Successful dual therapy of aztreonam and ceftazidime–avibactam for multidrug-resistant Stenotrophomonas maltophilia infection in a preterm neonate: A life-saving approach

Abstract

Stenotrophomonas maltophilia is a multidrug-resistant gram-negative pathogen associated with high morbidity and mortality, especially in immunocompromised patients. Its resistance mechanisms include aminoglycoside-modifying enzymes, qnrB-like quinolone resistance genes, multidrug efflux pumps, and β-lactamases (L1 and L2). With the increasing incidence of S. maltophilia infections, effective treatment strategies are urgently needed to combat its growing resistance. We present the case of a preterm male neonate, born at 30 weeks of gestation, who developed respiratory distress requiring mechanical ventilation. Empiric antibiotics were initiated but failed to prevent clinical deterioration. Respiratory cultures confirmed that multidrug-resistant S. maltophilia is resistant to standard therapies, necessitating a novel dual regimen of ceftazidime–avibactam and aztreonam. This combination therapy was administered for 14 days, leading to microbiological clearance and clinical improvement, allowing successful extubation. To the best of our knowledge, this is the first documented case of ceftazidime–avibactam and aztreonam successfully treating multidrug-resistant S. maltophilia infection in a preterm infant. This case underscores the potential of ceftazidime–avibactam and aztreonam as a viable therapeutic option for multidrug-resistant S. maltophilia infections in neonates. Further studies are warranted to validate its safety and efficacy in similar cases.

Keywords

Dual therapy aztreonam and ceftazidime–avibactam multidrug-resistant preterm neonate

Introduction

Stenotrophomonas maltophilia (formerly known as Xanthomonas maltophilia) is an aerobic, non-lactose-fermenting gram-negative bacillus that thrives in aqueous environments. It is frequently encountered as a colonizer in hospital settings, where it is found on medical equipment and surfaces as well as in solutions such as dialysis fluids. The pathogen is known to proliferate in environments characterized by extensive use of broad-spectrum antibiotics.^1,2 Although S. maltophilia is primarily associated with respiratory tract infections, it is capable of causing a diverse range of clinical syndromes, including catheter-associated bloodstream infections and skin and soft tissue infections.^3,4

The World Health Organization recognizes S. maltophilia as a critical multidrug-resistant (MDR) pathogen in healthcare settings, highlighting the urgent need for the development of effective prevention and treatment strategies.⁵ The crude mortality rate associated with S. maltophilia bacteremia ranges widely from 14% to as high as 69%, reflecting the severity and variability of infections caused by this organism.⁶ Historically, various antibiotics, such as ceftazidime (CAZ), levofloxacin, minocycline, and trimethoprim–sulfamethoxazole, have been employed to treat S. maltophilia infections. However, the susceptibility to these agents is declining, compounding the challenges in managing infections caused by this pathogen⁷ (Table 1).

Table 1.

Recommended treatment approach for Stenotrophomonas maltophilia infection.²⁵

Antibiotic class	Therapeutic ranking	Notes
Trimethoprim–sulfamethaxazole (TMP–SMX)	First line	Increasing resistance among cystic fibrosis patients
Fluoroquinolones	First line	Low resistance barrier caution in deep-seated infections
Tetracyclines	First line	Favorable tolerability profile, large volume of distribution to tissues Susceptibility is generally retained in the context of TMP–SMX and/or levofloxacin resistance Low drug recovery from urine and lower serum levels should raise caution with treatment for bacteremia and urinary tract infections Utilization of high dosing regimens may be preferred in these circumstances
Cefiderocol	Salvage	Favorable reported minimum inhibitory concentration data Used primarily against XDR isolates
Ceftazidime/avibactam+ aztreonam	Salvage	Efficacy is largely in vitro Clinical evidence limited to case reports Used against XDR isolates
Combination therapy of first-/second-line agents and their alternatives	Possible options	Lack of evidence to support routine clinical benefit or reduction in the emergence of resistance Success limited to case reports
Polymyxins	Possible options	Can be considered in deep-seated/polymicrobial infections Still considered standard of care in endocarditis Susceptibility testing is difficult to perform, with concern for heterogeneous resistance Its use is limited by toxicity, with lower efficacy reported compared with preferred options May be used empirically while awaiting definitive therapy When used for pneumonia, intravenous and nebulized therapy is recommended

XDR: extensively drug-resistant.

