Stenotrophomonas maltophilia
Authors: W.J. Looney, CSci FIBMS, Masashi Narita, M.D., Prof. Kathrin Mühlemann, MD PhD, Amjad Shidyak, M.D.
Microbiology
Stenotrophomonas maltophilia is a motile non-fermentative, gram negative bacillus that is readily isolated from environmental sources and water. It is an obligate aerobe, and is capable of growth between 5o and 40oC (18). S. maltophilia isolates from environmental and clinical sources represent a number of genomic groups, which may possibly be of clinical significance, although this remains to be established (13, 35, 37).
Epidemiology
S. maltophilia is widely distributed in natural and man-made environments, and can survive in chlorinated water distribution networks (38). Infection presumably results from human acquisition of environmental organisms, although in most instances the source of the organisms is not precisely known. Contamination of wounds with soil may lead to soft tissue infection (1). In developed countries, most recognized infections are nosocomial. The source and mode of transmission of the organism is often uncertain. In a number of hospitals with endemic or epidemic S. maltophiliainfection, multiple genetically distinct strains have been isolated from patients (6, 87). However, common source nosocomial outbreaks have resulted from contamination of medical equipment or hospital water systems (26, 96).
Clinical Manifestations
Most human isolates represent colonization rather than infection; it is, however, an opportunistic pathogen in highly debilitated patients (9, 42, 52, 92, 103). Patients at highest risk include those with underlying malignancy, neutropenia, chemotherapy, presence of an indwelling central catheter, and prior antimicrobial therapy. The major clinical syndromes are pneumonia and bacteremia; in bacteremia the portal of entry is typically a vascular catheter, or is unknown (2, 21, 28, 32, 44, 57, 63, 97, 103). Other reported clinical syndromes include urinary tract infection (89), soft tissue infection (1, 90), ocular infection (10, 41), endocarditis (36, 58), and meningitis (58, 61, 66).
Laboratory Diagnosis
Culture from normally sterile body sites is straightforward, and bacteremia and septicemia can be detected using standard blood-culture techniques (51). Selective media can improve culture sensitivity for specimens from non-sterile body sites, such as respiratory secretion from patients with cystic fibrosis (CF) (27). Isolation of the organism from normally sterile sites such as blood, pleural fluid or cerebrospinal fluid is indicative of infection. Isolation from non sterile sites such as sputum or wounds often represents colonization rather than infection. Differentiation of infection from colonization based on clinical criteria may be problematic.
Pathogenesis
S. maltophilia is not highly virulent, nevertheless several factors may promote its ability to colonize the respiratory tract and plastic surfaces, such as catheters and endotracheal tubes. These include a positively charged surface as well as flagella and fimbrial adhesion, the latter have been associated with biofilm formation (16, 17, 40, 95). The outer membrane lipopolysaccharide (LPS) plays a role in colonization and resistance to complement-mediated cell killing, and its lipid A moiety can stimulate peripheral blood monocytes and alveolar macrophages to produce TNFα, which plays a role in the pathogenesis of airway inflammation (53, 91, 95). S. maltophilia produces a number of extracellular enzymes, (18) whose contribution to virulence is currently uncertain (99).
SUSCEPTIBILITY IN VITRO AND IN VIVO
In Vitro and In Vivo
In vitro susceptibility testing of S. maltophilia poses numerous technical problems, however, the Clinical Laboratory Standards Institute (CLSI) and the British Society for Antimicrobial Chemotherapy (BSAC) have each published standard methods for the susceptibility testing of S. maltophilia (4, 12). The methods cover a limited range of antibiotics and are not interchangeable as they vary in numerous details. In-vitro synergy testing, sometimes used for particularly problematic cases, has indicated synergy between certain antibiotic combinations when tested against S. maltophilia (75, 78). The different kinds of synergy tests may either give the same or differing results when testing the same strain-antibiotic combinations, and this should be taken into consideration when interpreting the results (15, 69, 93).
Table 1 shows the in vitro susceptibility of S. maltophilia to selected antibiotics, the data being drawn from published studies.
In most reports, over 90% of strains are susceptible to trimethoprim-sulfamethoxazole (7, 24, 29, 57). A recent report from a major oncology centre found that only 75% of strains were susceptible (88). In two series reporting episodes of bacteremia from Taiwan, 60%-76% of strains were susceptible to trimethoprim-sulfamethoxazole (46, 94). The highest rate of trimethoprim-sulfamethoxazole resistance, 84% occurred in a study of S. maltophilia isolated from the sputum of patients with cystic fibrosis (78). Thus, susceptibility to trimethoprim sulfamethoxazole should not be assumed. Most isolates are susceptible in vitro to minocycline.
