On the Frontier of Treatment-Emergent Resistance in Stenotrophomonas maltophilia

Stenotrophomonas maltophilia is an opportunistic gram-negative pathogen most often observed colonizing vulnerable patients through nosocomial transmission.¹ Susceptible populations include patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, cancer, and other immunocompromised groups.^1,2 Within these populations, the organism has a propensity to cause a wide range of infections, including pneumonia, bloodstream infections, wound infections, bone and joint infections, skin and soft tissue infections, intra-abdominal infections, and urinary tract infections.³ There are several factors that contribute to suboptimal treatment of S maltophilia infections, including the challenge of discerning whether positive cultures are indicative of an infection, delayed time to the microbiologic identification of S maltophilia, intrinsic and acquired antibiotic resistance to multiple drug classes, limited clinical data to support the use of single or combined therapies, and inconsistencies in susceptibility testing leading to breakpoint uncertainties.^4-6 S maltophilia is a low-virulence pathogen and is often isolated concomitantly with more virulent gram positive and gram-negative pathogens, confounding our understanding of its contributions to propagate infection.^4,7 Thus, clinicians have historically interpreted positive S maltophilia cultures as colonization rather than a priority pathogen for aggressive treatment. ⁸ Nonetheless, isolation of S maltophilia is associated with high mortality rates among patients, and recent studies have called into question the historic dogma surrounding its importance and the need to define optimal antibiotic strategies.^3,9,10 Determining the best treatment course for S maltophilia infections is complicated by numerous mechanisms of resistance to antibiotics, including β-lactams, tetracyclines, aminoglycosides, fluoroquinolones, and polymyxins. ^5,8,11,12 In brief, β-lactam resistance is primarily attributable to L1 class B3 metallo-β-lactamase and L2 class A cephalosporinase.^4,8,11 Aminoglycoside resistance originates from efflux pumps and modifying enzymes.8 These enzymes include aminoglycoside phosphotransferases, aminoglycoside acetyltransferases, aminoglycoside nucleotidyltransferases, and proteases ClpA and HtpX.^4,8,13,14 The presence and overexpression of efflux pumps from multiple families contribute to S maltophilia resistance to multiple classes of antibiotics. These efflux pumps primarily belong to 3 families: resistance- nodulation division, which confers resistance to all first-line drugs; ATP-binding cassette, which confers quinolone, aminoglycoside, tetracycline, and polymyxin resistance; and major facilitator superfamily, which confers quinolone, aminoglycoside, and tetracycline resistance.^4,5,8,12 Biofilm formation further supports S maltophilia proliferation by preventing clearance.^2,15 This is exemplified by the high proportion of patients with cystic fibrosis (approximately 1 in 3) having S maltophilia colonized in their pulmonary tissue.⁵ The preferred treatment for S maltophilia infections is not well-defined.12 The limited number of agents to which S maltophilia generally remains susceptible include trimethoprim-sulfamethoxazole, levofloxacin, minocycline, and cefiderocol.^12,16 Trimethoprim-sulfamethoxazole, a sulfa drug, is the historically recommended first-line agent. However, toxicity and patient intolerance occasionally prevent its use.^11,17,18

Recommendations from the European Committee on Antimicrobial Susceptibility Testing have endorsed cefiderocol, a novel cephalosporin, as the best alternative to trimethoprim-sulfamethoxazole.⁴ Case reports of successful treatment of S maltophilia infections with cefiderocol have been published, and a neutropenic rabbit study indicated that cefiderocol may clear infections at a better rate than trimethoprim-sulfamethoxazole.^19-21 Fluoroquinolones, particularly levofloxacin, are commonly utilized in clinical practice despite cautions against their application due to treatment-emergent resistance and poorer in vitro activity compared with trimethoprim-sulfamethoxazole.^11,12,22,23

The Clinical and Laboratory Standards Institute (CLSI), in following Infectious Diseases Society of America (IDSA) guidelines, recently recommended against using levofloxacin as a monotherapy to treat S maltophilia given its propensity to develop resistance.16,22-25 However, data on suppression of treatment-emergent resistance to levofloxacin when administered in combination with another therapeutic agent are lacking. A meta-analysis has indicated that, at best, fluoroquinolones as a monotherapy are slightly superior to trimethoprim-sulfamethoxazole, and, at worst, are no different.4 Therefore, there is not sufficient evidence to suggest removing trimethoprim- sulfamethoxazole as the primary suggested treatment. Similar to levofloxacin, minocycline treatments were neither more nor less effective than trimethoprim-sulfamethoxazole.^4,16