The intrinsic resistance of S. maltophilia to multiple antibiotic classes—including aminoglycosides, tetracyclines, fosfomycin, and most β-lactams—coupled with its ability to acquire additional resistance mechanisms during therapy renders it a formidable challenge for clinicians. This resistance profile often leads to delays in initiating effective treatment, necessitates the use of high-dose antimicrobials, and increases the risk of therapeutic failure or toxicity.^8,9

Recent in vitro studies have highlighted the potential of combining aztreonam (ATM) with avibactam (AVI) to achieve a synergistic mechanism of action against resistant gram-negative pathogens, including those producing serine β-lactamases, metallo-β-lactamases (MBLs), and cephalosporinases. ATM demonstrates activity against L1, a class B3 MBL produced by S. maltophilia, while AVI, a potent serine β-lactamase inhibitor, targets L2, a class A cephalosporinase. This combination has shown promise in restoring bactericidal activity against S. maltophilia.^10,11 The dosing of the therapeutics used are shown in Table 2.

Table 2.

Dosing regimen for the therapeutics used.

Drug	Dosage	Route	Duration
Ceftazidime–avibactam	50 mg/kg (40 mg ceftazidime + 10 mg avibactam) every 8 h	IV	14 days
Aztreonam	30 mg/kg every 8 h	IV	14 days

IV: intravenous.

Notably, S. maltophilia naturally produces two β-lactamases: L1 and L2. L1 hydrolyzes carbapenems and other β-lactams, with the exception of ATM, and is resistant to all clinically available β-lactam inhibitors.^12–14 Conversely, L2 is a cephalosporinase conferring resistance to extended-spectrum cephalosporins and ATM; however, it remains susceptible to inhibition by serine β-lactamase inhibitors such as clavulanic acid and AVI.^11,15,16 AVI, a non-β-lactam β-lactamase inhibitor, offers a broader inhibitory spectrum than previously available inhibitors and has become an important component of combination therapy.¹⁷

This report documents the successful clinical management of a critically ill preterm neonate with hemodynamic instability caused by MDR S. maltophilia. This case highlights the effectiveness of a dual therapeutic approach of CAZ–AVI in combination with ATM. This combination re-established bactericidal activity against the MDR strain, leading to a favorable clinical outcome despite the complex and severe nature of the infection.¹⁸ The reporting of this study conforms to the Case Report (CARE) guidelines.¹⁹

Case report

We present the case of a preterm male neonate who was born at 30 weeks and 4 days of gestation to a gravida 2 mother with a history of premature rupture of membranes at 25 weeks. The mother received antenatal dexamethasone and anti-D immunoglobulin prior to delivery. The delivery was conducted at Alhada Armed Forces, Taif, Saudi Arabia, via cesarean section due to oligohydramnios. All patient details have been de-identified. The neonate’s APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores were 5 and 7 at 1 and 5 min, respectively. Birth parameters included a weight of 1135 g and a head circumference of 28 cm.

Following delivery, the neonate exhibited respiratory distress requiring intubation and ventilatory support with an assist/control pressure control mode. He received two doses of surfactant. Early-onset sepsis was suspected, and empiric antibiotic therapy with ampicillin and gentamicin was initiated, alongside fluconazole prophylaxis per the neonatal intensive care unit protocol.

At 14 days of age, the neonate exhibited signs of clinical deterioration, including tachycardia and oxygen desaturation. He was transitioned to high-frequency oscillatory ventilation, and a comprehensive sepsis workup was performed. Empiric antibiotics were escalated to vancomycin and CAZ. Blood and respiratory cultures subsequently revealed the growth of MDR Burkholderia cepacia. Based on these findings, CAZ was continued, and meropenem at a dose for managing meningitis was added via infusion over 3 h. Despite this, he remained critically ill, requiring dopamine and hydrocortisone for hemodynamic instability as well as platelet and albumin transfusions.