The majority of clinical isolates of S. maltophilia infections are resistant to multiple agents used to treat gram-negative infections. Resistance to beta-lactam antibiotics is mediated by two unique, inducible beta-lactamases, a zinc-containing penicillinase (77) and a cephalosporinase (76). Some isolates appear to produce additional beta-lactamases as well (67). A TEM-2 beta lactamase has been identified within a transposon in the genome of a clinical isolate of S. maltophilia (5). As a consequence, many strains are resistant to extended spectrum penicillins and third generation cephalosporins; nearly all strains are resistant to imipenem and meropenem (43, 60, 65). The majority of strains are susceptible to the combination of ticarcillin and the beta-lactamase inhibitor clavulanic acid in vitro; however, the degree of growth inhibition is dependent on testing conditions (60, 65). In a murine model of S. maltophilia pneumonia, the efficacy of ticarcillin/clavulanate acid was similar to that of trimethoprim-sulfamethoxazole (71). Piperacillin/tazobactam is less active in vitro; the majority of strains are resistant (22, 85). Ampicillin/sulbactam is generally inactive. Most strains are resistant to aztreonam (7).
The majority of strains are resistant to aminoglycosides. Three different mechanisms have been described so far: aminoglycoside-modifying enzymes, efflux pumps and outer-membrane permeability changes (48, 50, 53, 64). S. maltophilia strains are variably susceptible to fluoroquinolones such as ciprofloxacin and ofloxacin. Newer quinolones, such as moxifloxacin, clinafloxacin and gatifloxacin are significantly more active in vitro than the previously available members of the class (70, 85, 98). Emergence of resistance during quinolone therapy by an initially susceptible strain has been reported (11). Spontaneous mutants that are resistant to multiple quinolones occur at a frequency of 10-5 to 10-7 (49); exposure to a quinolone may result in selection of the resistant clone.
Combinations of Antimicrobials
The use of two or three antimicrobials to treat S. maltophilia infection has become established practice, although there are no clinical trials to support this approach. This strategy is, however, supported by in vitro synergy testing (101). Given the lack of clinical trials, caution must be exercised when attempting to extrapolate in vitro synergy testing into clinical practice. Synergistic bacterial killing occurs in vitro with ticarcillin/clavulanate plus trimethoprim/ sulfamethoxazole whether or not the isolates are susceptible to either of the two combination agents (69). In vitro synergy has also been reported for trimethoprim/sulfamethoxazole combined with ceftazidime, ciprofloxacin, gentamicin, and tobramycin (101) when the strain tested was susceptible to trimethoprim/sulfamethoxazole and susceptible or intermediately susceptible to the second agent. Synergy may also occur with either ticarcillin/clavulanate or ceftazidime plus ciprofloxacin for strains with a ciprofloxacin MIC < 32 ug/ml (69). Although most strains are resistant to aztreonam, the combination of aztreonam and clavulanate in a fixed 2:1 ratio shows synergistic activity (33). The addition of aztrenonam to ticarcillin/clavulanate reportedly increases the activity of the latter combination up to 128-fold, with synergy demonstrated by time-kill curves for the majority of isolates tested (45). These reports of synergy are based on a limited number of strains.
ANTIMICROBIAL THERAPY
Drug of Choice
There are no controlled trials of therapy of S. maltophilia infection in humans. Therapy should be guided by the results of in vitro susceptibility testing (see above section). Trimethoprim-sulfamethoxazole should be considered the primary therapeutic agent for susceptible strains (57).
Combination therapy is warranted in life-threatening infections including bacteremia and pneumonia (see below). In a large case series (57) bacteraemic patients who received at least two agents including trimethoprim-sulfamethoxazole, an extended spectrum penicillin or a third generation cephalosporin had a significantly lower mortality (11%) than patients who received only one of these agents (31%) or other therapies (55%).
Neutropenic patients, and those with bacteremia or pneumonia should be treated with combination antimicrobial therapy. The combination of trimethoprim/sulfamethoxazole (10 mg/kg/day) and ticarcillin/clavulanate may have synergistic bactericidal activity even if the isolate is resistant to one or both agents. Other potential combinations include trimethoprim/sulfamethoxozole and ceftazidime if the isolate is susceptible to ceftazidime. For patients allergic to trimethoprim/ sulfamethoxazole, a newer quinolone such as moxifloxacin or gatifloxacin combined with one of the aforementioned beta-lactam agents is a reasonable alternative.
Recommended dosages for specific agents are given in Table 2.
