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Introduction

Stenotrophomonas maltophilia (S. maltophilia) is a glucose non-fermenting, aerobic, Gram-negative bacillus that is ubiquitously found in aquatic environments and soil (1). Although it is considered a low virulence pathogen, it is increasingly recognised as a main cause of nosocomial infections (2,3).

S. maltophilia, due to his high virulence determinants, including biofilm production, can cause various type of infections, such as skin manifestations and bacteraemia (1), mainly those involving the respiratory tract (4). Major concerns particularly involve vulnerable hosts, such as patients in intensive care units (ICUs) or patients with cystic fibrosis, haematological malignancies, and other significant underlying illnesses (5,6). Moreover, its intrinsic multidrug resistance to several classes of antibiotics poses a major clinical and therapeutic challenge (7).

Historically, trimethoprim/sulfamethoxazole (TMP-SMX) has represented the drug of choice used in the treatment of S. maltophilia infections, playing a key role in antibiotic management. However, the emergence of TMP-SMX resistance has already been reported. Other treatment options may include minocycline, tigecycline, levofloxacin, cefiderocol and ceftazidime/avibactam plus aztreonam (8).

The differentiation between S. maltophilia infections and colonisation remains challenging, particularly in patients with ventilator devices (1,9). Over the past years, researchers have assessed S. maltophilia infections in ICUs, including bloodstream infections, skin and soft tissues infections, urinary tract infections and ventilator-associated pneumonia (VAP), reporting high mortality rates (5,10). Despite its undeniable clinical impact, solid data on S. maltophilia are limited compared with other Gram-negative bacteria (11). Moreover, S. maltophilia infections are often combined with other bacteria, rendering the clinical picture even more complex (1,11).

The present study, describes the case of a patient with VAP caused by S. maltophilia infection, highlighting the challenges in the management of this condition and the importance of prompt recognition and aggressive treatment. Furthermore, the present study highlights the need to consider alternative, effective antimicrobial agent in patients with VAP who are not responsive to broad-spectrum β-lactam antibiotics.

Case report

A 66-year-old male was admitted to the Emergency Department of ARNAS Garibaldi Hospital due to the onset of seizures along with a profoundly altered mental status and fever (maximum temperature, 38˚C). His medical history included type 2 diabetes mellitus, hypertension, benign prostatic hyperplasia, dyslipidaemia, and a history of smoking. The patient was taking ertugliflozin, ramipril, alfuzosin and atorvastatin.

Upon admission, the patient was transferred to the ICU and was intubated due to a severely impaired consciousness (Glasgow Coma Scale 8). A brain computed tomography (CT) scan did not reveal any abnormalities.

Lumbar puncture (LP) was performed and empirical antibiotic treatment with intravenous ceftriaxone, acyclovir, ampicillin, and dexamethasone was commenced. The examination of cerebrospinal fluid (CSF) revealed lymphocytic pleocytosis, normal glucose levels and a higher protein concentration. The analysis of CSF using the BIOFIRE® FILMARRAY® Meningitis/Encephalitis (ME) Panel (BioMérieux) yielded positive results for herpes simplex virus 1.

Therapy was continued only with acyclovir at 10 mg/kg three times. The CSF culture tested negative. His chest X-ray was negative (Fig. 1). The blood test results of the patient are presented in Table I.

Figure 1 X-ray image of the patient upon admission.

Table I Laboratory findings at the time of admission, at the time of VAP diagnosis and following treatment.

Table I

Laboratory findings at the time of admission, at the time of VAP diagnosis and following treatment.

Laboratory parameters (reference range)	At the time of admission	At the time of VAP diagnosis	Following treatment for VAP
WBC, cells/mmc (4,000-10,000)	10,330	15,100	7,200
Neutrophils, % (40-75)	73	85.6	57.3
Lymphocytes, % (25-50)	18.3	7.4	30.4
Monocytes, % (2-10)	8.8	6.3	9.8
Platelets, cells/mmc x103 (150-400)	150	123	309
Haemoglobin, g/dl (12-16)	13.1	12.6	12.4
AST, UI/l (15-35)	19	17	23
ALT, UI/l (15-35)	24	20	32
Creatinine, mg/dl (0.8-1.2)	0.59	0.44	0.47
Procalcitonin, ng/ml (<0.5)	0.04	0.04	0.01
CRP, mg/dl (0-0.5)	0.5	10.5	0.07

[i] VAP, ventilator-associated pneumonia; WBC, white blood cell count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein.

