Activity of Potential Alternative Treatment Agents for Stenotrophomonas maltophilia Isolates Nonsusceptible to Levofloxacin and/or Trimethoprim-Sulfamethoxazole

Stenotrophomonas maltophilia is difficult to treat due to the production of multiple intrinsic and acquired mechanisms of resistance. Trimethoprim-sulfamethoxazole (TMP-SMZ) and the fluoroquinolones have traditionally been considered the drugs of choice but are plagued by increasing resistance and adverse drug effects. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant antimicrobials against clinical S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ.

ABSTRACT

Stenotrophomonas maltophilia is difficult to treat due to the production of multiple intrinsic and acquired mechanisms of resistance. Trimethoprim-sulfamethoxazole (TMP-SMZ) and the fluoroquinolones have traditionally been considered the drugs of choice but are plagued by increasing resistance and adverse drug effects. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant antimicrobials against clinical S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ. A diverse panel of 41 clinical S. maltophilia isolates collected through the SENTRY Antimicrobial Surveillance Program from 2008 to 2018 was evaluated against ceftazidime, ceftazidime-avibactam, chloramphenicol, delafloxacin, levofloxacin, moxifloxacin, eravacycline, minocycline, omadacycline, polymyxin B, and tigecycline. MICs were determined in triplicate via reference broth microdilution and interpreted according to CLSI guidelines where available. MIC distributions and susceptibilities were also compared across infection type, acquisition setting, and geographic origin. Susceptibilities to levofloxacin and TMP-SMZ were 29.3% and 36.6%, respectively. Minocycline displayed the highest susceptibility rate overall (92.7%) and the lowest MIC₉₀ value (4 mg/liter) of any of the 12 agents tested. Only 3 isolates were resistant to levofloxacin, TMP-SMZ, and minocycline. Polymyxin B and tigecycline were the second most active agents. No significant differences were observed in MIC distributions across the 3 strata evaluated. These data demonstrate that few antimicrobials, old or new, maintain reliable activity against resistant S. maltophilia. The role of minocycline in the treatment of infections due to S. maltophilia warrants further clinical investigation given its potent in vitro activity and favorable adverse effect profile.

INTRODUCTION

On the brink of the postantibiotic era, clinicians frequently encounter multidrug-resistant (MDR) pathogens for which there is no known optimal treatment. One such organism is Stenotrophomonas maltophilia, an opportunistic pathogen often overshadowed by other MDR Gram-negative organisms such as carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii. However, S. maltophilia is the most prevalent carbapenem-resistant Gram-negative pathogen among bloodstream infections in U.S. hospitals (1) and is associated with significant morbidity and mortality (2–4). Furthermore, treatment is particularly challenging due to the production of multiple intrinsic and acquired mechanisms of resistance that render many first-line antimicrobials, particularly the β-lactams, ineffective (5).

Trimethoprim-sulfamethoxazole (TMP-SMZ) has traditionally been considered the treatment of choice for S. maltophilia, as it displays predictably high rates of in vitro susceptibility (6–8). However, increasing reports of resistance and adverse drug effects and a lack of robust pharmacokinetic-pharmacodynamic (PK-PD) data for which to optimize dosing limit its clinical utility (9–14). The fluoroquinolones are generally considered preferred alternatives to TMP-SMZ, with the majority of data existing for levofloxacin (11, 15, 16). However, the role of fluoroquinolones, including levofloxacin, is also limited by baseline and treatment-emergent resistance, growing safety concerns, and drug-drug interactions (7, 11, 15, 17, 18).

Additional agents with reliably high susceptibility rates against S. maltophilia include tetracycline derivatives like minocycline and tigecycline. Minocycline displays susceptibility rates similar to those of TMP-SMZ, and anecdotal data suggest that clinical outcomes with minocycline and TMP-SMZ monotherapy do not significantly differ (12, 15, 17, 19, 20). Despite these data and availability of interpretive susceptibility criteria (21), minocycline is rarely used clinically for the treatment of S. maltophilia due in large part to the fact that many clinical microbiology labs do not specifically perform susceptibility testing for minocycline (22). Tigecycline displays reliable in vitro activity against S. maltophilia, but clinical use is hampered by lack of an oral formulation, dose-limiting gastrointestinal toxicities, and reports of increased clinical failure and mortality (7, 23). Finally, the in vitro activities of recently approved tetracycline derivatives, eravacycline and omadacycline, have been reported for S. maltophilia (24–29), but no studies to date have simultaneously assessed the activity of both agents or either agent specifically against S. maltophilia isolates resistant to levofloxacin and/or TMP-SMZ, and no clinical data exist to support their use.

