotic-modifying enzymes, such as beta-lactamases.
Study Author Conclusions	This case illustrates the importance of TDM, and the logistical issues encountered with the use of alternative dosing strategies in pediatric patients with CF.

References:

Cowart MC, Ferguson CL. Optimization of Aztreonam in Combination With Ceftazidime/Avibactam in a Cystic Fibrosis Patient With Chronic Stenotrophomonas maltophilia Pneumonia Using Therapeutic Drug Monitoring: A Case Study. Ther Drug Monit. 2021;43(2):146-149. doi:10.1097/FTD.0000000000000857