Despite an initial improvement, 3 days following ICU admission and endotracheal intubation, the patient's clinical condition began to deteriorate, along with worsened respiratory parameters and blood test results (Table I). A chest-CT scan (SOMATOM Definition Flash, Siemens) revealed bilateral basal consolidative opacities, along with bilateral pleural effusion (Fig. 2A).

Figure 2 (A) Chest CT scan of the patient at the time of the diagnosis of ventilator-associated pneumonia. Blue stars indicate bilateral basal opacities with pleural effusion. (B) Chest CT scan following treatment with antibiotics. CT, computed tomography.

Due to the diagnosis of VAP, antibiotic therapy was empirically switched to intravenous meropenem at 1 g three times daily plus intravenous linezolid at 600 mg twice daily. Legionella and pneumococcal urinary antigens tested negative, as well as a nasopharyngeal swab for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The analysis of bronchoalveolar lavage (BAL) using the BIOFIRE® FILMARRAY® Pneumonia Panel (PN) (BioFire Diagnostics) tested positive for Pseudomonas aeruginosa (P. aeruginosa).

At 2 days after switching the therapy, the BAL culture tested positive for S. maltophilia on a blood agar plate (Vacutest Kima S.R.L.) (Fig. 3) with a total bacterial count of 105 CFU/ml performed diluting the BAL sample at 1:100 in sterile saline and plating 100 µl on Muheller Hintong agar (Vacutest Kima S.R.L.). Species identification was assessed using the BD Phoenix system, selecting a colony from the blood agar, and the antibiotic susceptibility test performed using the MIC test strip (Liofilchem) revealed susceptibility to TMP-SMX at an increased exposure [MIC 2 mg/l; according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), breakpoints are expressed as the trimethoprim concentration]; hence intravenous TMP-SMX at 12 mg/kg (dosing was based on the TMP component) was commenced, while linezolid treatment was terminated.

Figure 3 Stenotrophomonas maltophilia colonies on a blood agar plate.

At 4 days after the addition of TMP-SMX to the treatment schedule, the patient was extubated due to an amelioration in respiratory function and improved blood tests (Table I). The patient's mental status also improved, with no evidence of neurological deficits. The restored consciousness, along with a follow-up brain magnetic resonance imaging (Magneton, Siemens) not revealing any abnormalities, allowed for the discontinuation of acyclovir administration after 17 days of therapy. Furthermore, due to the resolution of consolidative opacities on a follow-up chest CT scan (Fig. 2B) along with a good general state, the antibiotic therapy with meropenem (14 days of therapy) and TMP-SMX (11 days of therapy) was terminated. Finally, the patient was discharged 7 days after the end of therapy, with no evidence of respiratory or neurological sequelae (Fig. 4).

Figure 4 Clinical and therapeutic management timeline. Blue squares represent clinical assessment, pink squares represent microbiological results and green squares represent therapeutic management. LP, lumbar puncture; HSV, herpes simplex virus; VAP, ventilator-associated pneumonia; BAL, bronchoalveolar lavage; TMP, trimethoprim; STX, sulfamethoxazole.

Discussion

Gram-negative drug-resistant bacteria pose a major threat to physicians due to the increasing incidence of multi-drug resistant (MDR) infections worldwide (12-14), particularly among hospitalised patients (15,16). VAP is a type of pneumonia that occurs >48 h following intubation and is influenced by factors, such as immunosuppression, a long duration of hospitalisation, and prolonged ventilation (17,18).

The SARS-CoV-2 pandemic (19) may have contributed to an increase the number of cases with VAP, due to the large number of affected patients requiring ICU care and mechanical ventilation (20).

Gram-negative bacilli are the most commonly identified causative agents of VAP, with P. aeruginosa, Enterobacter spp. and Klebsiella spp. being the most prevalent (21,22). MDR Gram-negative infections result in poor outcomes of patients with hospital-acquired pneumonia/VAP and their increasing prevalence makes it crucial for management to consider the local ecology and patient risk factors (15,23). The identification of causative agents of VAP also needs to be a priority, due to the complexity of clinical and therapeutic management (17).

