Stenotrophomonas Infection in a Patient with Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is estimated to affect 400 million people and is the most common enzymatic defect in humans. It is more common in African, Asian, Mediterranean, and Middle Eastern countries but is increasing in number in other locations as migration occurs. The geographic rates of G6PD deficiency are similar to patterns of malaria and are thought to be protective against the tropical illness. It occurs more often in males as it is a recessive X-linked disorder.1 

G6PD converts nicotinamide adenine dinucleo-tide phosphate (NADP⁺) to its reduced form (NADPH) which is utilized to convert oxidized glutathione to its reduced form. This allows hydrogen peroxide to be converted to water, avoiding oxidative injury to cells (Figure).2 This pathway is most vital to erythrocytes, as it is the only means by which they can produce NADPH and protect against oxidative cell injury. Thus, the most common problem in patients with G6PD deficiency is hemolytic anemia. It is usually associated with an infection or oxidative medication such as primaquine or dapsone. Other medications including sulfamethoxazole and fluoroquinolones have been associated with hemolysis in G6PD-deficient patients.

Stenotrophomonas maltophilia is a Gram-negative multidrug resistant organism that is similar to Pseudomonas and was once referred to as Pseudomonas maltophilia. It is a waterborne organism that can be found in numerous sources in the environment, including soil, rivers, and lakes. This organism is not highly virulent and is usually associated with respiratory infections. Sulfamethoxazole and fluoroquinolones are the first-line agents used for treatment of infections by these organisms.3 ,S maltophilia infection rates are increasing, especially, in immunocompromised patients. An associated mortality rate of up to 37.5% has been reported in the literature.4 Antimicrobial selection is limited because of the presence of multidrug resistant efflux pumps and low membrane permeability for beta-lactams.5 

Presented here is a patient with a history of G6PD deficiency who developed S maltophilia tracheitis. Currently, there is no known literature regarding treatment of S maltophilia infection in patients with G6PD deficiency. To our knowledge, this is the first case report of a patient with G6PD deficiency treated for S maltophilia tracheitis. Our experience may provide other practitioners with a possible therapy should a similar case present itself. This report was exempt from Institutional Review Board approval.

A 12-year-old African-American male patient with a history of congenital cytomegalovirus infection, microcephaly, cerebral palsy, developmental delay, seizure disorder, factor VII deficiency, tracheostomy, and G6PD deficiency was admitted to the hospital for long-term access placement. On the day of discharge, the patient began to have fever. Tracheal aspirate cultures were obtained, empirical treatment with cefdinir was started, and the patient was discharged. The white blood cell count on the previous day was 14.6 thousands per microliter. Previous cultures had shown the patient to be colonized with Pseudomonas aeruginosa. The new sputum culture grew P aeruginosa and S maltophilia. Despite treatment with cefdinir, the family reported the patient continued with fever and symptoms resembling respiratory distress. The outpatient clinic preferred to start the patient on oral antibiotics to avoid hospitalization. When a treatment plan was formulated, the decision was made to focus therapy on S maltophilia as the primary organism. The patient had multiple cultures previously positive for P aeruginosa, and the physician felt that it was a colonization and was not responsible for the patient's current symptoms. Because of the patient's G6PD deficiency, the standard first-line agent, sulfamethoxazole/trimethoprim, and second-line agent, a fluoroquinolone, for S maltophilia treatment were not options.

The patient was started on oral doxycycline, 100 mg twice daily, and nebulized colistimethate, 75 mg twice daily, for 10 days to treat the S maltophilia infection. The original culture was tested for response to ticarcillin/clavulanic acid as a possible alternative antibiotic. The organism was shown to be resistant to ticarcillin/clavulanic acid, and a minimum inhibitory concentration was not provided. Susceptibility to other antimicrobials was not conducted. A culture repeated 17 days after the initial culture was negative for S maltophilia. The patient's fever and respiratory symptoms resolved. Sputum cultures remained negative for S maltophilia for over 1 year (Table).

In this case report, a patient with G6PD deficiency that developed a possible S maltophilia tracheitis requiring therapy is presented. Upon review of the literature, the authors were unable to find examples of a similar case. Treatment of bacterial tracheitis consists of maintenance of the airway, antimicrobial therapy, and fluid resuscitation, if necessary. Tracheitis can be a serious illness that can require hospitalization and possible intubation even in a patient without complex medical history.6 Symptoms include fever, increased white blood cell count, and inflammation or irritation of the trachea. In this particular case, airway maintenance was already in place as the patient had had a tracheostomy. Other treatments might have included anti-inflammatory agents to decrease swelling and inflammation. However, treating tracheitis with glucocorticoids has not been found to provide additional benefit.7 Antibiotic therapy was the important factor in this case because of the S maltophilia that was cultured and the patient's other disease states.

