Current and Potential Treatment Options for Stenotrophomonas maltophilia Infections

Stenotrophomonas maltophilia is an aerobic, nonfermentative, gram-negative bacillus that causes various nosocomial and community-acquired infections in immunocompromised hosts.¹ Risk factors associated with S maltophilia infections include, but are not limited to, malignancy, chronic steroid use, and chronic respiratory disease.^1,2 This opportunistic pathogen is known to cause pneumonia, bacteremia, and catheter-related infections with high mortality in certain at-risk patient populations.^1,3

S maltophilia is intrinsically resistant to multiple antibiotics due to β-lactamase production and expression of multidrug-resistance efflux pumps.¹ As a result, S maltophilia infections are challenging to treat. Here, we aim to provide a brief review of current and potential treatment options for S maltophilia infections.

Commonly Used Treatment Options

Trimethoprim/sulfamethoxazole (TMP/SMX) is considered the treatment of choice for S maltophilia infections based on reliable in vitro activity against clinical isolates and extensive clinical experience with its use.⁴ However, due to adverse events associated with TMP/SMX as well as increasing prevalence of TMP/SMX resistance, alternative treatment options are needed.^1,2,4

Fluoroquinolones (FQs) have been reported as an alternative to TMP/SMX, as they have excellent in vitro activity. A meta-analysis demonstrated comparable mortality of S maltophilia infections treated with TMP/SMX and FQs. Although ciprofloxacin and moxifloxacin have clinical literature supporting their use, levofloxacin is the most studied and commonly used of the FQs.⁵ In a retrospective study of 98 patients comparing TMP/SMX with levofloxacin and ciprofloxacin for S maltophilia infections, there were no statistically significant differences in microbiological and clinical response rates at the end of therapy (65% vs 62%, P <.832; and 61% vs 52%, P <.451, respectively). Of note, 10 of 14 isolates that were recovered following FQ therapy were resistant to levofloxacin.⁶ In a retrospective study of 86 patients comparing TMP/SMX with levofloxacin for S maltophilia bacteremia, there was no difference in 30-day mortality (27.5% vs 20%, respectively; P = .429) and in recurrent bacteremia within 3 months (11.9% vs 5.7%, respectively; P = .464). Of note, 50% of patients who received levofloxacin therapy for the first bacteremic episode were found to have isolates resistant to levofloxacin in subsequent bacteremic infections.⁷ These retrospective studies are subject to patient selection bias; however, they highlight the emerging resistance to FQs. Thus, while FQs may be a viable alternative treatment option to TMP/SMX, they should be used with caution.

Minocycline is a tetracycline derivative with in vitro activity against S maltophilia.⁸ A retrospective cohort of 45 patients with various S maltophilia infections compared TMP/SMX with minocycline and reported treatment failures of 41% and 30% (P = .67), respectively. The overall mortality was the same between the 2 groups (9%).⁹ Furthermore, in a single-arm retrospective study of 92 patients with S maltophilia infections receiving minocycline, 18% had clinical failure, 24% had partial clinical success, and 58% had complete clinical success.¹⁰ Because these studies utilized different definitions of treatment failure and the latter study lacked a comparative arm, the recommendation at this time is that minocycline should be used judiciously.

Tigecycline, a derivative of minocycline, is the only glycylcycline commercially available. Farrell et al evaluated the efficacy of tigecycline on 491 clinical S maltophilia isolates from North America and found that 95% of isolates were susceptible to the tigecycline breakpoint for Enterobacteriaceae of minimum inhibitory concentration (MIC) ≤2 mg/L.¹¹ A retrospective cohort study of 45 patients compared clinical improvements and mortality in patients with nosocomial infections treated with TMP/SMX or tigecycline and reported no statistically significant differences in clinical improvement at 14 days (69% vs 68%, respectively; P = .95) and 30-day mortality (31% vs 21%, respectively; P = .52).¹² Eravacycline, a novel fluorocycline, is structurally similar to tigecycline.¹³ In an in vitro study, the efficacy of eravacycline and comparators such as tigecycline were evaluated on 105 clinical S maltophilia isolates. Sutcliffe et al found that eravacycline has lower MICs than that of tigecycline (≤0.016 to 8 mcg/mL vs 0.5 to >32 mcg/mL, respectively).¹⁴ Similarly results were found by Morrissey et al, who evaluated 293 clinical isolates (0.06 to 8 mcg/mL vs 0.12 to 16 mcg/mL, respectively).¹⁵ These studies brought to light that tigecycline and eravacycline may have a role in multidrug-resistant S maltophilia infections; however, further studies are needed to elucidate their role.