Taking into consideration the numerous limitations of these currently available agents, there is an urgent need to identify alternatives with meaningful activity against S. maltophilia. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant comparator agents against S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ.

(Results of this study were presented in part at ECCMID 2019 as abstract 6182.)

MATERIALS AND METHODS

Bacteria and susceptibility testing.

A diverse panel of 41 clinical S. maltophilia isolates collected through the SENTRY Antimicrobial Surveillance Program (2008 to 2018) nonsusceptible to levofloxacin and/or TMP-SMZ was evaluated. These 41 isolates were selected randomly from the collection of JMI Laboratories S. maltophilia isolates nonsusceptible to levofloxacin, TMP-SMZ, or both. Species identification was confirmed at JMI Laboratories by standard biochemical tests and via matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS; Bruker Daltonics, Billerica, MA). Among isolates with available data, strains were acquired either in the community (n = 17) or in a nosocomial setting (n = 16) and were cultured from patients with the following infection types: pneumonia (n = 32), bacteremia (n = 4), skin/soft tissue infection (n = 4), and urinary tract infection (n = 1). Isolates were collected primarily from sites in North America (n = 17) and Europe (n = 14), followed by Asia (n = 4), Australia (n = 3), and South America (n = 3). Isolates were maintained at –80°C in cation-adjusted Mueller-Hinton broth (CAMHB) with 20% glycerol and were subcultured twice on tryptic soy agar plates with 5% sheep blood prior to use.

Analytical-grade avibactam, ceftazidime, chloramphenicol, delafloxacin, levofloxacin, minocycline, moxifloxacin, polymyxin B, sulfamethoxazole, tigecycline, and trimethoprim powders were obtained commercially (Sigma-Aldrich, St. Louis, MO), along with eravacycline and omadacycline powders (MedChemExpress, Monmouth Junction, NJ). Stock solutions of each agent were freshly prepared as single-use aliquots at the beginning of each week and kept frozen at –80°C. MICs were determined in triplicate by reference broth microdilution at a standard inoculum according to Clinical and Laboratory Standards Institute (CLSI) guidelines using the same 0.5 McFarland suspension (30). Modal MIC values are reported. Susceptibility testing for omadacycline and tigecycline was performed using CAMHB freshly prepared the same day as MIC testing, as recommended. Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were included as quality control (QC) organisms. Susceptibility interpretations were based on current CLSI interpretive categories for agents with available criteria against S. maltophilia (21) unless otherwise noted for the purpose of comparison. MIC distributions and susceptibilities were compared across three strata: infection type (pneumonia versus nonpneumonia), acquisition setting (community versus nosocomial), and geographic origin (U.S. versus non-U.S.) via Mann-Whitney U test. A 2-tailed P value of ≤0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 26 (SPSS Inc., Chicago, IL).

RESULTS

The MIC₅₀, MIC₉₀, and MIC range of each agent against each phenotypic subset of isolates (1, all isolates [n = 41]; 2, levofloxacin-nonsusceptible [NS] isolates [n = 29]; 3, TMP-SMZ-resistant isolates [n = 26]; and 4, levofloxacin-NS and TMP-SMZ-resistant isolates [n = 14]) are summarized in Table 1.

TABLE 1.