A reevaluation of the clinical data that contributed to establishing ceftazidime breakpoints for the treatment of S maltophilia infections found insufficient support for the chosen minimum inhibitory concentrations breakpoints.16 Clinical studies showing positive clinical outcomes for patients treated with ceftazidime were also lacking, prompting CLSI to remove ceftazidime breakpoints for S maltophilia.¹⁶ This change was recognized by the Food and Drug Administration in 2024, and the susceptibility test interpretive criteria were removed.²⁶ Although ceftazidime breakpoints no longer exist for S maltophilia, the triple combination of ceftazidime-avibactam and aztreonam is suggested as an alternative to combination therapies consisting of 2 of the following: cefiderocol, minocycline, trimethoprim- sulfamethoxazole, or levofloxacin.¹⁶

S maltophilia infections resistant to each of the recommended traditional agents have been reported,¹² although it is unclear whether these resistance patterns are community acquired or the direct result of treatment. Trimethoprim-sulfamethoxazole-resistant isolates have shown variable rates of cross-resistance to levofloxacin and ceftazidime.²⁷ Treatment-emergent resistance for both fluoroquinolones and trimethoprim- sulfamethoxazole has been described, with rates between 7% and 30%, and 2% and 20% for patients treated with each agent, respectively.^11,22,23 However, these studies are few, with sample sizes not exceeding 150 patients, and longitudinal studies describing the genetic mechanisms by which this treatment-emergent resistance arises are scarce.

In vitro serial passage studies have indicated that S maltophilia isolates have the potential to become resistant to cefiderocol through modifications to the iron transporter gene tonB as well as the efflux pump smeDEF.²⁸ A potential for cross-resistance between ceftazidime and cefiderocol has been noted due to the role of tonB in ceftazidime resistance.²⁸ Another mechanism of resistance prompted by antibiotic exposure occurs through efflux pump modifications. Efflux pumps have been implicated in the rise of resistance after exposure to cefiderocol, trimethoprim- sulfamethoxazole, quinolones, and ceftazidime.^8,29 Positively, in vitro-induced trimethoprim-sulfamethoxazole- and levofloxacin-resistant isolates still retain minocycline susceptibility.²⁹

Although recent recommendations suggest that monotherapies are not appropriate for S maltophilia infections, meta-analyses have indicated that combination therapy may only be beneficial in cases of severely immunocompromised hosts, but there is no perceived benefit to combination therapy over monotherapy overall.^4,11,17 Still, IDSA guidelines endorsing combination therapy over monotherapy persist.³⁰ It is important to note that the prescription of agents in these studies is based on inconsistent/ suboptimal recommendations of dosing and prescription.

Pharmacokinetic/pharmacodynamic cutoffs have been found to be 2- to 8-fold lower than the current breakpoints for trimethoprim-sulfamethoxazole, levofloxacin, minocycline, tigecycline, and aztreonam-avibactam.^4,31 Lacking proper breakpoints for these agents (relative to treating S maltophilia) may result in inappropriate use based on faulty interpretations of in vitro susceptibility profiles. Consensus among different in vitro antimicrobial susceptibility testing methods for S maltophilia is lacking, further confounding interpretations of isolate profiles.⁶ These inconsistencies limit reproducibility and hinder large-scale studies that could establish strong corollaries between susceptibility profiles and patient outcomes to inform a revision of the breakpoints for these agents (or provide the current breakpoints with supporting data).

S maltophilia is gradually becoming a pathogen of interest in more research studies. Still, there is much left to uncover.⁸ Rates and mechanisms of treatment-emergent resistance remain scarce, and the application of combination therapy to either prevent or combat such resistance requires further study. For now, a thorough understanding of the limitations of antimicrobial susceptibility tests, trends of treatment-emergent resistance, and data supporting (or refuting) current breakpoints will help to inform the best possible clinical care.

References

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