Specific Infections
Bacteremia
Most bacteremic patients have serious underlying conditions including malignancy, immunosuppression, or neutropenia. Bacteremic patients should be treated with combination antimicrobial therapy (see above). Most bacteremias are associated with indwelling central venous catheters; removal of an infected catheter is a key component of successful treatment (21, 79). Bacteremia was polymicrobial in a variable proportion of cases in reported series; antimicrobial therapy should also be directed at concomitant blood isolates.
Respiratory Infection
Pulmonary infection occurs primarily in patients with malignancy or in those receiving mechanical ventilation. Patients rendered profoundly neutropenic after intensive chemotherapy for leukemia may develop fulminant pneumonia culminating in fatal pulmonary hemorrhage (20, 72). Combination antimicrobial therapy is warranted.
Meningitis
S. maltophilia meningitis may occur in infants, or as a complication of neurosurgical procedures (61, 66).Trimethoprim-sulfamethoxazole penetrates well into the cerebrospinal fluid; a limited number of cases have been treated with bacteriologic cure (58, 61, 66). One case of post-operative meningitis was cured following a three week course of ciprofloxacin (34). Intraventricular drains associated with infection should be removed if possible.
Endocarditis
S. maltophilia endocarditis occurs in the setting of intravenous drug abuse or following valve replacement surgery (36, 39, 54, 58, 59). Complications such as valve ring abscesses and emboli are frequent; therefore; in addition to combination antimicrobial therapy, early valve replacement is often indicated.
Ocular Infections
External infections such as keratitis and conjunctivitis predominate, although orbital cellulitis and endopthalmitis may occur (68). Most infections are preceded by surgery, corneal inflammation, or prosthetic devices including soft contact lenses. Treatment is limited by the organism's resistance to available ophthalmic antimicrobial preparations including aminoglycosides and quinolones. Keratitis may result from wearing of contact lenses or from corneal surgery. Topical therapy with an agent to which the isolate is susceptible is indicated. Topical quinolones have been effective (25); ciprofloxacin and ofloxacin are readily available as ophthalmic preparations. Treatment with alternative agents, for example, ceftazidime, may require compounding of an ophthalmic preparation from an intravenous preparation by the pharmacy.
Endopthalmitis following cataract extraction was successfully treated by vitrectomy, intravitreal injection of ceftazidime and gentimicin, topical application of polymixin, trimethoprim, and ciprofloxacin, and oral administration of Trimethoprim-sulfamethoxazole and ciprofloxacin (41). Endopthalmitis after implantation of a sustained-release ganciclovir failed to respond to vitrectomy, removal of the capsule, intravitreal injection of amikacin, ciprofloxacin, and ceftazidime, along with systemic administration of ceftazidime (10). It would appear from the limited number of reports that vitrectomy coupled with intravitreal and systemic administration of 2 or more agents with activity against the infecting isolate may result in bacteriologic cure and salvage of vision in cases of S. maltophilia endophthalmitis.
Skin and Soft Tissue Infection
S. maltophilia is an occasional pathogen in wounds contaminated with soil or occurring due to farm machinery related accidents (1, 14). Reported cases have responded to debridement and administration of Trimethoprim-sulfamethoxazole
Soft tissue infection may occur in the course of systemic S. maltophilia infection in neutropenic patients. Reported syndromes include cellulitis, multiple subcutaneous nodules, ecthyma gangrenosa, mucous membrane ulcerations, necrotizing gingivitis, and myositis (19, 55, 56, 90). Treatment appropriate for infection in neutropenic patients with combination therapy is indicated.
Peritonitis (Dialysis-Related)
S. maltophilia is an occasional cause of peritonitis complicating chronic peritoneal dialysis (3, 80). Combination antimicrobial therapy and removal of the dialysis catheter are usually necessary for cure. Immediate replacement of the catheter has resulted in therapeutic failure in the majority of the reported cases. Catheter removal with a temporary period of hemodialysis and completion of a course of antimicrobial therapy was required before re-insertion of a peritoneal catheter and resumption of peritoneal dialysis. There are reports of successful treatment of peritonitis without catheter removal (83). In these cases, there was no clinical evidence of inflammation at the catheter site. Patient initially received a 15 day course of intravenous trimethoprim/sulfamethoxazole with or without additional antimicrobial agents, which included intravenous ciprofloxacin, intraperitoneal ceftazidime, or intraperitoneal amikacin. This was followed by one month of therapy with oral trimethoprim/sulfamethoxazole.
Underlying Diseases
Neutropenia
Any clinical infection in a neutropenic patient should be treated with combination antimicrobial therapy.