It was decided to treat this patient's S maltophilia organism-infected respiratory culture given his fever and respiratory distress. Bacterial tracheitis may have varied presentations and organisms.8 Difficulty arises in therapeutic management of tracheitis, as organisms isolated from the tracheal aspirate may not be the causative organism of infection. In this case, the patient had had multiple previous positive respiratory cultures for P aeruginosa. S maltophilia was an organism newly found in this patient's tracheal aspirate. The culture had many colonies of S maltophilia, and the patient was clinically deteriorating. With the information available, the decision was made to treat the S maltophilia infection with appropriate antimicrobial therapy.

Sulfamethoxazole/trimethoprim is the drug of choice for treatment of S maltophilia infection. However, this drug should be avoided in patients with G6PD deficiency.9 Fluoroquinolones may be considered second-line therapy for S maltophilia infections. Nalidixic acid is an older quinolone that has been shown to cause hemolytic anemia in patients with G6PD deficiency.3 International medication guides for fluoroquinolones have a warning to avoid their use in patients with G6PD deficiency. In addition, a few cases of hemolytic anemia associated with fluoroquinolones have been reported.10,11 Due to the lack of evidence of hemolytic anemia with the newer quinolones, some authors suggest that these agents may still be used in this patient population.3 Because the patient was to undergo outpatient therapy, he would not be able to be monitored for hemolytic anemia associated with fluoroquinolone therapy. Therefore, it was decided to avoid using this class of medication in the outpatient setting.

Data have suggested that other treatment options can include doxycycline. Doxycycline has been shown to be an acceptable agent in vitro for third-line treatment of S maltophilia infection. An article by Valdezate et al12 compared resistance rates of various antimicrobials in 99 strains of S maltophilia at their institution. Doxycycline had a 1% rate of resistance compared to a 27.3% rate of resistance for sulfamethoxazole/trimethoprim and an approximate resistance rate of 50% for ticarcillin/clavulanic acid. In another article comparing S maltophilia isolates from patients with cystic fibrosis and those without, resistance rates for doxycycline were documented at 6.4% (n=47) and 0% (n=51), respectively.13 

Colistimethate has limited evidence for use in S maltophilia infections. In a recent case series, Iosifidis et al14 reported their results with use of intravenous colistimethate in several pediatric patients. Two patients had S maltophilia susceptible to colistimethate. In addition to colistimethate, both patients were taking several other antibiotic therapies. Both patients survived despite the serious nature of their infections. A recent article described a patient who had previously received courses of sulfamethoxazole/trimethoprim and fluoroquinolones. The patient developed ciprofloxacin-resistant S maltophilia, and a course of sulfamethoxazole/trimethoprim failed. The authors proceeded to treat the S maltophilia infection with intravenous doxycycline and inhaled colistimethate. The patient improved clinically over the course of therapy and was eventually discharged.15 Due to the successful treatment of this patient and the other literature reviewed, doxycycline and inhaled colistimethate were chosen.

Doxycycline is not recommended for patients younger than 8 years of age. Other therapy options would need to be pursued in those children who have G6PD deficiency and a S maltophilia infection. Ticarcillin/clavulanic acid may be an option in these very young patients. S maltophilia has been reported to be susceptible to ticarcillin/clavulanic acid in 18.6% to 55.7% of cases.16,17 Because of these low numbers, susceptibility would need to be determined prior to recommending ticarcillin/clavulanic acid.

Sulfamethoxazole/trimethoprim remains the standard of care for treatment of S maltophilia infection. Patients may have other medical conditions, such as G6PD deficiency, that increase the risk of injury if this therapy is used. Having knowledge of alternative regimens is useful to the clinician. This particular regimen is beneficial because it can be used on an outpatient basis.

In this case, S maltophilia infection was successfully treated with doxycycline and inhaled colistimethate in a patient with G6PD deficiency. After a thorough review of the literature, no other similar cases were found. Based on the patient's age, what is known about the disease state, and other case reports of S maltophilia infection treatment, this therapy was chosen. We also recommended inhaled colistimethate as a duplicate therapy in an effort to eradicate the organism. The patient's cultures remained negative for S maltophilia after combination treatment with doxycycline and inhaled colistimethate. This case report may provide a point of reference for practitioners caring for a similar patient.

ADP

adenosine diphosphate

ATP

adenosine triphosphate

G6PD

glucose-6-phosphate dehydrogenase

GSSG

oxidized glutathione

GSH

reduced glutathione

H₂O₂

hydrogen peroxide

H₂O

water

NADP⁺

nicotinamide adenine dinucleotide phosphate

NADPH

reduced nicotinamide adenine dinucleotide phosphate