Updates to Susceptibility Breakpoints for Stenotrophomonas maltophilia

Ceftazidime

Ceftazidime breakpoints for S. maltophilia were removed due to a lack of data supporting the previous breakpoint, along with the uncertainty as to whether the species identification of the organisms utilized in the clinical studies leading to FDA approval were actually S. maltophilia because of nomenclature changes. Notably, the package insert for ceftazidime never listed S. maltophilia or the previous names assigned to this species as an organism for which there were sufficient data to predict activity.

Contemporary microbiologic S. maltophilia data were reviewed when reassessing the breakpoints. Surveillance studies reported the frequent production of both L1 and L2 β-lactamases among clinical S. maltophilia isolates.1 The L1 β-lactamases (aka class B3 β-lactamases) are metallo-β-lactamases [MBLs] capable of hydrolyzing carbapenems and other β-lactams with the exception of aztreonam and L2 β-lactamases are class A cephalosporinases that confer resistance to extended-spectrum cephalosporins (e.g., ceftazidime) and aztreonam but are still inhibited by serine-β-lactamase inhibitors such as clavulanic acid and avibactam.1,5 In one study evaluating clinical strains of S. maltophilia collected over a 10-year period across the United States, L1 β-lactamases were detected in 100/130 (77%) isolates, and L2 β-lactamases were found in 116/130 (89%) isolates.1 Therefore, in isolates with L1/L2 β-lactamases, reduced ceftazidime activity is expected.

Contemporary data presented at CLSI indicated that neither reference broth microdilution (BMD) nor reference agar dilution minimum inhibitory concentrations (MICs) were reproducible. One large multicenter study reported poor accuracy when testing ceftazidime and S. maltophilia using three commercial antimicrobial susceptibility test (AST) systems, with 11.1 - 41.8% very major error rates when compared to reference BMD interpreted according to the former EUCAST pharmacokinetic/pharmacodynamic (PK/PD) reference breakpoints of ≤4 μg/mL, susceptible; 8 μg/mL, intermediate; and >8 μg/mL, resistant.6

Several PK/PD models demonstrated ceftazidime monotherapy to be insufficient for treatment of S. maltophilia.7-9 Garrison et al. used a simulated dosing regimen (1g q8h) that was not corrected for protein binding and noted S. maltophilia regrowth to baseline after treatment of both susceptible and resistant isolates.7 Additional data supporting removal of the ceftazidime breakpoints include an MIC distribution supporting an epidemiologic cutoff value (ECV) of 64 μg/mL, which is several dilutions higher than the ≤8 μg/mL clinical breakpoint previously set by CLSI for ceftazidime.4 Data used for these studies were composed of contemporary isolates from International Health Management Associates (IHMA) (n = 5826) and JMI Laboratories (n = 2107).10,11

Furthermore, the AHWG found a lack of high-quality clinical outcome studies comparing ceftazidime and other antimicrobials for treatment of S. maltophilia. Sparse data have been published for clinical outcomes, including only a limited number of reports of successful treatment with ceftazidime monotherapy in patients without removable foci of infection (e.g., indwelling devices or lines) or surgical intervention.12,13 Due to the lack of data supporting a breakpoint, as well as the lack of FDA-approved indications for S. maltophilia, ceftazidime breakpoints were removed from CLSI M100 in 2024.4 Importantly, this change was recognized by the FDA in May 2024, and ceftazidime breakpoints for S. maltophilia were subsequently removed from the FDA susceptibility test interpretive criteria (STIC) website.14

Levofloxacin

Several small PK/PD animal studies of levofloxacin and S. maltophilia were evaluated, including neutropenic murine pneumonia models and a neutropenic murine thigh model.15,16 Using a single clinical S. maltophilia isolate and a levofloxacin dose of 10 mg/ kg q24h for 5 days, Imoto et al. demonstrated a significantly longer mouse survival time (P = 0.0006) as compared to saline control in a hemorrhagic pneumonia model.15 Similar results were demonstrated by Nakamura et al. when using two clinical isolates and three different levofloxacin doses (10, 30, 100mg/kg).16 Although promising results were seen with these two studies, neither used human simulated dosing of 750 mg daily.17

Due to limited PK/PD studies using human simulated regimens and limited clinical outcome data, there was insufficient evidence for a levofloxacin breakpoint update. However, a change was made to CLSI M1004 with the addition of a comment stating that levofloxacin should not be used as monotherapy against S. maltophilia. This aligns with the Infectious Diseases Society of America (ISDA) “Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections,” which suggests that, if a clinician wishes to use levofloxacin for therapy of S. maltophilia infection, it should be used in combination with other antimicrobials rather than as monotherapy.18