Cystic Fibrosis
Approximately 10% of patients with cystic fibrosis have sputum colonized with S. maltophilia (8). These patients may be transiently or persistently colonized with S. maltophilia; persistent colonization is more likely among older patients aged 16 and older (86). The relationship between colonization and clinical deterioration in cystic brosis patients is unclear; there is no evidence that treating asymptomatic colonization is beneficial. S. maltophiliapneumonia in a cystic fibrosis patient should be treated with combination antimicrobial therapy.
Alternative Agents
Some authors recommend the addition of rifampin (100) or minocycline (88) as to the combination of trimethoprim/sulfamethoxazole and a beta-lactam agent. Fluoroquinolones are variably active against S. maltophilia, and may be an appropriate alternative to trimethoprim/sulfametholxazole in a combination regimen with a beta-lactam agent. Although there is little information regarding synergy between the newer quinolones, such as moxifloxacin, and gatifloxacin, and beta-lacatams against S. maltophilia, these agents are substantially more active against most strains than is ciprofloxacin, and may be preferable as one component of combination therapy. Fluoroquinolones should not be used as single agent therapy. Although the frequency of this phenomenon is uncertain, emergence of quinolone resistance during therapy has been reported (11). Synergy between ciprofloxacin and beta-lactam agents appears to be unlikely if the isolate has a ciprofloxacin MIC > 32 ug/ml. It is not clear if this is the case with the newer quinolones, but MIC’s to these agents are typically < 4 ug/ml. The combination of chloramphenicol and ciprofloxacin was clinically effective in a case of prosthetic valve endocarditis, with sterilization of blood cultures after 1 week of therapy (54). The combination of aztreonam and ticarcillin/clavulanate is highly active in an animal model; clinical experience is extremely limited.
ADJUNCTIVE THERAPY
Removal of foreign bodies associated with infection, including intravascular catheters, peritoneal dialysis catheters and intraventricular drains is usually necessary. Early valve replacement should be a consideration in prosthetic valve endocarditis.
ENDPOINTS FOR MONITORING THERAPY
In bacteremic patients, failure to clear the bacteremia should prompt consideration of an intravascular focus of infection, including an infected vascular catheter, septic thrombophlebitis, or endocarditis. Neutropenic patients may not clear bacteremia until the neutrophil count recovers.
VACCINES
No vaccine is available.
PREVENTION AND INFECTION CONTROL MEASURES
The ultimate source of the infecting strains is often uncertain. S. maltophilia is a common environmental contaminant. As noted, however, multiple strains are often in circulation at any one time in a hospital unit; these strains may not match those isolated from recognized environmental sources, including tap water. Surveillance of potable water or other environmental sources, with subsequent decontamination remains to be studied. If an environmental source, such as a contaminated medical device, can be identified, then this source should be removed. Prior broad spectrum antimicrobial therapy is a major risk factor for S. maltophilia infection. Reduction in unnecessary antimicrobial therapy should lead to a reduction in the incidence of S. maltophilia infection.
CAVEATS
There are no controlled trials of therapy for this bacterium. All of the recommendations contained herein are based on the results of in vitro susceptibility and synergy studies, animal studies, case series, and anecdotal reports.
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Tables
Table 1: In vitro Susceptibility of S. maltophilia to Selected Antibiotics
| Antibiotic | MIC50 mg/ml
(range) |
MIC90 mg/ml