The neonate developed cholestasis secondary to total parenteral nutrition. Repeated cultures confirmed the presence of persistent B. cepacia, with three positive blood cultures and two positive respiratory cultures. At 23 days of age, respiratory cultures also identified methicillin-resistant Staphylococcus aureus (MRSA), prompting re-initiation of vancomycin, which was administered for 14 days.

By 35 days of age, he experienced worsening hemodynamic instability. Respiratory cultures detected the presence of S. maltophilia. Levofloxacin was added to the treatment regimen. CAZ and meropenem were continued for 14 days to achieve clearance of B. cepacia, while vancomycin therapy was completed for the MRSA infection. Despite the sensitivity of S. maltophilia to levofloxacin in early cultures, subsequent cultures (three of five) revealed the presence of MDR S. maltophilia. At this stage, levofloxacin was discontinued, and a combination of CAZ–AVI and ATM was initiated.

At 53 days of age, the infant presented with fever, tachycardia, and hypoglycemia. Blood cultures identified Enterococcus faecium, leading to the addition of teicoplanin. Echocardiography revealed an echogenic mass measuring 3 × 4 mm at the junction of the inferior vena cava and right atrium, suggestive of vegetation. Trimethoprim–sulfamethoxazole was added to teicoplanin, and teicoplanin was continued for a total of 4 weeks.

The combination therapy of CAZ–AVI and ATM was administered for 14 days. Subsequent sputum cultures revealed no growth of organisms following the completion of this regimen. By 75 days of age, a repeat echocardiogram revealed resolution of the previously noted vegetation.

The infant demonstrated clinical improvement and was extubated onto nasal cannula oxygen. He remained in the neonatal intensive care unit, rooming with his mother. However, he developed bilateral retinopathy of prematurity in zone 3, which is currently being monitored.

Discussion

The current case involved a neonate with a positive respiratory culture for MDR S. maltophilia, accompanied with severe respiratory distress, desaturation, and the need for high-frequency oscillatory ventilation. The infant also exhibited hemodynamic instability requiring inotropic support. Infections caused by S. maltophilia pose a critical challenge for clinicians due to the pathogen’s limited susceptibility to antibiotics and its capacity for intrinsic and acquired resistance. The increasing incidence of nosocomial MDR S. maltophilia infections is particularly concerning in immunocompromised patients, those with prolonged intensive care unit stays, those under mechanical ventilation, or those with invasive devices and indwelling catheters. These risk factors are closely linked to S. maltophilia’s ability to form biofilms, colonize medical devices, and develop resistance mechanisms during treatment.^15,20

A cross-sectional descriptive study conducted at the Najran Maternity and Children’s Hospital in southwestern Saudi Arabia (January 2015–February 2016) evaluated S. maltophilia isolates. Of the 64 nonduplicated strains identified, 48 (75%) were associated with true infections, while 16 (25%) were deemed colonization flora. The primary types of infections included pneumonia (45.8%) and bloodstream infections (29.2%). Significant risk factors for infection included exposure to invasive procedures (p = 0.02) and underlying conditions such as acute leukemia (p = 0.02). The study found that trimethoprim–sulfamethoxazole demonstrated 100% sensitivity, while tigecycline exhibited 93.7% sensitivity, underscoring their potential utility in treating S. maltophilia infections.²¹

In recent studies, the susceptibility of S. maltophilia clinical isolates to various antibiotics has been evaluated, showing promising results with CAZ–AVI and ATM–AVI. A study demonstrated that ATM–AVI exhibited higher in vitro activity than ATM alone for 94.74% of the isolates. Furthermore, its efficacy was superior to that of CAZ, ATM, and CAZ alone.²² Another study found ATM–AVI to be the most reliable bactericidal combination among various options, including amoxicillin–clavulanate, CAZ, meropenem–vaborbactam, and imipenem–relebactam. AVI was shown to significantly reduce ATM’s minimum inhibitory concentrations and restore susceptibility in the majority of isolates tested.²³