Activities of selected agents against clinical Stenotrophomonas maltophilia isolates nonsusceptible to levofloxacin and/or trimethoprim-sulfamethoxazole

Isolate group and drug	MIC (mg/liter)			Susceptibility (%)a
	50%	90%	Range	S	I	R
All isolates (n = 41)
Ceftazidime	64	>128	1 to >128	17.1	7.3	75.6
Ceftazidime-avibactamb	64	128	0.125 to >128	19.5	4.9	75.6
Chloramphenicol	16	>64	2 to >64	24.4	24.4	51.2
Delafloxacin	8	16	0.5 to 32
Eravacycline	2	8	0.5 to 16
Levofloxacin	8	>16	0.25 to >16	29.3	12.2	58.5
Minocycline	2	4	0.125 to 8	92.7	7.3	0
Moxifloxacin	4	8	0.125 to 16
Omadacycline	8	32	0.5 to >64
Polymyxin Bc	0.5	>8	0.03 to >8	73.2	7.3	19.5
Tigecyclined	1	8	0.125 to >8	73.2	9.7	17.1
TMP-SMZe	8	>8	0.03 to >8	36.6		63.4
Levofloxacin nonsusceptible (n = 29)
Ceftazidime	128	>128	1 to >128	20.7	10.3	69.0
Ceftazidime-avibactamb	64	>128	0.125 to >8	24.1	6.9	69.0
Chloramphenicol	32	>64	2 to >64	10.3	24.1	65.5
Delafloxacin	8	16	2 to 32
Eravacycline	4	8	0.5 to 8
Levofloxacin	8	>16	4 to >16	0.0	17.2	82.8
Minocycline	2	8	0.125 to 8	89.7	10.3	0.0
Moxifloxacin	4	16	0.5 to 16
Omadacycline	16	64	0.5 to >64
Polymyxin Bc	0.25	>8	0.03 to >8	69.0	3.4	27.6
Tigecyclined	2	8	0.125 to 8	62.1	13.8	24.1
TMP-SMZe	2	8	0.03 to >8	51.7		48.3
TMP-SMZ resistant (n = 26)
Ceftazidime	64	>128	1 to >128	7.7	7.7	84.6
Ceftazidime-avibactamb	64	>128	0.125 to >128	11.5	3.8	84.6
Chloramphenicol	16	>64	2 to >64	38.4	30.8	30.8
Delafloxacin	4	16	0.5 to 32
Eravacycline	2	4	0.5 to 8
Levofloxacin	8	>16	0.25 to >16	46.2	0.0	53.8
Minocycline	2	8	1 to 8	88.5	11.5	0.0
Moxifloxacin	2	16	0.125 to 16
Omadacycline	4	32	2 to >64
Polymyxin Bc	2	>8	0.06 to >8	57.7	11.5	30.8
Tigecyclined	1	8	0.125 to >8	69.2	11.5	19.2
TMP-SMZe	8	>8	8 to >8	0.0		100.0
Levofloxacin nonsusceptible, TMP-SMZ resistant (n = 14)
Ceftazidime	128	>128	1 to >128	7.1	14.3	78.6
Ceftazidime-avibactamb	64	>128	0.125 to >128	14.3	7.3	78.6
Chloramphenicol	16	>64	2 to >64	21.4	35.7	42.9
Delafloxacin	8	16	4 to 32
Eravacycline	2	8	0.5 to 8
Levofloxacin	16	>16	8 to >16	0	0	100
Minocycline	2	8	1 to 8	78.6	21.4	0
Moxifloxacin	8	16	2 to 16
Omadacycline	16	64	4 to >64
Polymyxin Bc	8	>8	0.06 to >8	35.7	7.2	57.1
Tigecyclined	4	8	1 to >8	42.9	21.4	35.7
TMP-SMZe	8	8	8 to >8	0		100

^aS, susceptible; I, intermediate; R, resistant.

^bSusceptibility interpretations based on CLSI-approved breakpoints for ceftazidime alone.

^cBased on CLSI breakpoints for Pseudomonas aeruginosa.

^dBased on FDA breakpoints for Enterobacteriaceae.

^eTMP-SMZ, trimethoprim-sulfamethoxazole. Value reflects MIC of trimethoprim component only.

Twelve of the 41 isolates (29.3%) and 15/41 (36.6%) isolates were susceptible to levofloxacin and TMP-SMZ, respectively. Delafloxacin showed activity similar to that of levofloxacin, while the MIC₅₀/MIC₉₀ for moxifloxacin were ≥1 log₂ dilution less than those for the other fluoroquinolones tested. Ceftazidime, ceftazidime-avibactam, and chloramphenicol all demonstrated susceptibility rates of <25%. Evaluating polymyxin B and tigecycline using interpretive criteria against P. aeruginosa and Enterobacteriaceae, respectively, revealed susceptibility rates of 73.2% for each. Minocycline demonstrated the highest rate of susceptibility overall (at 92.7%), the lowest MIC₉₀ value of any of the 12 agents tested, and improved potency over the other tetracycline derivatives eravacycline and omadacycline.