Potential Alternative Treatment Options

The combination of aztreonam and avibactam has been used in instances of multidrug-resistant infections, including those caused by metallo-β-lactamase—producing Enterobacteriaceae.¹⁶ S maltophilia is intrinsically resistant to the majority of beta-lactams due to 2 inducible β-lactamases: L1, an Ambler class B metallo-β-lactamase and L2, an Ambler class A serine β-lactamase.^1,16 L1 hydrolyzes all beta-lactams (with the exception of aztreonam) and is not inhibited by commercially available beta-lactamase inhibitors. L2 hydrolyzes most cephalosporins and aztreonam, and it is inhibited by serine β-lactamase inhibitors such as clavulanate.^17,18 The addition of avibactam overcomes the β-lactam mediated resistance, as aztreonam is not hydrolyzed by L1 and avibactam inhibits L2. Mojica et al demonstrated that this combination led to restored aztreonam activity in 82% (23/28) of aztreonam-resistant clinical isolates.¹⁶ These results were replicated by Biagi et al, in which 97% of aztreonam-resistant clinical isolates (35/36) had restored activity of aztreonam with the addition of avibactam.¹⁹ Of note, aztreonam/avibactam is not commercially available and therefore, the combination of aztreonam with ceftazidime/avibactam must be employed clinically. This combination has been successfully used in practice for the treatment of a persistent S maltophilia bacteremia in a renal transplant patient.¹⁷ This synergistic combination suggests a potential therapeutic option for S maltophilia infections.

The combination of aztreonam and clavulanate has also been shown to restore aztreonam susceptibility; however, the utility of this combination is limited because clavulanate is not commercially available in intravenous formulation. Conversely, the combination of aztreonam and ceftolozane/tazobactam has failed to demonstrate restoration of aztreonam susceptibility.¹⁸ β-lactam/β-lactamase inhibitors such as imipenem/relebactam, meropenem/vaborbactam, and ceftolozane/tazobactam have limited activity against S maltophilia.^20,21 As a result, they are not viable alternatives for the treatment of S maltophilia.

Cefiderocol is a novel siderophore cephalosporin that employs ferric iron to form a chelating complex to enter the bacterial cell via iron transporters. Additionally, it is stable against hydrolysis by both serine and metallo-β-lactamases.²² This unique mechanism of action has exhibited in vitro activity against many resistant organisms, including S maltophilia.^21,23 Results of the SIDERO-WT program, which was composed of 3 consecutive multinational surveillance studies and tested a total of 1173 S maltophilia isolates between 2014 and 2017, demonstrated that cefiderocol suppressed growth of 99.8% of S maltophilia isolates at MIC of ≤4 mcg/mL.²³ The CREDIBLE-CR study, a randomized, open-label, active-controlled study of 150 patients with various gram-negative infections, compared cefiderocol with the best available therapy and found that overall mortality at day 28 was 24.8% and 18.4%, respectively. Five of the 150 patients were infected by S maltophilia and received cefiderocol, and their all-cause mortality at day 28 was 80% (4/5). Of note, 40% (2/5) of patients were found to have a MIC increase to cefiderocol from baseline.²⁴ Although the in vitro study was encouraging, the clinical study demonstrated that cefiderocol may not be a favorable alternative. However, further studies are needed to ascertain the clinical efficacy of cefiderocol and its role as a potential therapeutic option for multidrug-resistant S maltophilia infections.