According to the 2024 IDSA Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections, CAZ–AVI in combination with ATM is considered a candidate for treating infections caused by MDR S. maltophilia.²⁴

In our case, the infant initially received levofloxacin when respiratory cultures revealed susceptibility to the antibiotic. However, despite treatment, he remained symptomatic. Subsequent cultures revealed the presence of MDR S. maltophilia, prompting discontinuation of levofloxacin and initiation of combination therapy with CAZ–AVI and ATM for 14 days. This combination therapy resulted in clinical improvement and eradication of the infection. It offers a potential therapeutic option for life-threatening infections caused by gram-negative MBL-producing organisms. ATM–AVI is currently being tested in clinical trials to assess its efficacy against gram-negative bacteria, including MBL producers. ATM, the only clinically available monobactam, is stable against hydrolysis by MBLs, a characteristic unique among β-lactams. However, it is hydrolyzed by most clinically relevant serine β-lactamases.¹⁷ AVI, a non-β-lactam β-lactamase inhibitor, is effective against Ambler class A β-lactamases (including L2 produced by S. maltophilia), class C enzymes, and some class D enzymes.²⁵ Together, ATM–AVI has demonstrated efficacy against gram-negative bacteria producing a broad spectrum of β-lactamases, including MBLs.

The synergistic activity of CAZ, ATM, and AVI is particularly encouraging and warrants further investigation to better define its role in managing serious infections caused by MDR and MBL-producing gram-negative pathogens.⁸

Ultimately, S. maltophilia will continue to be a challenging pathogen, necessitating the development of evolving strategies to combat its growing resistance. The widespread utilization of broad-spectrum gram-negative antimicrobials in healthcare settings is anticipated to further increase the frequency of S. maltophilia recovery in nosocomial environments. This underscores the critical need for innovative therapeutic approaches and proactive management strategies to address the complexities of treating infections caused by this MDR organism.

Conclusion

S. maltophilia remains a critical clinical challenge, especially in hospital settings where its resistance mechanisms and persistence complicate treatment. Recognized by the World Health Organization as one of the leading MDR pathogens, S. maltophilia requires urgent attention to develop effective prevention and management strategies to combat its growing resistance.

The combination of ATM and CAZ–AVI has demonstrated potential in managing life-threatening infections caused by gram-negative MBL producers. As evidenced in this case, such innovative therapeutic approaches hold promise in overcoming the challenges posed by this pathogen and should be further explored for optimizing treatment outcomes.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251353486 - Supplemental material for Successful dual therapy of aztreonam and ceftazidime–avibactam for multidrug-resistant Stenotrophomonas maltophilia infection in a preterm neonate: A life-saving approach

Supplemental material, sj-pdf-1-imr-10.1177_03000605251353486 for Successful dual therapy of aztreonam and ceftazidime–avibactam for multidrug-resistant Stenotrophomonas maltophilia infection in a preterm neonate: A life-saving approach by Abdulrahman O Alghamdi, Abdulelah S Algethami, Majed S Aljuaeed, Faisal M Alkhammash, Faisal M Almalki, Sultan A Alharthi, Nejood M Aljaed, Salma AS Abosabie, Sara A Abosabie and Naglaa M Kamal in Journal of International Medical Research

Footnotes

Acknowledgements

We would like to thank our patient and his family for their kind participation in this work.

Authors’ contributions

All authors contributed substantially to writing of the manuscript, literature review, concept and design, acquisition and interpretation of data, drafting of the article, critical revision of the article for important intellectual content; and final approval of the version to be published.

Consent for publication

None.

Data availability statement

All data and materials related to the study are included in the current manuscript.

Declaration of competing interests

All authors declare no competing interests related to the study.

Ethical considerations

Ethical approval was not required as the patient’s information was anonymized.

Funding

No funds were received for the current research.

ORCID iD

Naglaa M Kamal

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