Just over half (51.7%) of the 29 levofloxacin-NS isolates were susceptible to TMP-SMZ (Table 1). The MIC₅₀/MIC₉₀ for delafloxacin and moxifloxacin were within 1 log₂ dilution of those from the first phenotypic subset once the 12 levofloxacin-susceptible isolates were removed in phenogroup 2. Susceptibilities to ceftazidime, ceftazidime-avibactam, and chloramphenicol remained under 25%, while those to polymyxin B and tigecycline dropped below 70%. Minocycline again retained the highest susceptibility rate, at 89.7%, although MIC₅₀/MIC₉₀ values were similar to those of eravacycline but were ≥8-fold lower than those of omadacycline. Figure 1 demonstrates the shift in MIC distributions for the tetracycline compounds against the levofloxacin-NS isolates compared to those against the isolates that were levofloxacin susceptible.

FIG 1.

MIC distributions of eravacycline, minocycline, omadacycline, and tigecycline against levofloxacin-susceptible (solid bars; n = 12) and -nonsusceptible (hatched bars; n = 29) Stenotrophomonas maltophilia isolates.

Similarly, approximately half (46.2%) of the TMP-SMZ-resistant isolates were susceptible to levofloxacin (Table 1). The activity of delafloxacin and moxifloxacin again remained largely unchanged. Ceftazidime, ceftazidime-avibactam, polymyxin B, and tigecycline were all below 70% susceptibility. Minocycline continued to be the only agent with >80% susceptibility, and MIC₅₀/MIC₉₀ values were comparable to those of eravacycline and tigecycline but less than that of omadacycline.

Finally, against the most resistant phenotypic subset of isolates nonsusceptible to both levofloxacin and TMP-SMZ, none of the agents with applicable interpretive criteria maintained susceptibility rates above 43% except minocycline (78.6%). Analogous to the previous groups, potency as determined by the MIC₅₀/MIC₉₀ was congruent among the tetracycline derivatives other than omadacycline.

Table 2 displays the MIC₅₀, MIC₉₀, and MIC range of each agent against all 41 isolates stratified across infection type, acquisition setting, and geographic origin. No statistically significant differences were observed for any drug across any stratum.

TABLE 2.

Activities of selected agents against clinical Stenotrophomonas maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ stratified according to infection type, acquisition setting, and geographic origin^a