Conclusions

Increasing rates of resistance to trimethoprim/sulfamethoxazole have created the need to search for alternative treatment options for S maltophilia infections. FQs and cefiderocol demonstrated resistance following their use; as a result, they may not be viable options. Minocycline, tigecycline, and eravacycline may each have a role, but they should be used cautiously. Lastly, the synergistic combination of aztreonam and avibactam appears be a reasonable treatment option, as it demonstrated clinical success in a persistent S maltophilia bacteremia patient. However, given the paucity of literature on alternative options, further trials are needed to elucidate the role that each agent, or combination of agents, may have, as well as to elucidate the implications on current practice in the treatment of S maltophilia infections.

Moc is a PGY-2 infectious diseases pharmacy resident at the University of Texas MD Anderson Cancer Center in Houston. She graduated from UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and completed her PGY-1 pharmacy practice residency at Scripps Mercy Hospital in San Diego.

Aitken is a pharmacy clinical specialist in infectious diseases at The University of Texas MD Anderson Cancer Center and a faculty member of the Center for Antimicrobial Resistance and Microbial Genomics at UTHealth McGovern Medical School, both in Houston. He is an active member of the Society of Infectious Diseases Pharmacists.

References

1. ^{Brooke JS.} Stenotrophomonas maltophilia^{: an emerging global opportunistic pathogen.} Clin Microbiol Rev^{. 2012;25(1):2-41. doi:10.1128/CMR.00019-11}
2. ^{Senol E, DesJardin J, Stark P, et al. Attributable mortality of} Stenotrophomonas maltophilia ^bacteremia. Clin Infect Dis. ^{2002;34(12):1653-1656. doi:10.1086/340707}
3. ^{Falagas ME, Kastoris AC, Vouloumanou EK, et al. Attributable mortality of} Stenotrophomonas maltophilia ^{infections: a systematic review of the literature.} Future Microbiol. ^{2009;4(9):1103-1109. doi:10.2217/fmb.09.84}
4. ^{Wei C, Ni W, Cai X, et al. Evaluation of trimethoprim/sulfamethoxazole (SXT), minocycline, tigecycline, moxifloxacin, and ceftazidime alone and in combinations for SXT-susceptible and SXT-resistant} Stenotrophomonas maltophilia ^{by in vitro time-kill experiments.} PLoS ONE. ^{2016;11(3):e0152132. doi:10.1371/journal.pone.0152132}
5. ^{Ko J-H, Kang C-I, Corenjo-Juárez P, et al. Fluoroquinolones versus trimethoprim-sulfamethoxazole for the treatment of} Stenotrophomonas maltophilia ^{infections: a systematic review and meta-analysis.} Clin Microb Infect. ^{2019;(25)5:546-554. doi:10.1016/j.cmi.2018.11.008}
6. ^{Wang YL, Scipione MR, Dubrovskaya Y, et al. Monotherapy with fluoroquinolone or trimethoprim-sulfamethoxazole for treatment of} Stenotrophomonas maltophilia ^infections. Antimicrob Agents Chemother^{. 2014;58(1):176-182. doi:10.1128/AAC.01324-13}
7. ^{Cho SY, Kang C, Kim J, et al. Can levofloxacin be a useful alternative to trimethoprim-sulfamethoxazole for treating} Stenotrophomonas maltophilia ^bacteremia? Antimicrob Agents Chemother^{. 2014;58(1):581-583. doi:10.1128/AAC.01682-13}
8. ^{Flamm RK, Shortridge D, Castanheira, et al.} In vitro ^{activity of minocycline against U.S. isolates of} Acinetobacter baumannii-Acinetobacter calcoaceticus ^{species complex,} Stenotrophomonas maltophilia^{, and} Burkholderia cepacia ^{complex: results from the SENTRY Antimicrobial Surveillance Program, 2014 to 2018.} Antimicrob Agents Chemother. ^{2019;63(11):e01154-19. doi:10.1128/AAC.01154-19}
9. ^{Hand E, Davis H, Kim T, Duhon B. Monotherapy with minocycline or trimethoprim/sulfamethoxazole for treatment of} Stenotrophomonas maltophilia ^infections. J Antimicrob Chemother. ^{2016;71(4):1071-1075. doi:10.1093/jac/dkv456}