Minocycline

New PK/PD data contributed significantly to the decision to lower the breakpoints for minocycline with S. maltophilia. Two studies were evaluated to support this decision. Fratoni et al. conducted dose fractionation studies in the neutropenic murine thigh infection model and determined the PD index needed for stasis and 1 log10 reduction in colony forming units (CFU) was a free area under the curve ( fAUC)/MIC of 9.6 and 23.6, respectively.19 Monte Carlo simulations using minocycline at 200 mg IV q12h achieved the 1 log10 kill threshold ( fAUC/MIC ≥23.6) with probability of target attainment (PTA) of 93% for isolates at MICs of 0.5 μg/mL and 51.7% at 1 μg/mL. When using the stasis threshold ( fAUC/MIC ≥9.6), PTA was 97% at 1 μg/mL. In contrast, the PTA at the previous breakpoint of 4 μg/mL was only 0.1%. A Monte Carlo simulation from another group using minocycline dosing of 100 mg IV q12 h demonstrated ≥94.4% PTA at <4 μg/mL however, they used a lower target fAUC/MIC >8.75 that was extrapolated from gram-positive bacteria.20

Updated MIC distribution data for minocycline obtained from testing isolates at IHMA (n = 942) and JMI Laboratories (n = 1977) showed a modal MIC of 0.5 μg/mL, though an ECV could not be calculated from data available at the time.

Additional support for the breakpoint revision included four retrospective observational clinical outcome studies that showed that rates of minocycline failure were similar to those of SXT, however noting limitations that these studies included primarily respiratory isolates and many polymicrobial samples.21-24 Jacobson et al. reported a significantly lower clinical failure rate for patients (n=93) treated with minocycline for S. maltophilia when the MIC was <4 μg/mL compared to those when infections were caused by isolates with MICs of 4 μg/mL (2.6% versus 29.4%, P = 0.004).24 Ultimately, the susceptible breakpoint was lowered to ≤1 μg/mL, with the breakpoint being based on a dose of 200 mg q12h.

Minocycline DD breakpoints were also revised using data generated in a multi-center disk correlation study coordinated by the CLSI AST subcommittee (data unpublished).25 The DD breakpoints were established using three media manufacturers and two disk manufacturers tested across three separate laboratories.

Trimethoprim-sulfamethoxazole

Existing data evaluating PK/PD and clinical outcomes data for SXT against S. maltophilia, some of which are summarized below, were reviewed but ultimately the breakpoints were not changed.16,26-28

A neutropenic rabbit model of S. maltophilia pneumonia demonstrated no significant reduction in lung weight, a marker of organism-mediated pulmonary injury, when compared to untreated control animals following an SXT dosing regimen of 5 mg/kg IV q12.26 However, lung weights of cefiderocol-treated rabbits were significantly decreased when compared to untreated control animals. Data from this study were difficult to translate to human experience since plasma concentrations were not obtained and it was therefore unclear how closely the regimen simulates human dosing. Furthermore, PK/PD modeling studies show that clinically equivalent AUC exposures achieved only a 0.5 log10 reduction in CFU at best.27,28

Nys et al. conducted a retrospective study of 45 patients who received SXT for monomicrobial S. maltophilia infection.29 Of these patients, 38/45 (84.4%) experienced microbiological cure and 3/45 (6.7%) harbored SXT-resistant isolates. Although the Nys et al. study provided positive evidence supporting use of SXT, Junco et al. reported no significant difference in clinical failure rates between SXT (77/217 [35.5%] patients) and minocycline (12/39 [30.8%] patients).21 Thus, clinical outcome studies show variable results.

Due to a lack of evidence that the current breakpoints are inappropriate, the SXT breakpoints remained unchanged and a comment was added that SXT should not be used alone for antimicrobial therapy in order to align with the IDSA “Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections”.18

See the table below for an excerpt of current zone diameters and MIC breakpoints for S. maltophilia from the 35th edition of CLSI M100.

Conclusions

In summary, S. maltophilia breakpoints for ceftazidime were removed, minocycline breakpoints were lowered, and comments warning against the use of monotherapy for levofloxacin and for SXT were added. Although CLSI generally refrains from making treatment-specific recommendations, the SXT and levofloxacin monotherapy comments align with the IDSA treatment guidance for S. maltophilia, which states that a “standard of care” regimen is not available and suggests that combination therapy with at least two active agents should be used.18 Specifically, the guidance suggests the use of either: (1) two of the following agents: cefiderocol, minocycline, TMP-SMX, or levofloxacin or (2) the combination of ceftazidime-avibactam and aztreonam.

As with any new breakpoint changes, clinical laboratories should try to implement as soon as possible. It is important for laboratories to discuss and collaborate with infectious diseases clinicians and antimicrobial stewardship teams to ensure that implementation is streamlined per institutional practices.

References

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