(range) |
% of strains susceptible* | % of strains resistant* | No. of strains tested† | References
|
|---|---|---|---|---|---|---|
| TMP-SMZ | 0·25 to >64‡ | 0·25 to >64 | 0 to 100§ | 4 to 100 | 3872 | 82, 23, 47, 94, 78, 75, 7, 98, 74, 88, 102, 85, 62 |
| Ticarcillin | 16 to 512 | 64 to >1024 | 29 to 69 | 32 to 74 | 329 | 47, 7, 85 |
| TIM | 2 to 128 | 32 to >1024 | 27 to 95 | 14 to 50 | 3764 | 82, 23, 47, 94, 78, 75, 7, 81, 74, 88, 85, 62 |
| Cefepime | 16 to 64 | >16 to ≥128 | 0 to 30 | 45 to 100 | 2508 | 23, 94, 7, 74, 102, 85 |
| Cefotaxime | 60 to ≥64 | ≥64 to 512 | 10 | 62 to 64 | 249 | 7, 85 |
| Ceftazidime | 8 to 128 | >16 to 256 | 5 to 53 | 34 to 86 | 2649 | 82, 23, 47, 94, 7, 74, 88, 85 |
| Ceftriaxone | >32 to 256 | >32 to >256 | 1 to 2 | 92 to 96 | 2184 | 74, 102 |
| Aztreonam | >16 to 256 | >16 to >1024 | 0 to 10 | 85 to 100 | 2347 | 94, 7, 74, 85 |
| Norfloxacin | 16 to ≥16 | ≥16 to 64 | 20 | 56 | 358 | 7, 85, 84 |
| Ofloxacin | 0·5 to 0·5 | 4 to 4 | 89 | 5 | 208 | 85, 84 |
| Ciprofloxacin | 0·25 to >8 | 2 to 32 | 0 to 82 | 13 to 96 | 3865 | 82, 23, 47, 94, 78, 7, 98, 74, 88, 102, 85, 84 |
| Gatifloxacin | 0·1 to 4 | 0·12 to 16 | 23 to 97 | 0 to 46 | 2642 | 23, 94, 98, 74, 85, 62 |
| Levofloxacin | 0·2 to 2 | 2 to 8 | 55 to 86 | 3 to 11 | 2631 | 94, 98, 74, 102, 85 |
| Moxifloxacin | 0·06 to 0·5 | 0·5 to 4 | 85 | 6 | 1405 | 30, 98, 102, 85, 84 |
| Doxycycline | 1 to 2 | 2 to 8 | 80 to 100 | 1 to 11 | 968 | 47, 78, 75, 85, 62 |
| Minocycline | 0·2 to 1 | 1 to 4 | 91 to 100 | 0 to 5 | 1014 | 94, 30, 88, 85 |
| Tetracycline | >8 to 32 | >8 to 64 | 8 to 9 | 70 to 86 | 2325 | 7, 74, 85 |
| Tigecycline | 1 to 1 | 2 to 4 | 90 | 3 | 239 | 102, 73 |
| Polymixin B | 1 to 2 | 4 to 8 | 72 to 77 | 28 | 1322 | 62, 31 |
| Chloramphenicol | 4 to 32 | 16 to 64 | 1 to 80 | 35 to 39 | 395 | 47, 7, 85, 62 |
| Amikacin | >32 to 512 | >32 to >512 | 0 to 31 | 61 to 100 | 2535 | 47, 94, 7, 74, 102, 85 |
| Gentamicin | >8 to 64 | >8 to >256 | 14 to 31 | 58 to 81 | 2433 | 7, 74, 102, 85 |
| Tobramycin | ≥16 to 64 | ≥16 to 512 | 2 to 25 | 68 to 78 | 2405 | 47, 7, 74, 85 |
| Imipenem | >8 to 512 | >8 to >1024 | 0 to 2 | 97 to 100 | 3261 | 23, 47, 78, 7, 74, 88, 85 |
| Meropenem | >8 to >64 | >8 to 256 | 0 to 4 | 88 to 100 | 2433 | 7, 74, 102, 85 |
Table 2. Antimicrobial Agents Used in Treatment of S. maltophilia Infections.
| Drug | Dose |
|---|---|
| Trimethoprim/sulfamethoxazole | 15mg/kg/day divided in 2 to 3 doses |
| Ticarcillin/clavulanate | 3.1 g q6h IV |
| Ceftazidime | 2 gm q8h IV |
| Ciprofloxacin | 400 mg q12h IV |
| Levofloxacin | 500-750 mg q24h IV |
| Moxifloxacin | 1 x 400mg/day |
| Doxycycline | 100 mg q12h IV |
Dosages for adults with normal renal function and weight about 70 kg.
What's New
Betts JW, et al. Activity of colistin in combination with tigecycline or rifampicin against multidrug-resistant Stenotrophomonas maltophilia. Eur J Clin Microbiol Infect Dis 2014;33:1565-1572.
Wang YL. Monotherapy with Fluoroquinolone or Trimethoprim-Sulfamethoxazole for Treatment of Stenotrophomonas maltophilia infections. Antimicrob Agents Chemother 2014;58:176-182.
Huang CR, et al. Clinical characteristics of Stentrophomonas maltophilia meningitis in adults: A high incidence in patients with a postneurosurgical state, long hospital staying and antibiotic use. Clin Neurol Neurosurg 2013 [Epub ahead of publication].
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Reviews
Brooke JS. Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen. Clin Microbiol Rev 2015;25:2-41.
Baron EJ. Flow Diagram for Gram Neg Rods on BAP & MacConkey (NOT for stool isolates)
Javey G, Zuravleff J. Retinitis and Endophthalmitis.
Raad, I., Hanna, H. and Maki, D. Intravascular Catheter-related Infections: Advances in Diagnosis, Prevention and Management. The LANCET Infectious Diseases 2007; Vol.7, Issue 10, 645-657.