10. ^{Jacobson S, Junco Noa L, Wallace MR, Bowman MC. Clinical outcomes using minocycline for} Stenotrophomonas maltophilia ^infections. J Antimicrob Chemother. ^{2016;71(12):3620. doi:10.1093/jac/dkw327}
11. ^{Farrell DJ, Sader HS, Jones RN. Antimicrobial susceptibilities of a worldwide collection of} Stenotrophomonas maltophilia ^{isolates tested against tigecycline and agents commonly used for} S maltophilia ^infections. Antimicrob Agents Chemother. ^{2010;54(6):2735-2737. doi:10.1128/AAC.01774-09}
12. ^{Tekçe YT, Erbay A, Cabadak H, Sen S. Tigecycline as a therapeutic option in} Stenotrophomonas maltophilia ^infections. J Chemother. ^{2012;24(3):150-154. doi:10.1179/1120009X12Z.00000000022}
13. ^{Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent.} Drugs^{. 2016;76(5):567-588. doi:10.1007/s40265-016-0545-8}
14. ^{Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.} Antimicrob Agents Chemother. ^{2013;57(11):5548-5558. doi:10.1128/AAC.012880-13}
15. ^{Morrissey I, Bassetti M, Magnet S, et al.} In vitro ^{activity of eravacycline and comparators against} Acinetobacter baumannii^, Stenotrophomonas maltophilia ^{and Enterobacteriaceae, including carbapenem-resistant and ESBL phenotype subgroups, collected from European hospitals in 2015. Poster presented at: 27th ECCMID; 2017 Apr 25; Vienna, Austria}
16. ^{Mojica MF, Papp-Wallace, Taracila MA, et al. Avibactam restores the susceptibility of clinical isolates of} Stenotrophomonas maltophilia ^{to aztreonam.} Antimicrob Agents Chemother. ^{2017;61(10):e00777-17. doi:10.1128/AAC.00777-17}
17. ^{Mojica MF, Ouellette CP, Leber A, et al. Successful treatment of bloodstream infection due to metallo-β-lactamase—producing} Stenotrophomonas maltophilia ^{in a renal transplant patient.} Antimicrob Agents Chemother^{. 2016;60(9):5130-5134. doi:10.1128/AAC.00264-16}
18. ^{Emeraud C, Escaut L, Boucly A, et al. Aztreonam plus clavulanate, tazobactam, or avibactam for treatment of infections caused by metallo-β-lactamase—producing gram-negative bacteria.} Antimicrob Agents Chemother. ^{2019;62(5):e00010-19. doi:10.1128/AAC.00010-19}
19. ^{Biagi M, Qasmieh S, Lamm D, et al. Searching for optimal treatment regimens for} Stenotrophomonas maltophilia ^{resistant to levofloxacin and/or sulfamethoxazole-trimethoprim: aztreonam in combination with avibactam or vaborbactam. Poster presented at: 29th ECCMID; 2019 Apr 13-16; Amsterdam, Netherlands}
20. ^{Zhanel GG, Lawrence CK, Adam H. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations.} Drugs. ^{2018;78(1):65-98. doi:10.1007/s40265-017-0851-9}
21. ^{Hsueh SC, Lee YJ, Huang YT, et al. In vitro activities of cefiderocol, ceftolozane/tazobactam, ceftazidime/avibactam and other comparative drugs against imipenem-resistant} Pseudomonas aeruginosa ^and Acinetobacter baumannii^{, and} Stenotrophomonas maltophilia^{, all associated with bloodstream infections in Taiwan.} J Antimicrob Chemother. ^{2019;74(2):380-386. doi:10.1093/jac/dky425}
22. ^{Sato T, Yamawaki K. Cefiderocol: discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin.} Clin Infect Dis. ^{2019;69(suppl 7):S538-S543. doi:10.1093/cid/ciz826}
23. ^{Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important gram-negative bacteria.} Clin Infect Dis. ^{2019;69(suppl 7):S544-S551. doi:10.1093/cid/ciz827}
24. ^{Rubin D. Statistical Assessment of the Study in Carbapenem-Resistant Organisms (CREDIBLE-CR). Presentation presented at: U.S. Food & Drug Administration Antimicrobial Drugs Advisory Committee Meeting. 2019 Oct 16; Silver Spring, Maryland}