In the case described herein, the patient developed VAP due to S. maltophilia infection at 3 days after hospital admission. The categorisation of early- and late-onset VAP, of which late-onset VAP is more likely to be due to a MDR pathogen, is being challenged, as the timing of VAP development needs to be evaluated in the context of other risk factors (24,25).

Although often considered a colonizing pathogen, S. maltophilia, an ubiquitous, motile, free-living, aerobic, non-fermenting bacillus, multidrug-resistant Gram-negative bacterium (1), represents the causative agent of various infections, from skin manifestations to bacteraemia (26), particularly in patients with underlying illnesses (6). Recent research has reported that S. maltophilia-associated pneumonia is increasingly being isolated, describing this pathogen as one of the most common infectious agents in patients in ICUs, with a high morbidity and mortality rates. Risk factors for S. maltophilia-associated pulmonary diseases include ICU admission and mechanical ventilation, as well as prior broad-spectrum antibiotic therapy, prolonged hospitalization, and immunosuppression (27).

As patients with respiratory tract infections sustained by S. maltophilia are usually severely ill and hospitalised, and due to the drug-resistant profile of this bacteria, these conditions often lead to an increase in medical expenses, prolonged durations of hospitalisation and higher mortality rates. Therefore, identifying the right early targeted treatment is the key to reducing the mortality rates associated with S. maltophilia infection. A previously published meta-analysis demonstrated that previous carbapenem treatment was associated with lower respiratory tract infections by S. maltophilia with the highest odd ratio (OR, 3.69), followed by glycopeptide drugs (OR, 3.22), aminoglycoside drugs (OR, 2.57) and β-lactamase inhibitors (OR, 1.76) (28). That study suggested that when the clinical use of this type of drug is not effective, attention should be paid to the possibility of S. maltophilia infection; furthermore it was stated that more types of antibiotics, longer treatment durations and a greater number replacements can significantly increase the risk of respiratory tract infections caused by this bacterium (28).

These data may be explained by S. maltophilia features resulting in intrinsic or acquired resistance mechanisms to several antibiotics. Resistance to β-lactams is primarily mediated by L1 and L2, two chromosomal-mediated inducible β-lactamases. L1 is a molecular class B Zn2+-dependent metallo-β-lactamase, whilst L2 is a molecular class A clavulanic acid-sensitive cephalosporinase. The mrcA gene (encodes penicillin-binding protein 1α) and regulatory proteins AmpR (transcriptional regulator) and AmpN-AmpG (permease system) influence basal β-lactamase activity. mrcA inactivation causes L1/L2 β-lactamase hyperproduction (29,30). S. maltophilia has demonstrated resistance to aminoglycosides as well, through efflux pumps and aminoglycoside modifying enzyme, such as 6'-N-aminoglycoside acetyltransferases. Fortunately, the new generation cephalosporin, cefiderocol, appears to be able to evade the chromosomally encoded L1 and L2 β-lactamases, as demonstrated by the 100% susceptibility of S. maltophilia to this molecule (29,30), as well as an in vivo model promising efficacy (31). The resistance of S. maltophilia to quinolones is mainly caused by mutations in the gyrA and parC genes at the target site (QRDRs) of the DNA gyrase enzyme, which is also related to the outer membrane barrier and high-efficiency efflux pump (32,33). Additionally, S. maltophilia can accumulate multidrug efflux pumps that reduce tetracycline and fluoroquinolone activity. Increased fluoroquinolone MICs are also observed in isolates that harbour the chromosomal Smqnr gene, the determinants of which interfere through binding to gyrase and topoisomerase (1). Furthermore, S. maltophilia produces a wide variety of potential virulence factors, such as biofilm and extracellular enzymes, thus rendering treatment challenging (1,5,34).

Despite the lack of definitive evidence on the most effective available treatment, the current IDSA guidelines suggest TMP-SMX as the preferred treatment strategy for mild infections or in combination with another antibacterial agent for moderate to severe S. maltophilia infections. To date, combination therapy fails to exhibit evident superiority, with similar rates of clinical efficacy and resistance development compared with monotherapy (7,35), as reported by Shah et al (36) in a large retrospective cohort study.

