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Rationale for FDA's Position on Ceftazidime Breakpoints against Stenotrophomonas Maltophilia

FDA has reviewed data supporting ceftazidime breakpoints against Stenotrophomonas maltophilia. The review was conducted after the Clinical and Laboratory Standards Institute (CLSI) removed the breakpoints from the 34th edition of CLSI supplement M100 published in February 2024.1 FDA has reviewed the data supporting the removal of the breakpoints, which were discussed during a CLSI Subcommittee on Antimicrobial Susceptibility Testing (AST SC) meeting in January 2023.2

S. maltophilia was initially described as Pseudomonas maltophilia in 1960.3 In 1983, the bacterium was transferred to the genus Xanthomonas as Xanthomonas maltophilia4,5 , and in 1993 it was reclassified under a new genus Stenotrophomonas as S. maltophilia.6S. maltophilia is intrinsically resistant to most beta-lactams including cephalosporins and carbapenems due to low membrane permeability, chromosomally encoded multidrug resistance efflux pumps, and the production of two inducible beta-lactamases (L1 and L2).7 L1 is a metallo--lactamase (MBL) hydrolyzing carbapenems and other beta-lactams, excluding aztreonam. L2 is a class A cephalosporinase conferring resistance to broad-spectrum cephalosporins and aztreonam. Ceftazidime is considered a weak inducer of L2.8

Ceftazidime for injection is a cephalosporin antibacterial drug that was approved on 07/19/1985. Currently ceftazidime for injection is approved for the following indications:

  1. Lower respiratory tract infections, including pneumonia
  2. Skin and skin-structure Infections
  3. Urinary tract infections, both complicated and uncomplicated
  4. Bacterial septicemia
  5. Bone and joint Infections
  6. Gynecologic Infections
  7. Intra-abdominal Infections
  8. Central Nervous System Infections, including meningitis

Ceftazidime breakpoints against S. maltophilia were established by CLSI in 2004. FDA recognized CLSI’s ceftazidime breakpoints against S. maltophilia in December 2020 when ceftazidime susceptibility test interpretive criteria (STIC) were transferred from the ceftazidime prescribing information (PI) to the FDA STIC website.9 Prior to that the ceftazidime PI had not included breakpoints for Pseudomonas maltophilia, Xanthomonas maltophilia or Stenotrophomonas maltophilia. Table 1 below depicts prior and current ceftazidime breakpoints for S. maltophilia.

Table 1. Current FDA and CLSI Ceftazidime Breakpoints for Stenotrophomonas maltophilia

 

Minimum Inhibitory Concentrations
(mcg/mL)

Disk Diffusion (zone diameter in mm)

S

I

R

S

I

R

FDA a

≤8

16

≥32

-

-

-

CLSI M100- Ed 34 [2024]

-

-

-

-

-

-

MIC: minimal inhibitory concentration; R: resistant; S: susceptible; I: intermediate.
a FDA recognized CLSI M100-Ed 33; 2023

In support of their decision to remove ceftazidime breakpoints for S. maltophilia, CLSI noted that no substantive data supporting the establishment of the current breakpoints were found, the breakpoints split the wild-type distribution, susceptibility testing by reference methods and commercial methods were not consistently reproducible, and nonclinical PK/PD data and clinical data needed to validate the breakpoints were limited.

FDA has reviewed the available information and agrees that microbiological, nonclinical PK/PD, and clinical data are insufficient to determine susceptibility testing interpretive criteria for ceftazidime against S. maltophilia and agrees with CLSI that the current breakpoints should be removed.


1 Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing, 34th ed. CLSI supplement M100; 2024. https://clsi.org/all-free-resources/
2https://clsi.org/meetings/ast-file-resources/
3 Hugh R, Ryschenkow E. An Alcaligenes-like Pseudomonas species (abstract). Bacteriol Proc 1960; 60:78.
4 Swings J, De Vos P, Van den Mooter M, De Ley J. Transfer of Pseudomonas maltophilia Hugh 1981 to the genus Xanthomonas as Xanthomonas maltophilia (Hugh 1981) comb. nov. Int. J. Syst. Bacteriol. 1983; 33:409-413.
5 Marshall WF, Keating MR, Anhalt JP, Steckelberg JM. Xanthomonas maltophilia: an emerging nosocomial pathogen. Mayo Clin Proc. 1989 Sep;64(9):1097-104.
6 Palleroni NJ, Bradbury JF. Stenotrophomonas, a new bacterial genus for Xanthomonas maltophilia (Hugh 1980) Swings et al. 1983. Int J Syst Bacteriol. 1993 Jul;43(3):606-9.
7 Sader HS et al. Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents When Tested against a Large Collection of Contemporary Stenotrophomonas maltophilia Isolates from Medical Centers Worldwide. Antimicrob Agents Chemother. 2020; Oct 20;64(11):e01433-20.
8 Gibb J, Wong DW. Antimicrobial Treatment Strategies for Stenotrophomonas maltophilia: A Focus on Novel Therapies. Antibiotics (Basel). 2021 Oct 9;10(10):1226.
9 FDA-Recognized Antimicrobial Susceptibility Test Interpretive Criteria; https://www.fda.gov/drugs/development-resources/fda-recognized-antimicrobial-susceptibility-test-interpretive-criteria

 
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