Parameter and drug	MIC (mg/liter)			% susceptible
	50%	90%	Range
Infection type
Pneumonia (n = 32)
Ceftazidime	64	>128	1 to >128	15.6
Ceftazidime-avibactamb	64	128	0.125 to >128	18.2
Chloramphenicol	16	>64	2 to >64	28.1
Delafloxacin	8	16	0.5 to 16
Eravacycline	2	8	0.5 to 8
Levofloxacin	8	>16	0.25 to >16	28.1
Minocycline	2	4	0.125 to 8	93.8
Moxifloxacin	4	8	0.125 to 16
Omadacycline	8	32	0.5 to 64
Polymyxin Bc	0.25	>8	0.06 to >8	75.0
Tigecyclined	1	8	0.125 to 8	71.9
TMP-SMZe	8	>8	0.03 to >8	37.5
Nonpneumonia (n = 9)
Ceftazidime	64		1 to >128	22.2
Ceftazidime-avibactamb	64		1 to >128	22.2
Chloramphenicol	32		8 to >64	11.1
Delafloxacin	8		1 to 32
Eravacycline	2		0.5 to 16
Levofloxacin	8		0.5 to >16	33.3
Minocycline	2		1 to 8	88.8
Moxifloxacin	4		0.5 to 16
Omadacycline	16		2 to >64
Polymyxin Bc	2		0.03 to >8	66.7
Tigecyclined	1		0.125 to >8	77.7
TMP-SMZe	8		1 to >8	33.3
Acquisition setting
Community (n = 17)
Ceftazidime	64	>128	1 to >128	23.5
Ceftazidime-avibactamb	64	>128	0.125 to >128	29.4
Chloramphenicol	16	64	2 to 64	35.3
Delafloxacin	8	16	1 to 16
Eravacycline	2	8	0.5 to 16
Levofloxacin	4	16	0.5 to >16	35.3
Minocycline	2	8	0.5 to 8	82.4
Moxifloxacin	2	8	0.25 to 16
Omadacycline	8	64	0.5 to >64
Polymyxin Bc	0.25	4	0.03 to 8	82.3
Tigecyclined	1	8	0.125 to >8	82.3
TMP-SMZe	8	>8	0.25 to >8	35.3
Nosocomial (n = 16)
Ceftazidime	64	>128	1 to >128	12.5
Ceftazidime-avibactamb	64	128	1 to >128	12.5
Chloramphenicol	32	>64	8 to >64	6.3
Delafloxacin	8	16	0.5 to 32
Eravacycline	2	8	1 to 8
Levofloxacin	16	>16	0.25 to >16	18.8
Minocycline	2	4	0.125 to 4	100
Moxifloxacin	4	16	0.125 to 16
Omadacycline	16	64	2 to 64
Polymyxin Bc	0.5	>8	0.06 to >8	68.8
Tigecyclined	2	8	0.5 to 8	62.5
TMP-SMZe	8	>8	0.5 to >8	37.5
Geographic origin
U.S. (n = 17)
Ceftazidime	128	>128	1 to >128	17.6
Ceftazidime-avibactamb	64	128	0.125 to >128	23.5
Chloramphenicol	16	32	2 to 64	35.3
Delafloxacin	8	16	0.5 to 16
Eravacycline	2	8	0.5 to 8
Levofloxacin	8	>16	0.25 to >16	35.3
Minocycline	2	8	0.5 to 8	88.2
Moxifloxacin	4	16	0.125 to 16
Omadacycline	8	64	1 to 64
Polymyxin Bc	0.5	>8	0.03 to >8	70.6
Tigecyclined	1	8	0.25 to 8	76.5
TMP-SMZe	8	>8	0.03 to >8	29.4
Non-U.S. (n = 24)
Ceftazidime	64	>128	1 to >128	16.7
Ceftazidime-avibactamb	64	>128	1 to >128	16.7
Chloramphenicol	32	>64	4 to >64	16.7
Delafloxacin	8	16	1 to 32
Eravacycline	2	8	0.5 to 16
Levofloxacin	8	>16	0.5 to >16	25.0
Minocycline	2	4	0.125 to 8	95.8
Moxifloxacin	4	8	0.5 to 16
Omadacycline	16	32	0.5 to >64
Polymyxin Bc	0.5	>8	0.06 to >8	75.0
Tigecyclined	1	8	0.125 to >8	70.8
TMP-SMZe	8	>8	0.25 to >8	41.7

^aNo statistically significant differences in MIC distribution were present for any agent based on infection type, acquisition setting, or location using the Mann-Whitney U test.

^bSusceptibility interpretations based on CLSI-approved breakpoints for ceftazidime alone.

^cBased on CLSI breakpoints for Pseudomonas aeruginosa.

^dBased on FDA breakpoints for Enterobacteriaceae.

^eReflects MIC of trimethoprim component only.

DISCUSSION

S. maltophilia is an opportunistic pathogen that primarily infects vulnerable hosts and is resistant to many first-line antimicrobials. Long considered the drugs of choice for S. maltophilia, TMP-SMZ and the fluoroquinolones have recently come under increased scrutiny due to reports of resistance, lack of established efficacy in controlled trials, and high toxicity (18, 31, 32). Consequently, there is an urgent need to identify alternative treatment strategies for this difficult-to-treat pathogen.