As with other MDR Gram-negative bacteria, such as Acinetobacter spp., for which new antimicrobial agents are intensively being studied due to limited therapeutic options (37-39), S. maltophilia poses a major threat, particularly when resistant to TMP-SMX. When TMP-SMX is not a suitable treatment option, due to resistance or patients' intolerance, minocycline, tigecycline, other options include ticarcillin-clavulanate, cefiderocol, or ceftazidime/avibactam plus aztreonam (8).

While interpretive criteria for seven antibiotics have been established by the Clinical & Laboratory Standards Institute (CLSI), EUCAST has only provided breakpoints for TMP-SMX (40).

Of note, isolates resistant to this drug have already been reported (41,42). Previous studies have demonstrated that the sul1, sul2 and drfA genes may represent important determinants of TMP-SMX resistance in S. maltophilia isolates (1,43,44).

In the case described in the present study, the patient was diagnosed with VAP caused by a strain of S. maltophilia with a MIC for TMP-SMX equal to 2 mg/l, the same epidemiological cut-off value reported by the EUCAST. This value is close to the resistance breakpoint (>4 mg/l) and its treatment required an increased exposure to this antibiotic to assure the success of the therapy. This led to the addition of a higher dose of TMP-SMX. After only 11 days, the patient's condition improved, and the pneumonia had resolved according to a follow-up chest CT scan.

It is worth mentioning that while the IDSA guidelines do not provide specific recommendations on therapy duration, they suggest considering factors, such as the patient's immune status, source control, and treatment response when deciding when to terminate antibiotics (8).

However, the nationwide study by Guerci et al (7) found no benefit in prolonged antimicrobial therapy beyond 7 days for patients admitted to ICUs. Nonetheless, the persistence of the infection caused a mistreatment could lead to the development of resistance phenotypes, particularly due to the commonly reported co-infection rate of S. maltophilia with other species, and its capability to obtain new resistance genes, such as sul1 and sul2, through horizontal gene transfer (45).

Furthermore, according to previous studies, S. maltophilia is often part of polymicrobial infections, with other non-fermenting Gram-negative bacteria, such as P. aeruginosa, Acinetobacter spp. and Burkholderia cepacia complex (2,11). Interactions between these bacteria may play a key role in clinical outcomes, with higher morbidity and mortality rates (46). For example, co-infection with P. aeruginosa and S. maltophilia has been linked to a higher mortality rate in patients with pneumonia. These two pathogens can form a polymicrobial biofilm in the lungs, interact through quorum-sensing signals and create a favourable environment for each other (47). McDaniel et al (48) found that the presence of P. aeruginosa facilitated S. maltophilia persistence in the lungs during polymicrobial infections.

In the case described herein, the FILMARRAY® test of BAL was positive for P. aeruginosa, even though it was not recovered on BAL culture. Given the higher risk of mortality associated with VAP caused by these two pathogens, it was decided to continue treatment with both meropenem and TMP-SMX.

In conclusion, the present study aimed to emphasize the importance of recognizing S. maltophilia as a potential pathogen in hospital settings where MDR bacteria are prevalent. The case described herein highlights the common co-occurrence of S. maltophilia and P. aeruginosa infections, reinforcing the need for considering this bacterium as a potential cause of VAP.

However, inadequate initial antimicrobial treatment is often the norm for S. maltophilia infections due to its resistance to commonly used antibiotics such as β-lactams. Thus, the consideration of alternative, effective treatment options for patients with VAP who are not responding to broad-spectrum β-lactam antibiotics is crucial, as well as in patients with S. maltophilia identified through bronchoalveolar lavage culture.

Notably however, more research is required in order to better understand the risk factors of VAP caused by S. maltophilia and to develop effective prevention strategies and early antimicrobial treatments, ultimately improving the outcomes of patients.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Authors' contributions

All authors (EC, AM, SS, RR, CM, GN, BC and MC) contributed to the conception and design of the study. EC and AM wrote the manuscript. SS, CM and MC revised the literature and references. RR provided clinical assistance to the patient. BC was responsible for the laboratory tests and pharmacological treatments. GN and BC revised the manuscript. All authors have read and approved the final manuscript. EC and AM confirm the authenticity of all the raw data.

Ethics approval and consent to participate

Written informed consent was obtained from the patient included in the present case report.

Patient consent for publication

Written informed consent was obtained from the patient for the publication of his data in the present case report.

Competing interests

The authors declare that they have no competing interests.

References