This study demonstrated that the tetracyclines as a class maintain the most reliable in vitro activity against S. maltophilia, regardless of resistance phenotype. Among the tetracyclines, minocycline was as active as or more active than tigecycline, eravacycline, and omadacycline and demonstrated the highest susceptibility (78.6%) against the most difficult-to-treat group of isolates nonsusceptible to both levofloxacin and TMP-SMZ. These results are consistent with those of a recent study by Flamm et al., who reported that 64/69 (92.8%) TMP-SMZ-resistant S. maltophilia isolates (including 54/69 levofloxacin-NS isolates) were susceptible to minocycline (20). While rare in the clinical setting, we did identify three S. maltophilia isolates nonsusceptible to levofloxacin, minocycline, and TMP-SMZ, and no agent tested in this study was active against all three of these isolates.

Other notable findings from this work include the following. First, we observed an association between levofloxacin and/or TMP-SMZ resistance and decreased activity of other agents outside these two classes. For example, the MIC_50/MIC₉₀ of polymyxin B seemed to correlate with TMP-SMZ susceptibility. Against TMP-SMZ-susceptible isolates, the MIC_50/MIC₉₀ were 0.125/0.5 mg/liter, compared to 2/>8 mg/liter against TMP-SMZ-resistant isolates. Second, we observed a correlation between levofloxacin susceptibilities and the activities of the tetracyclines other than minocycline (eravacycline, omadacycline, and tigecycline) (Fig. 1). The MIC₅₀ and MIC₉₀ values for eravacycline, omadacycline, and tigecycline were consistently higher against levofloxacin-NS isolates than against those that were levofloxacin susceptible, irrespective of susceptibility to TMP-SMZ (data not shown). This correlation may be due to expression of the SmeDEF efflux pump, which is known to be associated with both levofloxacin and tigecycline susceptibilities in S. maltophilia (33). Third, we observed improved potency of moxifloxacin over levofloxacin and delafloxacin against all 41 isolates. Cumulatively, delafloxacin was the least active fluoroquinolone, while moxifloxacin demonstrated the lowest MIC_50/MIC₉₀. Although the improved potency of moxifloxacin has been previously reported (34–36), the most recent CLSI guidelines (37) continue to provide only interpretive criteria for levofloxacin against S. maltophilia despite its decreased activity and the overall lack of supporting clinical data for either agent. As discussed, many clinical microbiology laboratories do not routinely test susceptibility of S. maltophilia to agents other than those recommended by the CLSI, so the between-class associations observed in this study may be useful clinically in the absence of an MIC or approved interpretive criteria.

Strengths of this study include the use of clinical isolates from a wide geographic distribution and from many different infection types and acquisition settings. Importantly, no significant differences in MIC distributions were observed across these three strata, suggesting that these results are applicable regardless of patient- or location-specific factors. Bacterial isolates were specifically chosen by their phenotypic resistance to first-line agents to elucidate potential alternative treatment options, although this obviously enriched the sample with isolates outside the normal MIC distribution, which may not accurately reflect the activity of the antimicrobial agents tested in routine clinical practice (17, 38). A recent evaluation of 1,289 isolates of S. maltophilia collected in the United States via the SENTRY program from 2014 to 2018 demonstrated MIC₅₀, MIC₉₀, and percent susceptibility for levofloxacin and TMP-SMZ of 1 mg/liter, >4 mg/liter, and 75.8% and ≤0.5 mg/liter, 1 mg/liter, and 94.6%, respectively (20). Additional limitations include the number of isolates, lack of molecular analysis of all isolates, and exclusion of pipeline agents that may have activity against MDR S. maltophilia (e.g., cefiderocol and aztreonam-avibactam). Further studies evaluating the genotypic mechanisms of resistance among S. maltophilia, particularly to the tetracyclines, are needed in order to elucidate the within-class differences in phenotypes observed in this study. Finally, the susceptibility rates reported for agents without approved interpretive criteria for S. maltophilia (e.g., tigecycline and polymyxin B) should be interpreted with caution, as they may over- or undercall true resistance rates.

In summary, these data demonstrate how few antimicrobial agents, old or new, have reliable activity against S. maltophilia, particularly against strains resistant to one or both current first-line agents. Minocycline demonstrated the most reliable in vitro activity, and its role in the clinical arena for the treatment of infections due to S. maltophilia warrants further investigation given its favorable adverse event profile, minimal drug-drug interactions, extensive body site penetration, and the availability of both and intravenous (i.v.) and oral formulations.